This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

This past year will likely be remembered as one of breakthrough advances in reducing the burden of cancer, with some landmark “firsts” coming out of the US Food and Drug Administration (FDA). Among the notable approvals were the first CART [chimeric antigen receptor T-cell] immunotherapies – tisagenlecleucel (Kymriah) for B-cell precursor acute lymphoblastic leukemia, and axicabtagene ciloleucel (Yescarta) for relapsed or refractory large B-cell lymphoma; the first US-approved biosimilar for cancer, bevacizumab-awwb (Mvasi) for multiple types of cancer; and first-time approvals for neratinib (Nerlynx) as an extended adjuvant therapy for early-stage human epidermal growth factor receptor 2 (HER2)-overexpressed/amplified breast cancer, and avelumab (Bavencio) for the treatment of metastatic Merkel cell carcinoma. But our excitement about those advances will undoubtedly be tempered by the continued challenges in expanding access to better quality health care, piloting more effective payment models, and consolidating delivery systems.

Our excitement has also been tempered by the rapid rise in the cost of effective biologic, immunologic, and targeted therapies. With the approval of trastuzumab-dkst (Ogivri), the first targeted biosimilar for HER2-positive breast and gastrointestinal cancers, we can look forward to price decreases possibly in the 20%-30% range over time from a targeted therapy with remarkable clinical efficacy. We know that approved biosimilars have demonstrated clinical efficacy along with similar minor biologic diversity that is also seen in the reference biologic.¹ We can also hope that increasing competition among biosimilar and reference compounds will lead to improvements in production methodologies that can allow further price reductions so that even more patients can gain access to these highly effective therapies.

In addition, the first FDA approval for the next-generation sequencing (NGS) FoundationOne profiling test and the rapid announcement by the Centers for Medicare & Medicaid Services (CMS) that it will cover the cost of that testing brings us a step closer to knowing which patients most likely will or won’t benefit from costly and toxic targeted therapies. Along with the many clinical trials studying which mutations predict which efficacies of individual or combinations of targeted agents, the approval and CMS coverage policy will help us improve value to our patients; when we can recommend the most beneficial therapies and avoid futile ones.

Finally, the approval for the DigniCap Scalp Cooling System for patients on chemotherapy for all solid tumors is of great importance. Pending coverage availability, it may influence some patients to get chemotherapy they might otherwise have forgone to avoid hair loss (see related article).

More consolidation: the best of all worlds?

In my 27 years in private practice, during which practice revenues grew with the favorable profit margins on novel therapies, forward-thinking physician leaders piloted innovations in oncology electronic medical records (EMRs), the delivery of team-based care, clinical research partnerships, and more comprehensive care services to better serve diverse communities, including those in rural areas. At my previous practice, that included adding clinicians to our group to serve patients at hospital clinics in 2 counties in southern California, each county with populations larger than 15 states. Our private practice worked with these public entities to bring state-of-the art care and private practice efficiencies to the uninsured and underserved in our region.

Unfortunately, revenues plummeted with changes in reimbursement after passage of the Medicare Modernization Act in 2003 and they continue to destabilize and reduce the number of community practices across the country. Many oncologists and oncology practices, including mine, chose to join larger academic or hospital systems or larger oncology networks at a time they are also facing growing pressures to contain costs, focus on out-patient care, complex clinical trials, and expanded access to care.

Although we may lament the shrinking landscape of private oncology practices, we can also be inspired by the physicians who have joined ranks with the better-funded, better-resourced, more traditional hospital and academic systems. These larger systems have more resources, more clincial trial offerings, staffing, technology, and analytics to expand value-based care initiatives to larger numbers of patients.

The hub-and-spoke models of oncology care with integrated networks linked by technology, and networked into larger analytic and decision support systems such as CancerLinQ, the health information technology program of the American Society of Clinical Oncology (ASCO),² could facilitate documentable delivery of comprehensive, evidence-based care, moving us closer to meeting the Quadruple Aim of optimal health care: improving the patient experience of care (including quality and satisfaction); improving the health of populations; reducing the per capita cost of health care; and improving the work life of those who deliver care.^3,4

Payment reform: working to align incentives

Everyone seems to agree that the fee-for-service payment models do not align incentives for improving total health outcomes at the lowest costs, but at the moment, there seems to be no best way of aligning them. Robinson has reported on the oncology payment initiatives at four major health insurance plans – Medicare (public) and Anthem, Aetna, and UnitedHealthcare (all private), noting that:⁵

• Medicare is testing its Oncology Care Model at more than 200 sites in the United States, and early data are expected to be released in 2018.
• Anthem continues with its Cancer Care Quality Program that includes adherence to 2 key requirements: that participants are compliant with Anthem-approved drug pathways, and that they register their patients at the insurer’s oncology website and enter their clinical data. Anthem is also considering expanding the management fee for certain high priority clinical trials.
• Aetna’s Oncology Solutions takes a different approach by providing increased payments for generic chemotherapies.
• United has eliminated the mark-up for new drugs and continues to mark up the prices of the older and generic therapies. Its episode-based pricing gives practices upfront payments based on expected drug margins so that practices can fund more comprehensive evidence-based care. In a presentation at a Washington State Medical Oncology Society meeting recently, United’s Lee Newcomer, reported that the insurer continues to see improved clinical and financial outcomes as well as encouraging early data showing that patients might do better in the real-world setting on some therapies that have not been fully compared in head-to-head randomized clinical trials.^6,7

ASCO is pulling these ideas together at the national level with its Patient-Centered Oncology Payment (PCOP) model, which is similar to Medicare’s alternative payment model. The PCOP model focuses on high-value, quality care. Higher upfront payments would cover the additional diagnostic services, care planning, and management to improve compliance and adherence as well as clinical trial evaluations. The model was developed and vetted by the ASCO Clinical Practice Committee and practicing oncologists, and is supported by staff and consultants. It is currently in its second year of operation with a commercial payer and will be submitted for review to the Physician-Focused Payment Model Technical Advisory Committee of the Health and Human Services. The results of the review are expected in 2018. If the model is approved, it could provide a uniform approach for payers that would align incentives for high-quality cancer care and allow for better predictive modeling for practices, irrespective of size, to invest in infrastructure and staffing to meet the growing demand for high-quality, value-based cancer care.

Better science: the promise of more cures

The FDA approved a record number drugs and biologics in 2017 for various cancers,⁸ including the landmark approval of the first CART therapy for cancer, tisagenlecleucel, which targets CD19 on B cells in the treatment of acute leukemia. That approval was rapidly followed by a second anti-CD19 CART therapy, axicabtagene ciloluecel, for refractory, aggressive B-cell non-Hodgkin lymphoma.^9,10 Although these therapies can achieve remarkable response and even complete response rates in otherwise refractory patients, only some achieve a long-term remission, and the costs are an order of magnitude above most other cancer therapies. That raises the question of what duration of benefit we should expect for treatments that cost in the range of $500,000 for the therapy alone, along with the additional costs for care, hospitalization, monitoring, expensive biologics (eg, tocilizumab, for the severe and potentially life-threatening cytokine-release syndrome associated with CART therapies), and significant neurologic and other therapy-related toxicities.

Novel arrangements between pharmaceutical companies and payers are currently being discussed so that only patients who meet specific response criteria would be charged for the therapy. In addition, we await findings from ongoing research to see if new approaches can find specific targetable sites on solid tumors that could spare the healthy organ tissues while eliminating highly resistant or heterogeneous populations of mutations in patients with advanced solid tumors. Such development of highly specific targets for CART therapies would improve their efficacy and safety, and with defined protocols in place to address toxicities and efforts to reduce the costs of the therapies, we can hopefully ensure broader access for patients to this potentially transformative therapeutic tool.

In addition to the excitement around the CART therapies, many of the years other new approvals will bring incremental but meaningful improvement in outcomes for patients with common cancers. The approval of neratinib, the first agent approved as extended adjuvant therapy for women with early-stage HER2/neu-positive breast cancer, is welcome, given the current 30% recurrence risk that extends past 10 years for women in that disease population who have completed standard adjuvant HER2-directed therapies. The 34% reduction in recurrence risk with a year of extended oral adjuvant therapy, as reported by Martin and colleagues,¹¹ with benefits sustained out to 5 years and with controllable diarrhea as the major toxicity, are encouraging. This oral therapy may be especially beneficial for hormone-receptor–positive women in whom blocking the HER2/neu pathway may enhance cell signaling through the hormone pathways, which can be blocked with oral agents at the same time to provide significant reduction of recurrence risk.

Diagnostics

The concept of personalized medicine is based on identifying biomarkers that are predictive of a patient’s response to treatment. There has been much progress toward applying NGS of tumors for use in the clinic, but we are still awaiting evidence from randomized clinical trials that such approaches prolong overall or progression-free survival.¹² Dr Julie Lange, an associate professor of clinical surgery and director of the Breast Cancer Program at the Keck School of Medicine at the University of Southern California, Los Angeles, provided me with the references to key studies in this field in which she is a leading researcher.¹³ However, she pointed out that in the absence of effective therapies, advanced biomarker testing may be less helpful, as is the case in heavily pretreated patients,¹⁴ unless a molecular test can pinpoint a potentially clinically actionable mutation. With the plethora of available assays and the high costs of molecular testing, clinicians are challenged in knowing what testing is best for which patients. Findings from a number of key ongoing national trials may eventually help us understand which tumor mutations in which tumor types can be most effectively targeted when multiple targetable mutations are found (TAPUR,¹⁵ MATCH,¹⁶ and QUILT¹⁷ and other basket trials¹⁸). The complexity of molecular testing has led to the development of institutional, trial-based, or co-operative group molecular tumor boards to provide guidance on specific targeted therapies for specific tumor mutations.

ASCO has launched a monthly series called Molecular Oncology Tumor Boards¹⁹ to expand the knowledge base in this field. It is presented as user-driven discussions designed to help providers integrate the use of the new genetic and genomic tests and their results into the day-to-day clinical care of patients with cancer.²⁰

Liquid biopsies

As busy clinicians, we need to understand the differences in liquid biopsy tests and their correlation with actionable targets, especially given the rapid progress in this field. Again, Dr Lange offered clarity on those differences. Liquid biopsy, refers to using a blood draw to isolate circulating tumor cells (CTCs) or circulating tumor DNA (ctDNA) to assess tumor biomarkers.²¹ Both CTCs and ctDNA tests have been shown to be prognostic of worse survival.^22-24 Liquid biopsies are currently supplemental to direct tumor biopsies, not replacements for them. The theoretical advantage of liquid biopsies is that they may reflect tumor heterogeneity by examining the repertoire of mutations contributed by diverse metastatic sites that shed CTCs or ctDNA into the circulation. The question is which type of testing can best inform therapy decisions.

Assays for ctDNA using droplet digital PCR [polymerase chain reaction], a digital PCR method based on water-oil emulsion droplet technology, require a priori knowledge of the specific mutation associated with response or lack of response to a specific therapy.^25,26 Technical issues related to the detection of rare alleles present within a mixed population of leukocytes, and ctDNA remains a challenge for many ctDNA assays. However, there is evidence to suggest that whole-exome sequencing of ctDNA is concordant with mutations in metastases,²⁷ however benchmarking ctDNA against tissue biopsies of metastases was not possible in all studies because tumor blocks were not available or because of the failure of tumor NGS assays. ^28,29

Newer generations of CTC assays take advantage of the circulating tumor cell as a functional assay for mutational status, gene expression, proteomics, epigenetics, and/or chemosensitivity of cultured cells. The relationship between CTCs and ctDNA remains uncertain as to whether CTCs are the cell of origin for ctDNA or if ctDNA may reflect responding or resistant tumor populations. The use of NGS on tumor specimens, ctDNA, and CTCs as a discovery tool is advancing the field by improving the understanding of disease heterogeneity and potential treatment targets. These results require correlation with patterns of response to therapy, and ultimately require validation in randomized clinical trials to provide strong evidence justifying their use outside of clinical trials. We can look forward to a time in the not distant future when specific liquid biopsy assays will reflect the array of mutations in different metastatic sites with validation that they correlate with efficacy of targeting those mutations that have targetable therapies.

From the FDA

New approvals

• Trastuzumab-dkst (Ogivri, Mylan; Dec 1) was approved as a biosimilar to trastuzumab (Herceptin, Genentech) for the treatment of patients with HER2-overexpressing breast or metastatic stomach cancer (gastric or gastroesophageal junction adenocarcinoma).
• Sunitinib malate (Sutent, Pfizer; Nov 16) was approved for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma after nephrectomy.
• Obinutuzumab (Gazyva, Genentech; Nov 16) received regular approval in combination with chemotherapy, followed by obinutuzumab monotherapy in patients achieving partial remission, for adult patients with previously untreated stage II bulky, III, or IV follicular lymphoma.
• Emicizumab-kxwh (Hemlibra, Genentech; Nov 16) was approved for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with factor VIII inhibitors.
• Dasatinib (Sprycel, Bristol-Myers Squibb; Nov 9) was approved for the treatment of pediatric patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase.
• Brentuximab vedotin (Adcetris, Seattle Genetics; Nov 9) for the treatment of previously treated adult patients with primary cutaneous anaplastic large cell lymphoma (pcALCL) or CD30-expressing mycosis fungoides.
• Alectinib (Alecensa, Hoffmann-La Roche/Genentech; Nov 6) was approved for treatment of patients with anaplastic lymphoma kinase–positive metastatic non-small cell lung cancer (NSCLC), as detected by an FDA-approved test.
• Vemurafenib (Zelboraf, Hoffmann-La Roche; Nov 6) received approval for the treatment of Acalabrutinib (Calquence, AstraZeneca/Acerta; Oct 31) was granted accelerated approval for treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one previous therapy.
• Axicabtagene ciloleucel (Yescarta, Kite; Oct 18), a CART therapy, was approved for treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. The complete remission rate reviewed by the FDA for trial patients was 51%.³⁰ It was the second CART therapy this year to receive approval (see tisagenlecleucel; Aug 30). The agency granted orphan drug designation and priority review to therapy for this indication.
• Abemaciclib (Verzenio, Eli Lilly; Sep 28) was approved in combination with fulvestrant for women with hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
• Copanlisib (Aliqopa, Bayer; Sep 14) got accelerated approval for the treatment of adult patients with relapsed follicular lymphoma who have received at least two prior systemic therapies.
• Bevacizumab-awwb (Mvasi, Amgen; Sep 14) was approved as a biosimilar to bevacizumab (Avastin, Genentech) for treating multiple types of cancer. It was the first biosimilar approved in the US for the treatment of cancer.
• Gemtuzumab ozogamicin (Mylotarg, Pfizer; Sep 1) was approved for the treatment of newly diagnosed CD33-positive acute myeloid leukemia (AML) in adults and of relapsed/refractory CD33-positive AML in adults and pediatric patients aged 2 or older. It can be used in combination with daunorubicin and cytarabine for adults with newly diagnosed AML, or as a standalone treatment for certain adult and pediatric patients. The drug was originally approved in 2000 as a standalone treatment for CD33-positive AML in patients older than 60 years, but was withdrawn in 2010 because of safety concerns and postmarketing trials could not confirm benefit. The current approval is for a lower recommended dose and schedule.³¹
• Tisagenlecleucel (Kymriah, Novartis; Aug 30) was approved for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (ALL) that is refractory or in second or later relapse. It is the first CART immunotherapy approved by the agency.
• Inotuzumab ozogamicin (Besponsa, Wyeth; Aug 17) was approved for the treatment of adults with relapsed or refractory B-cell precursor ALL.
• A liposome-encapsulated combination of daunorubicin and cytarabine (Vyxeos, Jazz; Aug 3) was approved for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC), two types of AML having a poor prognosis.
• Enasidenib (Idhifa, Celgene; Aug 1) was approved for the treatment of adult patients with relapsed or refractory AML with an isocitrate dehydrogenase-2 mutation as detected by an FDA-approved test.
• Neratinib (Nerlynx, Puma; Jul 17) was approved as the first extended adjuvant therapy for adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.
• Blinatumomab (Blincyto, Amgen; Jul 11) was approved for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia in adults and children.
• L-glutamine oral powder (Endari, Emmaus; Jul 7) was approved for oral administration to reduce the acute complications of sickle cell disease in adult and pediatric patients 5 years and older.
• Betrixaban (Bevyxxa, Portola; Jun 23) was approved for the prophylaxis of venous thromboembolism (VTE) in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications because of moderate or severe restricted mobility and other risk factors for VTE.
• The combination of rituximab and hyaluronidase human (Rituxan Hycela, Genentech; Jun 22) was approved for adult patients with follicular lymphoma, DLBCL, and chronic lymphocytic leukemia. Hyaluronidase human is an enzyme that helps deliver the rituximab. This formulation allows subcutaneous administration of the combination, which will shorten patient visit times and potentially even allow at-home therapy delivery.
• Ceritinib (Zykadia, Novartis; May 26) was approved for patients with metastatic NSCLC whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
• Avelumab (Bavencio, EMD Serono; May 9) got accelerated approval for patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
• Durvalumab (ImfinzI, AstraZeneca; May 1) got accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Brigatinib (Alunbrig tablets, Takeda through Ariad; Apr 28) got accelerated approval for the treatment of patients with metastatic anaplastic lymphoma kinase (ALK)-positive NSCLC who have progressed on or are intolerant to crizotinib.
• Midostaurin (Rydapt, Novartis; Apr 28) was approved for the treatment of adult patients with newly diagnosed AML who are FLT3 mutation-positive, as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.
• Osimertinib (Tagrisso, AstraZeneca; Mar 30) got regular approval for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine-kinase inhibitor therapy.
• Niraparib (Zejula, Tesaro; Mar 27), a poly ADP-ribose polymerase (PARP) inhibitor, was approved for the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy.
• Avelumab (Mar 23), a PD-L1–blocking human IgG1 lambda monoclonal antibody, got accelerated approval for the treatment of patients 12 years and older with metastatic Merkel cell carcinoma. It is the first FDA-approved product to treat this type of cancer.
• Ribociclib (Kisqali, Novartis; Mar 13), a CDK4/6 inhibitor, was approved as a breakthrough therapy after priority review for use in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer.

Expanded/additional indications

• Nivolumab (Opdivo, Bristol-Myers Squibb; Sep 22) got accelerated expanded indication approval for treatment of hepatocellular carcinoma (HCC) in patients previously treated with sorafenib.
• Pembrolizumab (Keytruda, Merck; Sep 22) got accelerated expanded indication approval for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma in patients whose tumors express PD-L1 as determined by an FDA-approved test.
• DigniCap Scalp Cooling System (Dignitana Inc; Jul 3) was cleared for expanded use for reducing hair loss during chemotherapy for all solid tumors. Marketing authorization for the cooling cap had been granted in 2015 for patients with breast cancer.
• Olaparib tablets (Lynparza, AstraZeneca; Aug 17) got approval for an expanded indication as maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer, who are in a complete or partial response to platinum-based chemotherapy.
• Ibrutinib (Imbruvica, Pharmacyclics; Aug 2) got expanded indication approval for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy. It was the first FDA-approved therapy for the treatment of cGVHD. (Ibrutinib was previously approved for chronic lymphocytic leukemia/small lymphocytic lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma, and mantle cell lymphoma).
• Nivolumab (Aug 2) got an accelerated expanded indication for the treatment of patients 12 years and older with mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) metastatic colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Dabrafenib and trametinib (Tafinlar and Mekinist, Novartis; Jun 22) were approved for the expanded indication in combination for patients with metastatic NSCLC with BRAF V600E mutation as detected by an FDA-approved test. The combination demonstrated superior efficacy compared with dabrafenib alone (overall response rate: 61% and 27%, respectively).³²
• Pembrolizumab (May 23) got approved for expanded indication for adult and pediatric patients with unresectable or metastatic, MSI-H or dMMR solid tumors that have progressed after treatment and who have no satisfactory alternative treatment options or with MSI-H or dMMR colorectal cancer that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
• Pembrolizumab (May 18) got approval for expanded indication for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
• Pembrolizumab (May 10) got accelerated expanded indication for use combination with pemetrexed and carboplatin for the treatment of patients with previously untreated metastatic NSCLC.
• Regorafenib (Stivarga, Bayer; Apr 27) got an additional indication for the treatment of patients with HCC who have been previously treated with sorafenib.
• Palbociclib (Ibrance, Pfizer; Mar 31) got an expanded indication that includes first-line therapy for the treatment of hormone receptor–positive, HER2-negative advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women.
• Pembrolizumab (Mar 15) got an accelerated additional indication approval for treatment of adult and pediatric patients with refractory classical Hodgkin lymphoma, or those who have relapsed after three or more previous lines of therapy.
• Lenalidomide (Revlimid, Celgene; Feb 22) got an additional indication as maintenance therapy for patients with multiple myeloma following autologous stem cell transplant.
• Nivolumab (Feb 2) got an accelerated expanded indication for treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy.

Modified use

• Cabazitaxel (Jevtana, Sanofi-Aventis; Sep 14) in combination with prednisone was approved at a lower dose of 20 mg/m² every 3 weeks for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It had been approved at 25 mg/m² every 3 weeks for this indication in 2010.

Tests/diagnostics

• Marketing approval was given to the FoundationOne CDx (Foundation Medicine; Nov 30), an NGS-based in vitro diagnostic to detect genetic mutations in 324 genes and 2 genomic signatures in any solid tumor type.
• Marketing approval was given to the Praxis Extended RAS Panel (Illumina; Jun 29), a next generation sequencing test to detect certain genetic mutations in RAS genes in tumor samples of patients with metastatic colorectal cancer. The test is used to aid in the identification of patients who may be eligible for treatment with panitumumab (Vectibix, Amgen).
• Marketing was approved for ipsogen JAK2 RGQ PCR Kit (Qiagen ; Mar 27) to detect mutations affecting the Janus tyrosine kinase 2 gene. This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected polycythemia vera.

Imaging and pathology aids

• Aminolevulinic acid hydrochloride, known as ALA HCl (Gleolan, NX; Jun 6) was approved as an optical imaging agent indicated in patients with gliomas (suspected World Health Organization grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery.
• Marketing was approved for the Philips IntelliSite Pathology Solution (PIPS, Philips Medical Systems Nederland; Apr 17), as an aid to the pathologist to review and interpret digital images of surgical pathology slides prepared from formalin-fixed paraffin embedded tissue.
   

Challenges and uncertainties

The current administration’s initiatives to reduce administrative burdens is underway with the Patients Over Paperwork initiative. Eliminating and streamlining regulations to increase efficiency and improve beneficiary experience could be helpful to both oncologists and patients. For now, the Medicare Access and CHIP Reauthorization Act (MACRA) program, allows you to “pick your pace” in the 2017 performance year and report on at least one measure to avoid a payment reduction penalty on your Medicare payments in 2019. In the final rule for 2018, the CMS finalized a proposal to apply the MIPS [Merit-based Incentive Payment System] adjustment to all Part B items and services, which will include Part B drugs. This would be unfair to oncologists who treat on the basis of evidence-based guidelines and pathways and have no control over the costs of the drugs they prescribe.

In addition, more requirements will be imposed in 2018 in a move toward full MACRA implementation. All four composite categories (Quality – 60% for 2017; Advancing Care Information (ACI, renamed from Meaningful Use) – 25% for 2017; Improvement Activities (IA) – 15% for 2017; and Cost – 0% for 2017, but weighted in the future) will be scored, including resource use (cost) at 10%. CMS will collect data to assess the total cost of care and the Medicare Spend per Beneficiary to assess use. Full program implementation, with cost being assessed at 30% of your score is expected in the 2019 performance year. ASCO’s clinical affairs and policy experts have studied the implications of Part B chemotherapy drugs being included in the cost component of the MIPS scoring and will continue advocating for policies that hold clinicians responsible only for the aspects of care they can control, such as providing high-quality care based on the patient’s disease, biomarkers, comorbidities, and preferences, and not the costs of the evidence-based therapies needed by patients.
 

Toward a better 2018 for ourselves and our patients

As an eternal optimist, I remain enthusiastic that despite the many challenges, we will find effective ways to bring standard as well as newer, cell-based and targeted therapies to our patients and cover the costs of highly effective therapies. I also remain hopeful that improving technological capabilities and payment reforms will be used by innovative clinical and administrative care teams to give clinicians more time to improve the care and health of patients while validating the methodologies so that real world data can help us further craft therapies to improve the health of each individual who needs our care. As we close this 15th year of our journal, we hope our presentations of practical science and implementation content has helped support your work while freeing some time for you to enjoy the journey. Our best wishes for a joyful holiday season celebrated with friends and family and the patients who entrust us to help them face and live beyond their cancer diagnoses.

Neuroendocrine tumors (NETs) are an extremely diverse group of cancers that have steadily increased in incidence in recent years. They can prove challenging to treat but, as we discuss here, a steady evolution in our understanding of NETs has significantly expanded the scope of therapeutic options.

A unique tumor type

NETs arise from neuroendocrine cells – cells with features of both nerve and endocrine cells that have important physiological functions, including the production and release of hormones. These tumors were first recognized by a German pathologist in the mid-1800s and were initially referred to as carcinoids in reference to their carcinoma-like appearance but lack of other malignant features.¹

Unlike other solid tumors, which are associated with a particular primary location, NETs can arise anywhere in the body where neuroendocrine cells are found. They are also unique in their ability to oversecrete bioactive substances that regulate bodily functions, which results in an associated clinical syndrome, known as carcinoid syndrome, in up to 35% of patients.^2,3

Although they are considered to be a relatively rare type of tumor, the incidence of NETs has been increasing in recent years. According to data from the Surveillance, Epidemiology and End Results (SEER) program, the age-adjusted incidence of NETs increased more than two-and-a-half fold during 1973-2004 and the rise is predicted to continue at an accelerated rate.⁴

Historically, NETs have been thought of as relatively benign because of their slow-growing nature, but it is now widely appreciated that they often metastasize. Furthermore, many patients are not symptomatic at first, so around half of all cases are not diagnosed until they have reached this more aggressive stage.⁴
 

The challenge of NET diversity

The most common type of NETs are those that arise in the gastrointestinal tract (GI-NET), representing more than 65% of cases, and for which the “carcinoid” terminology often is still applied. GI-NETs most frequently arise in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%).^4,5

About a quarter of NETs originate in the bronchopulmonary system, including the lungs and the thymus. Thymic NETs are particularly aggressive and are associated with a poor prognosis. Pancreatic NETs (pNETs) make up the next largest group, although they represent less than 1% of total NETs. Compared with the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, they have a more favorable prognosis. pNETs are often grouped together with GI-NETs and referred to as gastroenteropancreatic NETs (GEP-NETs).^3-5 Other rarer types of NET include Merkel cell carcinoma (a type of skin cancer) and medullary thyroid cancers.
 

The classification network

NETs are classified according to the anatomic site from which they originate, as well as their histology, grade, and stage. Another important consideration is their level of hormone secretion. “Functional” and “nonfunctional” NETs both produce hormones, but only the former cause related symptoms.^3,4,6

Functionality plays a particularly important role in the subclassification of GEP-NETs. Functional pNETs, for instance, are further divided according to the clinical syndromes associated with the hormones they produce, as insulinomas, glucagonomas, gastrinomas, somatostatinomas, and VIPomas (producing vasoactive intestinal peptide).^7,8

In 2010, the World Health Organization developed a classification system for GEP-NETs that categorized these tumors as well differentiated (grade 1 or 2, depending on their rate of proliferation) and poorly differentiated (grade 3).⁹ The WHO classification of bronchopulmonary NETs, published in 2015, is slightly different; broken down into 3 subgroups, typical carcinoid, atypical carcinoid (corresponding to grade 1 and 2 GEP-NETs), and large and small-cell NETs (equivalent to grade 3 GEP-NETs).¹⁰

Although NETs develop from the same cell type, they in fact comprise a spectrum of diseases that vary extensively in their underlying biology, histology, and clinical behavior. Both the diversity and unique nature of NETs have become increasingly evident in recent years with the application of next-generation sequencing technologies to this tumor type. In general, NETs seem to be more genetically stable than other tumor types from the same primary location, and have fewer somatic mutations. The classic tumor suppressors and oncogenes that drive other tumor types are not common in NETs.^6,11

The diversity of NETs presents a diagnostic and therapeutic challenge and, until recently, there was a paucity of effective treatment options. In the past decade, an evolution in our understanding of the molecular mechanisms underlying these tumors has altered the treatment landscape for well-differentiated tumors as an expanding array of targeted therapies with proven efficacy have become available (Table 1).

Somatostatin analogs lead the charge

The fact that many NETs overexpress hormone receptors presents a significant therapeutic opportunity, and among the most successful targets to date are the somatostatin receptors (SSTRs). There are 5 main SSTRs that each bind to somatostatin with different effects on cell signaling and expression that varies according to the type of NET.

More stable synthetic analogs of the somatostatin hormone (somatostatin analogs [SSAs]), which has a very short half-life in the circulation, have been developed that act as SSTR agonists. Two long-acting SSAs, octreotide (Sandostatin LAR Depot) and lanreotide (Somatuline Depot), which bind SSTR2 and SSTR5, have been approved by the United States Food and Drug Administration (FDA), but were primarily used for the alleviation of the symptoms associated with NETs resulting from carcinoid syndrome.

In recent years, evidence has begun to emerge that SSAs also have an anti-tumor effect, which is thought to be both direct and indirect in nature. Direct effects result from the interaction between the SSA and SSTRs expressed on tumor cells, blocking the protumor cellular effects of SSTR signaling that are poorly understood but thought to involve the mitogen-activated protein kinase (MAPK) pathway. Indirect effects are fortuitous side effects mediated through off-target effects, such as the suppression of other cellular activities of SSTRs and the other growth factors that they bind to, which can impact processes such as angiogenesis and immune modulation.^7,12

Several clinical trials have been designed to test the anti-tumor effects of NETs, including the PROMID trial of octreotide and the CLARINET trial of lanreotide, the latter leading to the 2014 approval of lanreotide for the improvement of progression-free survival (PFS) in patients with advanced GI- and pNETs.

The randomized phase 3 study compared lanreotide 120 mg with placebo in 204 patients with locally advanced or metastatic nonfunctioning pancreatic or intestinal NETs. Lanreotide treatment resulted in a significant improvement in PFS (Not yet reached vs 18 months for placebo; hazard ratio [HR], 0.47; P < .001).¹³

Meanwhile, the PROMID trial compared octreotide 30 mg with placebo in 85 patients with advanced midgut NETs and demonstrated that octreotide increased time to progression (TTP; 14.3 months vs 6 months for placebo; P = .000072) with no significant difference in side effects.¹⁴

Pasireotide is a second-generation SSA with improved binding affinity to SSTR1, 3, and 5. Despite its improved specificity, pasireotide has not proved more effective than other SSAs and its development for the treatment of NETs has been discontinued.

Coupling radioisotopes to SSAs provides another promising therapeutic option for NETs, known as peptide receptor radionuclide therapy, or PRRT, which uses SSAs to deliver therapeutic radiation directly to the tumor cells. Several variations have been studied with different radioactive isotopes, but most promising is lutetium-177 (¹⁷⁷Lu). A ¹⁷⁷Lu-labelled octreotide (¹⁷⁷Lu-Dotatate) recently demonstrated significant efficacy in the phase 3 NETTER-1 clinical trial in patients with advanced stage NETs of the small bowel. The trial randomly assigned 229 patients who were progressing on an SSA to either ¹⁷⁷Lu-Dotatate or high-dose octreotide LAR (long-acting release). There was a significant increase in PFS in the ¹⁷⁷Lu-Dotatate arm (Not yet reached vs 8.4 months; P < .0001). There was also a trend toward improved overall survival (OS), and longer follow-up is eagerly anticipated for confirmation. ¹⁷⁷Lu-Dotatate has been granted priority review by the FDA, and a decision on its approval is expected in the next few months.^11,15-17
 

Molecularly and immune-targeted therapies continue to take aim

The mammalian target of rapamycin, or mTOR, is a serine/threonine kinase that sits at the confluence of a number of different upstream signaling pathways and mediates key cellular processes including cell proliferation and survival (Figure 1).

The involvement of the mTOR pathway in the pathogenesis of NETs first came into focus in pNETs and the mTOR inhibitor, everolimus (Afinitor) has been extensively studied in this indication, culminating in its regulatory approval in 2011. In the pivotal trial (RADIANT-3), everolimus monotherapy was compared with placebo in 410 patients with low- and intermediate-grade pNETs. There was a statistically significant improvement in PFS from 4.6 months to 11 months (HR, 0.77; P = .026).¹⁹ The final OS analysis for this trial also revealed a benefit of more than 6 months in the everolimus arm, although this was not statistically significant, which the study authors attribute to the high rate of crossover from the placebo arm after progression.²⁰

More recently, the results of the RADIANT-4 trial, in which everolimus was compare with placebo in patients with advanced, well-differentiated, nonfunctioning NETs of the GI tract and lung, led to a new approved indication for the mTOR inhibitor and the first approved targeted therapy for advanced lung NETs. In the overall study population (n = 285), everolimus prolonged PFS by more than 7 months (11 months vs 3.9 months for placebo; HR, 0.48; P = .000001), corresponding to a 52% reduction in the risk of disease progression or death.^21,22

Everolimus continues to be evaluated, with a particular focus on combination therapy to overcome the resistance that commonly occurs after treatment with molecularly targeted drugs (Table 2). For example, preclinical studies suggested that mTOR inhibitors and SSAs may have synergistic activity owing to combined inhibition of the mTOR and insulin-like growth factor pathways. In a phase 1 study, the combination of pasireotide and everolimus was found to be safe and to have preliminary anti-tumor activity. However, the subsequent phase 2 COOPERATE-2 study failed to show improved PFS.^23,24

Neuroendocrine tumors (NETs) are an extremely diverse group of cancers that have steadily increased in incidence in recent years. They can prove challenging to treat but, as we discuss here, a steady evolution in our understanding of NETs has significantly expanded the scope of therapeutic options.

A unique tumor type

NETs arise from neuroendocrine cells – cells with features of both nerve and endocrine cells that have important physiological functions, including the production and release of hormones. These tumors were first recognized by a German pathologist in the mid-1800s and were initially referred to as carcinoids in reference to their carcinoma-like appearance but lack of other malignant features.¹

Unlike other solid tumors, which are associated with a particular primary location, NETs can arise anywhere in the body where neuroendocrine cells are found. They are also unique in their ability to oversecrete bioactive substances that regulate bodily functions, which results in an associated clinical syndrome, known as carcinoid syndrome, in up to 35% of patients.^2,3

Although they are considered to be a relatively rare type of tumor, the incidence of NETs has been increasing in recent years. According to data from the Surveillance, Epidemiology and End Results (SEER) program, the age-adjusted incidence of NETs increased more than two-and-a-half fold during 1973-2004 and the rise is predicted to continue at an accelerated rate.⁴

Historically, NETs have been thought of as relatively benign because of their slow-growing nature, but it is now widely appreciated that they often metastasize. Furthermore, many patients are not symptomatic at first, so around half of all cases are not diagnosed until they have reached this more aggressive stage.⁴
 

The challenge of NET diversity

The most common type of NETs are those that arise in the gastrointestinal tract (GI-NET), representing more than 65% of cases, and for which the “carcinoid” terminology often is still applied. GI-NETs most frequently arise in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%).^4,5

About a quarter of NETs originate in the bronchopulmonary system, including the lungs and the thymus. Thymic NETs are particularly aggressive and are associated with a poor prognosis. Pancreatic NETs (pNETs) make up the next largest group, although they represent less than 1% of total NETs. Compared with the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, they have a more favorable prognosis. pNETs are often grouped together with GI-NETs and referred to as gastroenteropancreatic NETs (GEP-NETs).^3-5 Other rarer types of NET include Merkel cell carcinoma (a type of skin cancer) and medullary thyroid cancers.
 

The classification network

NETs are classified according to the anatomic site from which they originate, as well as their histology, grade, and stage. Another important consideration is their level of hormone secretion. “Functional” and “nonfunctional” NETs both produce hormones, but only the former cause related symptoms.^3,4,6

Functionality plays a particularly important role in the subclassification of GEP-NETs. Functional pNETs, for instance, are further divided according to the clinical syndromes associated with the hormones they produce, as insulinomas, glucagonomas, gastrinomas, somatostatinomas, and VIPomas (producing vasoactive intestinal peptide).^7,8

In 2010, the World Health Organization developed a classification system for GEP-NETs that categorized these tumors as well differentiated (grade 1 or 2, depending on their rate of proliferation) and poorly differentiated (grade 3).⁹ The WHO classification of bronchopulmonary NETs, published in 2015, is slightly different; broken down into 3 subgroups, typical carcinoid, atypical carcinoid (corresponding to grade 1 and 2 GEP-NETs), and large and small-cell NETs (equivalent to grade 3 GEP-NETs).¹⁰

Although NETs develop from the same cell type, they in fact comprise a spectrum of diseases that vary extensively in their underlying biology, histology, and clinical behavior. Both the diversity and unique nature of NETs have become increasingly evident in recent years with the application of next-generation sequencing technologies to this tumor type. In general, NETs seem to be more genetically stable than other tumor types from the same primary location, and have fewer somatic mutations. The classic tumor suppressors and oncogenes that drive other tumor types are not common in NETs.^6,11

The diversity of NETs presents a diagnostic and therapeutic challenge and, until recently, there was a paucity of effective treatment options. In the past decade, an evolution in our understanding of the molecular mechanisms underlying these tumors has altered the treatment landscape for well-differentiated tumors as an expanding array of targeted therapies with proven efficacy have become available (Table 1).

Somatostatin analogs lead the charge

The fact that many NETs overexpress hormone receptors presents a significant therapeutic opportunity, and among the most successful targets to date are the somatostatin receptors (SSTRs). There are 5 main SSTRs that each bind to somatostatin with different effects on cell signaling and expression that varies according to the type of NET.

More stable synthetic analogs of the somatostatin hormone (somatostatin analogs [SSAs]), which has a very short half-life in the circulation, have been developed that act as SSTR agonists. Two long-acting SSAs, octreotide (Sandostatin LAR Depot) and lanreotide (Somatuline Depot), which bind SSTR2 and SSTR5, have been approved by the United States Food and Drug Administration (FDA), but were primarily used for the alleviation of the symptoms associated with NETs resulting from carcinoid syndrome.

In recent years, evidence has begun to emerge that SSAs also have an anti-tumor effect, which is thought to be both direct and indirect in nature. Direct effects result from the interaction between the SSA and SSTRs expressed on tumor cells, blocking the protumor cellular effects of SSTR signaling that are poorly understood but thought to involve the mitogen-activated protein kinase (MAPK) pathway. Indirect effects are fortuitous side effects mediated through off-target effects, such as the suppression of other cellular activities of SSTRs and the other growth factors that they bind to, which can impact processes such as angiogenesis and immune modulation.^7,12

Several clinical trials have been designed to test the anti-tumor effects of NETs, including the PROMID trial of octreotide and the CLARINET trial of lanreotide, the latter leading to the 2014 approval of lanreotide for the improvement of progression-free survival (PFS) in patients with advanced GI- and pNETs.

The randomized phase 3 study compared lanreotide 120 mg with placebo in 204 patients with locally advanced or metastatic nonfunctioning pancreatic or intestinal NETs. Lanreotide treatment resulted in a significant improvement in PFS (Not yet reached vs 18 months for placebo; hazard ratio [HR], 0.47; P < .001).¹³

Meanwhile, the PROMID trial compared octreotide 30 mg with placebo in 85 patients with advanced midgut NETs and demonstrated that octreotide increased time to progression (TTP; 14.3 months vs 6 months for placebo; P = .000072) with no significant difference in side effects.¹⁴

Pasireotide is a second-generation SSA with improved binding affinity to SSTR1, 3, and 5. Despite its improved specificity, pasireotide has not proved more effective than other SSAs and its development for the treatment of NETs has been discontinued.

Coupling radioisotopes to SSAs provides another promising therapeutic option for NETs, known as peptide receptor radionuclide therapy, or PRRT, which uses SSAs to deliver therapeutic radiation directly to the tumor cells. Several variations have been studied with different radioactive isotopes, but most promising is lutetium-177 (¹⁷⁷Lu). A ¹⁷⁷Lu-labelled octreotide (¹⁷⁷Lu-Dotatate) recently demonstrated significant efficacy in the phase 3 NETTER-1 clinical trial in patients with advanced stage NETs of the small bowel. The trial randomly assigned 229 patients who were progressing on an SSA to either ¹⁷⁷Lu-Dotatate or high-dose octreotide LAR (long-acting release). There was a significant increase in PFS in the ¹⁷⁷Lu-Dotatate arm (Not yet reached vs 8.4 months; P < .0001). There was also a trend toward improved overall survival (OS), and longer follow-up is eagerly anticipated for confirmation. ¹⁷⁷Lu-Dotatate has been granted priority review by the FDA, and a decision on its approval is expected in the next few months.^11,15-17
 

Molecularly and immune-targeted therapies continue to take aim

The mammalian target of rapamycin, or mTOR, is a serine/threonine kinase that sits at the confluence of a number of different upstream signaling pathways and mediates key cellular processes including cell proliferation and survival (Figure 1).

The involvement of the mTOR pathway in the pathogenesis of NETs first came into focus in pNETs and the mTOR inhibitor, everolimus (Afinitor) has been extensively studied in this indication, culminating in its regulatory approval in 2011. In the pivotal trial (RADIANT-3), everolimus monotherapy was compared with placebo in 410 patients with low- and intermediate-grade pNETs. There was a statistically significant improvement in PFS from 4.6 months to 11 months (HR, 0.77; P = .026).¹⁹ The final OS analysis for this trial also revealed a benefit of more than 6 months in the everolimus arm, although this was not statistically significant, which the study authors attribute to the high rate of crossover from the placebo arm after progression.²⁰

More recently, the results of the RADIANT-4 trial, in which everolimus was compare with placebo in patients with advanced, well-differentiated, nonfunctioning NETs of the GI tract and lung, led to a new approved indication for the mTOR inhibitor and the first approved targeted therapy for advanced lung NETs. In the overall study population (n = 285), everolimus prolonged PFS by more than 7 months (11 months vs 3.9 months for placebo; HR, 0.48; P = .000001), corresponding to a 52% reduction in the risk of disease progression or death.^21,22

Everolimus continues to be evaluated, with a particular focus on combination therapy to overcome the resistance that commonly occurs after treatment with molecularly targeted drugs (Table 2). For example, preclinical studies suggested that mTOR inhibitors and SSAs may have synergistic activity owing to combined inhibition of the mTOR and insulin-like growth factor pathways. In a phase 1 study, the combination of pasireotide and everolimus was found to be safe and to have preliminary anti-tumor activity. However, the subsequent phase 2 COOPERATE-2 study failed to show improved PFS.^23,24

Neuroendocrine tumors (NETs) are an extremely diverse group of cancers that have steadily increased in incidence in recent years. They can prove challenging to treat but, as we discuss here, a steady evolution in our understanding of NETs has significantly expanded the scope of therapeutic options.

A unique tumor type

NETs arise from neuroendocrine cells – cells with features of both nerve and endocrine cells that have important physiological functions, including the production and release of hormones. These tumors were first recognized by a German pathologist in the mid-1800s and were initially referred to as carcinoids in reference to their carcinoma-like appearance but lack of other malignant features.¹

Unlike other solid tumors, which are associated with a particular primary location, NETs can arise anywhere in the body where neuroendocrine cells are found. They are also unique in their ability to oversecrete bioactive substances that regulate bodily functions, which results in an associated clinical syndrome, known as carcinoid syndrome, in up to 35% of patients.^2,3

Although they are considered to be a relatively rare type of tumor, the incidence of NETs has been increasing in recent years. According to data from the Surveillance, Epidemiology and End Results (SEER) program, the age-adjusted incidence of NETs increased more than two-and-a-half fold during 1973-2004 and the rise is predicted to continue at an accelerated rate.⁴

Historically, NETs have been thought of as relatively benign because of their slow-growing nature, but it is now widely appreciated that they often metastasize. Furthermore, many patients are not symptomatic at first, so around half of all cases are not diagnosed until they have reached this more aggressive stage.⁴
 

The challenge of NET diversity

The most common type of NETs are those that arise in the gastrointestinal tract (GI-NET), representing more than 65% of cases, and for which the “carcinoid” terminology often is still applied. GI-NETs most frequently arise in the small intestine (41.8%), rectum (27.4%), and stomach (8.7%).^4,5

About a quarter of NETs originate in the bronchopulmonary system, including the lungs and the thymus. Thymic NETs are particularly aggressive and are associated with a poor prognosis. Pancreatic NETs (pNETs) make up the next largest group, although they represent less than 1% of total NETs. Compared with the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma, they have a more favorable prognosis. pNETs are often grouped together with GI-NETs and referred to as gastroenteropancreatic NETs (GEP-NETs).^3-5 Other rarer types of NET include Merkel cell carcinoma (a type of skin cancer) and medullary thyroid cancers.
 

The classification network

NETs are classified according to the anatomic site from which they originate, as well as their histology, grade, and stage. Another important consideration is their level of hormone secretion. “Functional” and “nonfunctional” NETs both produce hormones, but only the former cause related symptoms.^3,4,6

Functionality plays a particularly important role in the subclassification of GEP-NETs. Functional pNETs, for instance, are further divided according to the clinical syndromes associated with the hormones they produce, as insulinomas, glucagonomas, gastrinomas, somatostatinomas, and VIPomas (producing vasoactive intestinal peptide).^7,8

In 2010, the World Health Organization developed a classification system for GEP-NETs that categorized these tumors as well differentiated (grade 1 or 2, depending on their rate of proliferation) and poorly differentiated (grade 3).⁹ The WHO classification of bronchopulmonary NETs, published in 2015, is slightly different; broken down into 3 subgroups, typical carcinoid, atypical carcinoid (corresponding to grade 1 and 2 GEP-NETs), and large and small-cell NETs (equivalent to grade 3 GEP-NETs).¹⁰

Although NETs develop from the same cell type, they in fact comprise a spectrum of diseases that vary extensively in their underlying biology, histology, and clinical behavior. Both the diversity and unique nature of NETs have become increasingly evident in recent years with the application of next-generation sequencing technologies to this tumor type. In general, NETs seem to be more genetically stable than other tumor types from the same primary location, and have fewer somatic mutations. The classic tumor suppressors and oncogenes that drive other tumor types are not common in NETs.^6,11

The diversity of NETs presents a diagnostic and therapeutic challenge and, until recently, there was a paucity of effective treatment options. In the past decade, an evolution in our understanding of the molecular mechanisms underlying these tumors has altered the treatment landscape for well-differentiated tumors as an expanding array of targeted therapies with proven efficacy have become available (Table 1).

Somatostatin analogs lead the charge

The fact that many NETs overexpress hormone receptors presents a significant therapeutic opportunity, and among the most successful targets to date are the somatostatin receptors (SSTRs). There are 5 main SSTRs that each bind to somatostatin with different effects on cell signaling and expression that varies according to the type of NET.

More stable synthetic analogs of the somatostatin hormone (somatostatin analogs [SSAs]), which has a very short half-life in the circulation, have been developed that act as SSTR agonists. Two long-acting SSAs, octreotide (Sandostatin LAR Depot) and lanreotide (Somatuline Depot), which bind SSTR2 and SSTR5, have been approved by the United States Food and Drug Administration (FDA), but were primarily used for the alleviation of the symptoms associated with NETs resulting from carcinoid syndrome.

In recent years, evidence has begun to emerge that SSAs also have an anti-tumor effect, which is thought to be both direct and indirect in nature. Direct effects result from the interaction between the SSA and SSTRs expressed on tumor cells, blocking the protumor cellular effects of SSTR signaling that are poorly understood but thought to involve the mitogen-activated protein kinase (MAPK) pathway. Indirect effects are fortuitous side effects mediated through off-target effects, such as the suppression of other cellular activities of SSTRs and the other growth factors that they bind to, which can impact processes such as angiogenesis and immune modulation.^7,12

Several clinical trials have been designed to test the anti-tumor effects of NETs, including the PROMID trial of octreotide and the CLARINET trial of lanreotide, the latter leading to the 2014 approval of lanreotide for the improvement of progression-free survival (PFS) in patients with advanced GI- and pNETs.

The randomized phase 3 study compared lanreotide 120 mg with placebo in 204 patients with locally advanced or metastatic nonfunctioning pancreatic or intestinal NETs. Lanreotide treatment resulted in a significant improvement in PFS (Not yet reached vs 18 months for placebo; hazard ratio [HR], 0.47; P < .001).¹³

Meanwhile, the PROMID trial compared octreotide 30 mg with placebo in 85 patients with advanced midgut NETs and demonstrated that octreotide increased time to progression (TTP; 14.3 months vs 6 months for placebo; P = .000072) with no significant difference in side effects.¹⁴

Pasireotide is a second-generation SSA with improved binding affinity to SSTR1, 3, and 5. Despite its improved specificity, pasireotide has not proved more effective than other SSAs and its development for the treatment of NETs has been discontinued.

Coupling radioisotopes to SSAs provides another promising therapeutic option for NETs, known as peptide receptor radionuclide therapy, or PRRT, which uses SSAs to deliver therapeutic radiation directly to the tumor cells. Several variations have been studied with different radioactive isotopes, but most promising is lutetium-177 (¹⁷⁷Lu). A ¹⁷⁷Lu-labelled octreotide (¹⁷⁷Lu-Dotatate) recently demonstrated significant efficacy in the phase 3 NETTER-1 clinical trial in patients with advanced stage NETs of the small bowel. The trial randomly assigned 229 patients who were progressing on an SSA to either ¹⁷⁷Lu-Dotatate or high-dose octreotide LAR (long-acting release). There was a significant increase in PFS in the ¹⁷⁷Lu-Dotatate arm (Not yet reached vs 8.4 months; P < .0001). There was also a trend toward improved overall survival (OS), and longer follow-up is eagerly anticipated for confirmation. ¹⁷⁷Lu-Dotatate has been granted priority review by the FDA, and a decision on its approval is expected in the next few months.^11,15-17
 

Molecularly and immune-targeted therapies continue to take aim

The mammalian target of rapamycin, or mTOR, is a serine/threonine kinase that sits at the confluence of a number of different upstream signaling pathways and mediates key cellular processes including cell proliferation and survival (Figure 1).

The involvement of the mTOR pathway in the pathogenesis of NETs first came into focus in pNETs and the mTOR inhibitor, everolimus (Afinitor) has been extensively studied in this indication, culminating in its regulatory approval in 2011. In the pivotal trial (RADIANT-3), everolimus monotherapy was compared with placebo in 410 patients with low- and intermediate-grade pNETs. There was a statistically significant improvement in PFS from 4.6 months to 11 months (HR, 0.77; P = .026).¹⁹ The final OS analysis for this trial also revealed a benefit of more than 6 months in the everolimus arm, although this was not statistically significant, which the study authors attribute to the high rate of crossover from the placebo arm after progression.²⁰

More recently, the results of the RADIANT-4 trial, in which everolimus was compare with placebo in patients with advanced, well-differentiated, nonfunctioning NETs of the GI tract and lung, led to a new approved indication for the mTOR inhibitor and the first approved targeted therapy for advanced lung NETs. In the overall study population (n = 285), everolimus prolonged PFS by more than 7 months (11 months vs 3.9 months for placebo; HR, 0.48; P = .000001), corresponding to a 52% reduction in the risk of disease progression or death.^21,22

Everolimus continues to be evaluated, with a particular focus on combination therapy to overcome the resistance that commonly occurs after treatment with molecularly targeted drugs (Table 2). For example, preclinical studies suggested that mTOR inhibitors and SSAs may have synergistic activity owing to combined inhibition of the mTOR and insulin-like growth factor pathways. In a phase 1 study, the combination of pasireotide and everolimus was found to be safe and to have preliminary anti-tumor activity. However, the subsequent phase 2 COOPERATE-2 study failed to show improved PFS.^23,24

About 1 in 5 U.S. adults used tobacco in 2015 every day or on some days, according to the CDC and the FDA. The most common tobacco product was cigarettes (15%). About 9.5 million adults used ≥ 2 tobacco products.

This is the first time the CDC and FDA have used the National Health Interview Survey to assess the range of tobacco products used. Survey questions asked about current cigarette smoking since 1965, but only recently began to track other tobacco products.

About 42 million adults, or > 87% of the nearly 49 million tobacco product users in the U.S., reported using cigarettes, cigars, or pipes; the remaining tobacco users reported using e-cigarettes or smokeless tobacco products (eg, chewing tobacco and snuff).

The survey also found that men were more likely than women to use tobacco products (25% vs 15%). Adults aged 25 to 44 years were more likely than those aged ≥ 65 years to use tobacco products (23% vs 11%). By race and ethnicity, tobacco product use ranged from 9% among Asians to 27% among American Indians/Alaska Natives.

Using tobacco products was more common among adults in the Midwest; people with annual incomes less than $35,000; the uninsured or Medicaid insured; those with a disability; and those who are lesbian, gay, or bisexual. Adults with serious psychological distress were more than 2 times as likely to use tobacco as those who reported no serious psychological distress (47% vs 19%).

Cigarette smoking remains the leading preventable cause of death and disease in the U.S. The CDC urges full implementation of comprehensive state tobacco control programs along with FDA regulation of tobacco products and targeted interventions to reach subpopulations with the greatest burden of use.

About 1 in 5 U.S. adults used tobacco in 2015 every day or on some days, according to the CDC and the FDA. The most common tobacco product was cigarettes (15%). About 9.5 million adults used ≥ 2 tobacco products.

This is the first time the CDC and FDA have used the National Health Interview Survey to assess the range of tobacco products used. Survey questions asked about current cigarette smoking since 1965, but only recently began to track other tobacco products.

About 42 million adults, or > 87% of the nearly 49 million tobacco product users in the U.S., reported using cigarettes, cigars, or pipes; the remaining tobacco users reported using e-cigarettes or smokeless tobacco products (eg, chewing tobacco and snuff).

The survey also found that men were more likely than women to use tobacco products (25% vs 15%). Adults aged 25 to 44 years were more likely than those aged ≥ 65 years to use tobacco products (23% vs 11%). By race and ethnicity, tobacco product use ranged from 9% among Asians to 27% among American Indians/Alaska Natives.

Using tobacco products was more common among adults in the Midwest; people with annual incomes less than $35,000; the uninsured or Medicaid insured; those with a disability; and those who are lesbian, gay, or bisexual. Adults with serious psychological distress were more than 2 times as likely to use tobacco as those who reported no serious psychological distress (47% vs 19%).

Cigarette smoking remains the leading preventable cause of death and disease in the U.S. The CDC urges full implementation of comprehensive state tobacco control programs along with FDA regulation of tobacco products and targeted interventions to reach subpopulations with the greatest burden of use.

About 1 in 5 U.S. adults used tobacco in 2015 every day or on some days, according to the CDC and the FDA. The most common tobacco product was cigarettes (15%). About 9.5 million adults used ≥ 2 tobacco products.

This is the first time the CDC and FDA have used the National Health Interview Survey to assess the range of tobacco products used. Survey questions asked about current cigarette smoking since 1965, but only recently began to track other tobacco products.

About 42 million adults, or > 87% of the nearly 49 million tobacco product users in the U.S., reported using cigarettes, cigars, or pipes; the remaining tobacco users reported using e-cigarettes or smokeless tobacco products (eg, chewing tobacco and snuff).

The survey also found that men were more likely than women to use tobacco products (25% vs 15%). Adults aged 25 to 44 years were more likely than those aged ≥ 65 years to use tobacco products (23% vs 11%). By race and ethnicity, tobacco product use ranged from 9% among Asians to 27% among American Indians/Alaska Natives.

Using tobacco products was more common among adults in the Midwest; people with annual incomes less than $35,000; the uninsured or Medicaid insured; those with a disability; and those who are lesbian, gay, or bisexual. Adults with serious psychological distress were more than 2 times as likely to use tobacco as those who reported no serious psychological distress (47% vs 19%).

Cigarette smoking remains the leading preventable cause of death and disease in the U.S. The CDC urges full implementation of comprehensive state tobacco control programs along with FDA regulation of tobacco products and targeted interventions to reach subpopulations with the greatest burden of use.

Prostate cancer treatments are associated with various physical after-effects, including urinary, sexual, and bowel symptoms.¹ These after-effects can have an impact on survivors’ health-related quality of life (HRQoL).² Pharmaceutical and surgical interventions are available to manage or ameliorate many of these after-effects (eg, sildenafil citrate taken during and after radiotherapy improves sexual function),³ and their receipt has a positive impact on HRQoL.⁴

However, studies of clinicians suggest that such interventions may not be used widely.^5,6 Patient-reported data on this topic is lacking. Therefore, we investigated the use of supportive medications and interventions in this population-based study of prostate cancer survivors.

Methods

The PiCTure (Prostate Cancer Treatment, Your Experience) study methods have been described elsewhere.⁷ Briefly, 6,559 prostate cancer survivors 2-15 years after diagnosis (diagnosed during January 1, 1995-March 31, 2010, and alive in November 2011), identified from population-based cancer registries in the Republic of Ireland and Northern Ireland, were invited to complete a postal survey. Information was sought on after-effects (incontinence, impotence, gynaecomastia, hot flashes/sweats, bowel problems, depression) that had been experienced at any time after treatment. For each after-effect, men were asked if they had received any medication or interventions to alleviate symptoms, and, if so, what they had received; examples of common interventions were provided. Men were also asked if they had been told they may become infertile and, if so, whether they had preserved their sperm. The Decisional Regret Scale⁸ was used to measure survivors’ regret over their entire treatment experience. This 5-item scale, rated on a 5-point Likert scale from 1 (strongly agree) to 5 (strongly disagree) was summed and standardized to a value of 0-100, with higher scores reflecting higher levels of decisional regret. ⁸ This scale has good psychometric properties⁸ and strong reliability in our sample (Cronbach’s alpha = 0.85). Responders were categorized as having any regret (score ≥1) or no regret (score = 0).

The number of men who reported receiving an intervention was expressed as a percentage of survey responders and of men who reported ever having the relevant after-effect. Chi-square tests were used to investigate variations in receipt by: age at diagnosis (≤59, 60-69, ≥70 years); time since diagnosis (≤5, 5-10, >10 years); jurisdiction (Republic of Ireland, or Northern Ireland); and primary treatment(s) received (radical prostatectomy [RP], external beam radiotherapy [EBRT] with androgen deprivation therapy [ADT], EBRT without ADT, brachytherapy, ADT [without other therapies], and active surveillance/watchful waiting). Among survivors who ever experienced an after-effect, chi-square tests were used to investigate whether the percentage who reported decisional regret differed depending on whether or not they received the relevant supportive intervention.

Ethics approval was from the Irish College of General Practitioners (Republic of Ireland) and the Office for Research Ethics Committee Northern Ireland.
 

Results

In all, 3,348 survivors participated in the survey (adjusted response rate, 54%). Compared with nonresponders, responders were more often from the Republic of Ireland (P = .007), <70 years at diagnosis (P < .001), 5-10 years post diagnosis (P < .001), with low or medium Gleason grade (Gleason scores of ≤6 [good prognosis] and 7, respectively; P < .001), and clinical stage II-IV (P < .001; Table 1).

Impotence (70%) was the most commonly reported after-effect, followed by hot flashes/sweats (40%), incontinence (37%), bowel problems (23%), gynaecomastia (19%), and depression (18%; Table 2).

Incontinence medication was received by 8% of participants (21% of those who experienced incontinence). Use varied significantly by age, jurisdiction, and treatment. For impotence, medications were more commonly used (20% of participants; 28% with impotence) than were injections (5% and 7%, respectively) or penile implants/pumps (2% and 3%, respectively). Use of all 3 types of intervention was highest in men who had RP; injections and implants/pumps were significantly more common among younger men. Of those experiencing gynaecomastia, 13% received interventions; receipt was highest in men who had EBRT with ADT, were <5 years post diagnosis and from Northern Ireland. For hot flashes/sweats, 3% of participants (8% who experienced symptoms) received mediations; this was higher in men who had EBRT. Of those who reported depression, 28% received medication; receipt was highest in younger men and in Northern Ireland. Medication for bowel problems was used by 35% of men who experienced these; use was highest in older men, those diagnosed more recently, and those who had EBRT. Sixty percent of men reported having been told they would become infertile; 11 (0.3% of participants) preserved their sperm, 7 from the Republic of Ireland and 4 from Northern Ireland.

A total of 35.6% of survivors reported any decisional regret. Among survivors who ever had an after-effect, a higher percentage of those who used a supportive intervention reported decisional regret compared with those who did not; this was only statistically significant for those using medication or alprostadil injections for impotence (Table 2).
 

Discussion

This study documents, for the first time, population-based data on patient-reported use of supportive medications and interventions to alleviate adverse effects of prostate cancer and its treatment. Among survivors who experienced after-effects, use was highest for bowel problems, impotence, and depression, but even for those, only 28%-35% of men took medication. Although it is possible that some survivors declined medications or other interventions, these low levels of use strongly suggest that not all survivors who might benefit from supports receive them.

There was little evidence that utilisation was higher in survivors diagnosed more recently. This suggests that, although the number of prostate cancer survivors has grown, and there is greater focus on survivorship issues in clinical practice, this has not translated into more men receiving support to manage after-effects. Care is needed to ensure that the newer models of post-cancer follow-up being considered or adopted in many settings,⁹ do not exacerbate this issue.

As expected, patterns of utilisation varied by treatment(s) received. Higher use of surgical and pharmaceutical interventions to alleviate incontinence among survivors in the Republic of Ireland than in Northern Ireland is likely owing to the higher rate of radical prostatectomy in the Republic of Ireland, whereas greater use of treatments for gynaecomastia in Northern Ireland reflects higher use of hormone therapy there.¹⁰ Other variations in intervention use were more surprising. Younger men were significantly more likely to report using supportive interventions for depression and impotence, the latter finding being consistent with findings in a Swedish population-based study.¹¹ Older men were significantly more likely to report interventions for incontinence and bowel problems. Although those trends could be explained by differences in treatment receipt by age, it is possible that men of different ages may be more likely to seek, or be offered, help for certain types of after-effects. With the exception of interventions for bowel problems, a higher percentage of men who received intervention(s) for an after-effect reported decisional regret. There are a number of possible explanations: these men may have experienced more severe after-effects, which required interventions; they may have been less satisfied with their posttreatment function and/or more proactive about recovering or treating their after-effects. This requires further investigation.

This is a large, international, population-based study, the first such study to describe patient-reported use of supportive care following a range of prostate cancer treatments. Although this study is novel, there are a number of limitations. It is a cross-sectional, descriptive study. We did not ask survivors whether the supportive interventions received matched their needs and wants, and whether they were satisfied with the supportive care received. Furthermore, although the response rate is comparable with other similar studies,^12,13 it is possible that the supportive care of nonresponders was different to that of responders.

Our study included men from 2 jurisdictions with separate health care systems, suggesting that low use of supportive interventions may be common across systems. There is a need for further research into patient and health care system factors associated with the receipt of supportive interventions and how satisfied men are with these, in this and other health care settings. Presently, it is clear that more needs to be done in the clinical setting to support prostate cancer survivors manage treatment after-effects; this in turn could improve survivors’ HRQoL.

Prostate cancer treatments are associated with various physical after-effects, including urinary, sexual, and bowel symptoms.¹ These after-effects can have an impact on survivors’ health-related quality of life (HRQoL).² Pharmaceutical and surgical interventions are available to manage or ameliorate many of these after-effects (eg, sildenafil citrate taken during and after radiotherapy improves sexual function),³ and their receipt has a positive impact on HRQoL.⁴

However, studies of clinicians suggest that such interventions may not be used widely.^5,6 Patient-reported data on this topic is lacking. Therefore, we investigated the use of supportive medications and interventions in this population-based study of prostate cancer survivors.

Methods

The PiCTure (Prostate Cancer Treatment, Your Experience) study methods have been described elsewhere.⁷ Briefly, 6,559 prostate cancer survivors 2-15 years after diagnosis (diagnosed during January 1, 1995-March 31, 2010, and alive in November 2011), identified from population-based cancer registries in the Republic of Ireland and Northern Ireland, were invited to complete a postal survey. Information was sought on after-effects (incontinence, impotence, gynaecomastia, hot flashes/sweats, bowel problems, depression) that had been experienced at any time after treatment. For each after-effect, men were asked if they had received any medication or interventions to alleviate symptoms, and, if so, what they had received; examples of common interventions were provided. Men were also asked if they had been told they may become infertile and, if so, whether they had preserved their sperm. The Decisional Regret Scale⁸ was used to measure survivors’ regret over their entire treatment experience. This 5-item scale, rated on a 5-point Likert scale from 1 (strongly agree) to 5 (strongly disagree) was summed and standardized to a value of 0-100, with higher scores reflecting higher levels of decisional regret. ⁸ This scale has good psychometric properties⁸ and strong reliability in our sample (Cronbach’s alpha = 0.85). Responders were categorized as having any regret (score ≥1) or no regret (score = 0).

The number of men who reported receiving an intervention was expressed as a percentage of survey responders and of men who reported ever having the relevant after-effect. Chi-square tests were used to investigate variations in receipt by: age at diagnosis (≤59, 60-69, ≥70 years); time since diagnosis (≤5, 5-10, >10 years); jurisdiction (Republic of Ireland, or Northern Ireland); and primary treatment(s) received (radical prostatectomy [RP], external beam radiotherapy [EBRT] with androgen deprivation therapy [ADT], EBRT without ADT, brachytherapy, ADT [without other therapies], and active surveillance/watchful waiting). Among survivors who ever experienced an after-effect, chi-square tests were used to investigate whether the percentage who reported decisional regret differed depending on whether or not they received the relevant supportive intervention.

Ethics approval was from the Irish College of General Practitioners (Republic of Ireland) and the Office for Research Ethics Committee Northern Ireland.
 

Results

In all, 3,348 survivors participated in the survey (adjusted response rate, 54%). Compared with nonresponders, responders were more often from the Republic of Ireland (P = .007), <70 years at diagnosis (P < .001), 5-10 years post diagnosis (P < .001), with low or medium Gleason grade (Gleason scores of ≤6 [good prognosis] and 7, respectively; P < .001), and clinical stage II-IV (P < .001; Table 1).

Impotence (70%) was the most commonly reported after-effect, followed by hot flashes/sweats (40%), incontinence (37%), bowel problems (23%), gynaecomastia (19%), and depression (18%; Table 2).

Incontinence medication was received by 8% of participants (21% of those who experienced incontinence). Use varied significantly by age, jurisdiction, and treatment. For impotence, medications were more commonly used (20% of participants; 28% with impotence) than were injections (5% and 7%, respectively) or penile implants/pumps (2% and 3%, respectively). Use of all 3 types of intervention was highest in men who had RP; injections and implants/pumps were significantly more common among younger men. Of those experiencing gynaecomastia, 13% received interventions; receipt was highest in men who had EBRT with ADT, were <5 years post diagnosis and from Northern Ireland. For hot flashes/sweats, 3% of participants (8% who experienced symptoms) received mediations; this was higher in men who had EBRT. Of those who reported depression, 28% received medication; receipt was highest in younger men and in Northern Ireland. Medication for bowel problems was used by 35% of men who experienced these; use was highest in older men, those diagnosed more recently, and those who had EBRT. Sixty percent of men reported having been told they would become infertile; 11 (0.3% of participants) preserved their sperm, 7 from the Republic of Ireland and 4 from Northern Ireland.

A total of 35.6% of survivors reported any decisional regret. Among survivors who ever had an after-effect, a higher percentage of those who used a supportive intervention reported decisional regret compared with those who did not; this was only statistically significant for those using medication or alprostadil injections for impotence (Table 2).
 

Discussion

This study documents, for the first time, population-based data on patient-reported use of supportive medications and interventions to alleviate adverse effects of prostate cancer and its treatment. Among survivors who experienced after-effects, use was highest for bowel problems, impotence, and depression, but even for those, only 28%-35% of men took medication. Although it is possible that some survivors declined medications or other interventions, these low levels of use strongly suggest that not all survivors who might benefit from supports receive them.

There was little evidence that utilisation was higher in survivors diagnosed more recently. This suggests that, although the number of prostate cancer survivors has grown, and there is greater focus on survivorship issues in clinical practice, this has not translated into more men receiving support to manage after-effects. Care is needed to ensure that the newer models of post-cancer follow-up being considered or adopted in many settings,⁹ do not exacerbate this issue.

As expected, patterns of utilisation varied by treatment(s) received. Higher use of surgical and pharmaceutical interventions to alleviate incontinence among survivors in the Republic of Ireland than in Northern Ireland is likely owing to the higher rate of radical prostatectomy in the Republic of Ireland, whereas greater use of treatments for gynaecomastia in Northern Ireland reflects higher use of hormone therapy there.¹⁰ Other variations in intervention use were more surprising. Younger men were significantly more likely to report using supportive interventions for depression and impotence, the latter finding being consistent with findings in a Swedish population-based study.¹¹ Older men were significantly more likely to report interventions for incontinence and bowel problems. Although those trends could be explained by differences in treatment receipt by age, it is possible that men of different ages may be more likely to seek, or be offered, help for certain types of after-effects. With the exception of interventions for bowel problems, a higher percentage of men who received intervention(s) for an after-effect reported decisional regret. There are a number of possible explanations: these men may have experienced more severe after-effects, which required interventions; they may have been less satisfied with their posttreatment function and/or more proactive about recovering or treating their after-effects. This requires further investigation.

This is a large, international, population-based study, the first such study to describe patient-reported use of supportive care following a range of prostate cancer treatments. Although this study is novel, there are a number of limitations. It is a cross-sectional, descriptive study. We did not ask survivors whether the supportive interventions received matched their needs and wants, and whether they were satisfied with the supportive care received. Furthermore, although the response rate is comparable with other similar studies,^12,13 it is possible that the supportive care of nonresponders was different to that of responders.

Our study included men from 2 jurisdictions with separate health care systems, suggesting that low use of supportive interventions may be common across systems. There is a need for further research into patient and health care system factors associated with the receipt of supportive interventions and how satisfied men are with these, in this and other health care settings. Presently, it is clear that more needs to be done in the clinical setting to support prostate cancer survivors manage treatment after-effects; this in turn could improve survivors’ HRQoL.

Prostate cancer treatments are associated with various physical after-effects, including urinary, sexual, and bowel symptoms.¹ These after-effects can have an impact on survivors’ health-related quality of life (HRQoL).² Pharmaceutical and surgical interventions are available to manage or ameliorate many of these after-effects (eg, sildenafil citrate taken during and after radiotherapy improves sexual function),³ and their receipt has a positive impact on HRQoL.⁴

However, studies of clinicians suggest that such interventions may not be used widely.^5,6 Patient-reported data on this topic is lacking. Therefore, we investigated the use of supportive medications and interventions in this population-based study of prostate cancer survivors.

Methods

The PiCTure (Prostate Cancer Treatment, Your Experience) study methods have been described elsewhere.⁷ Briefly, 6,559 prostate cancer survivors 2-15 years after diagnosis (diagnosed during January 1, 1995-March 31, 2010, and alive in November 2011), identified from population-based cancer registries in the Republic of Ireland and Northern Ireland, were invited to complete a postal survey. Information was sought on after-effects (incontinence, impotence, gynaecomastia, hot flashes/sweats, bowel problems, depression) that had been experienced at any time after treatment. For each after-effect, men were asked if they had received any medication or interventions to alleviate symptoms, and, if so, what they had received; examples of common interventions were provided. Men were also asked if they had been told they may become infertile and, if so, whether they had preserved their sperm. The Decisional Regret Scale⁸ was used to measure survivors’ regret over their entire treatment experience. This 5-item scale, rated on a 5-point Likert scale from 1 (strongly agree) to 5 (strongly disagree) was summed and standardized to a value of 0-100, with higher scores reflecting higher levels of decisional regret. ⁸ This scale has good psychometric properties⁸ and strong reliability in our sample (Cronbach’s alpha = 0.85). Responders were categorized as having any regret (score ≥1) or no regret (score = 0).

The number of men who reported receiving an intervention was expressed as a percentage of survey responders and of men who reported ever having the relevant after-effect. Chi-square tests were used to investigate variations in receipt by: age at diagnosis (≤59, 60-69, ≥70 years); time since diagnosis (≤5, 5-10, >10 years); jurisdiction (Republic of Ireland, or Northern Ireland); and primary treatment(s) received (radical prostatectomy [RP], external beam radiotherapy [EBRT] with androgen deprivation therapy [ADT], EBRT without ADT, brachytherapy, ADT [without other therapies], and active surveillance/watchful waiting). Among survivors who ever experienced an after-effect, chi-square tests were used to investigate whether the percentage who reported decisional regret differed depending on whether or not they received the relevant supportive intervention.

Ethics approval was from the Irish College of General Practitioners (Republic of Ireland) and the Office for Research Ethics Committee Northern Ireland.
 

Results

In all, 3,348 survivors participated in the survey (adjusted response rate, 54%). Compared with nonresponders, responders were more often from the Republic of Ireland (P = .007), <70 years at diagnosis (P < .001), 5-10 years post diagnosis (P < .001), with low or medium Gleason grade (Gleason scores of ≤6 [good prognosis] and 7, respectively; P < .001), and clinical stage II-IV (P < .001; Table 1).

Impotence (70%) was the most commonly reported after-effect, followed by hot flashes/sweats (40%), incontinence (37%), bowel problems (23%), gynaecomastia (19%), and depression (18%; Table 2).

Incontinence medication was received by 8% of participants (21% of those who experienced incontinence). Use varied significantly by age, jurisdiction, and treatment. For impotence, medications were more commonly used (20% of participants; 28% with impotence) than were injections (5% and 7%, respectively) or penile implants/pumps (2% and 3%, respectively). Use of all 3 types of intervention was highest in men who had RP; injections and implants/pumps were significantly more common among younger men. Of those experiencing gynaecomastia, 13% received interventions; receipt was highest in men who had EBRT with ADT, were <5 years post diagnosis and from Northern Ireland. For hot flashes/sweats, 3% of participants (8% who experienced symptoms) received mediations; this was higher in men who had EBRT. Of those who reported depression, 28% received medication; receipt was highest in younger men and in Northern Ireland. Medication for bowel problems was used by 35% of men who experienced these; use was highest in older men, those diagnosed more recently, and those who had EBRT. Sixty percent of men reported having been told they would become infertile; 11 (0.3% of participants) preserved their sperm, 7 from the Republic of Ireland and 4 from Northern Ireland.

A total of 35.6% of survivors reported any decisional regret. Among survivors who ever had an after-effect, a higher percentage of those who used a supportive intervention reported decisional regret compared with those who did not; this was only statistically significant for those using medication or alprostadil injections for impotence (Table 2).
 

Discussion

This study documents, for the first time, population-based data on patient-reported use of supportive medications and interventions to alleviate adverse effects of prostate cancer and its treatment. Among survivors who experienced after-effects, use was highest for bowel problems, impotence, and depression, but even for those, only 28%-35% of men took medication. Although it is possible that some survivors declined medications or other interventions, these low levels of use strongly suggest that not all survivors who might benefit from supports receive them.

There was little evidence that utilisation was higher in survivors diagnosed more recently. This suggests that, although the number of prostate cancer survivors has grown, and there is greater focus on survivorship issues in clinical practice, this has not translated into more men receiving support to manage after-effects. Care is needed to ensure that the newer models of post-cancer follow-up being considered or adopted in many settings,⁹ do not exacerbate this issue.

As expected, patterns of utilisation varied by treatment(s) received. Higher use of surgical and pharmaceutical interventions to alleviate incontinence among survivors in the Republic of Ireland than in Northern Ireland is likely owing to the higher rate of radical prostatectomy in the Republic of Ireland, whereas greater use of treatments for gynaecomastia in Northern Ireland reflects higher use of hormone therapy there.¹⁰ Other variations in intervention use were more surprising. Younger men were significantly more likely to report using supportive interventions for depression and impotence, the latter finding being consistent with findings in a Swedish population-based study.¹¹ Older men were significantly more likely to report interventions for incontinence and bowel problems. Although those trends could be explained by differences in treatment receipt by age, it is possible that men of different ages may be more likely to seek, or be offered, help for certain types of after-effects. With the exception of interventions for bowel problems, a higher percentage of men who received intervention(s) for an after-effect reported decisional regret. There are a number of possible explanations: these men may have experienced more severe after-effects, which required interventions; they may have been less satisfied with their posttreatment function and/or more proactive about recovering or treating their after-effects. This requires further investigation.

This is a large, international, population-based study, the first such study to describe patient-reported use of supportive care following a range of prostate cancer treatments. Although this study is novel, there are a number of limitations. It is a cross-sectional, descriptive study. We did not ask survivors whether the supportive interventions received matched their needs and wants, and whether they were satisfied with the supportive care received. Furthermore, although the response rate is comparable with other similar studies,^12,13 it is possible that the supportive care of nonresponders was different to that of responders.

Our study included men from 2 jurisdictions with separate health care systems, suggesting that low use of supportive interventions may be common across systems. There is a need for further research into patient and health care system factors associated with the receipt of supportive interventions and how satisfied men are with these, in this and other health care settings. Presently, it is clear that more needs to be done in the clinical setting to support prostate cancer survivors manage treatment after-effects; this in turn could improve survivors’ HRQoL.

For patients with cancer, acknowledgment of mental and emotional distress is critically important when developing and implementing a treatment plan. The psychosocial distress associated with cancer diagnosis and treatment can have an impact on a patient’s quality of life, influence a patient’s ability to adhere to treatment regimens, and increase cost of care.^1-4 Rates of depression have been reported to range from 8%-36%, with a 29% risk of anxiety in cancer patients.^{5, 6} Emotional distress is linked to increased hopelessness about their cancer diagnosis, increased issues with chronic pain, and negative treatment outcomes.⁷ Timely screening of psychosocial distress at the first clinical visit enables providers to make appropriate referrals to resources early in their course of treatment; however, referrals to psychosocial interventions remain infrequent nationwide in the United States.⁸

There is some evidence of a differential impact of cancer on mental health diagnoses between racial/ethnic groups; however, results are not entirely consistent across studies. Using the Kessler Pyschological Distress Scale (K6) score, Alcala and colleagues found that cancer was more detrimental to mental health for black patients than for non-Hispanic white patients.⁹ Black breast cancer survivors have also been shown to be more likely to stop working during the early phases of their treatment, indicating that they and their physicians need to take steps to minimize long-term employment consequences.¹⁰ However, in a study of women with breast cancer, black women reported fewer depressive symptoms than did non-Hispanic whites.¹¹

The American College of Surgeons’ Commission on Cancer (ACS CoC) developed a set of Continuum of Care standards in 2012, including the implementation of psychosocial distress screening for patients with cancer. Since 2015, all accredited cancer programs are now required to evaluate these patients for signs of distress during at least 1 pivotal physician visit.¹² The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology has developed a tool that provides a mechanism for meeting the requirements of the ACS CoC accreditation requirements. The NCCN defines distress in cancer as “a multifactorial unpleasant emotional experience of a psychological (cognitive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment.”¹³ The recommendation of the NCCN is to provide a brief screening for psychosocial distress to identify individuals in need of additional support and to provide referrals for patients at high risk of psychosocial distress. The NCCN Distress Thermometer screening tool has been widely accepted as an effective method of identifying and characterizing distress. The NCCN tool provides a visual analogue scale for patients to rate their current distress on a scale of 1-10, as well as a problem checklist. The problem checklist includes 22 stressors addressing the practical, spiritual/religious, emotional, and physical concerns of patients. Although the NCCN tool is used widely, differences in distress scores between black and white cancer patients have not been previously described. The purpose of the study was to compare the global distress screening scores of black and white patients at an academic comprehensive cancer center in the Midwest. A second objective was to examine the distribution of individual stressors between black and white women.
 

Methods

Study sample

The study included all cancer patients from a cancer center in the Midwest who completed the NCCN distress thermometer during January 1, 2015-February 19, 2016. The patient population for this cancer center was primarily non-Hispanic white and non-Hispanic black, therefore, only patients identifying as non-Hispanic white and non-Hispanic black are included in this analysis. As part of routine clinical care, patients are asked to complete the NCCN distress thermometer at their first visit to the center. All patients in this analytic sample were newly diagnosed patients. Some patients also completed the NCCN screening tool at additional appointments; therefore, for patients with more than 1 completed tool, only the first distress screening was used in this analysis. Overall scores and individual stressor scores were entered into the electronic medical record by clinic staff at the time the patients were roomed for their visit. Patient demographics were collected through a reporting mechanism within the electronic medical record that allows for monitoring of the psychosocial screening process.
 

Variables

Race was assessed through self-report and classified as non-Hispanic white and non-Hispanic black. There were not enough patients of any other racial/ethnic group to be included in this analysis. Age was categorized as 18-40 years, 41-60 years, 61-84 years, and 85 years and older. Cancer type was grouped as follows: head and neck cancer, gastrointestinal cancer (esophagus, stomach, small intestine, colon, rectum, anus), hepatobiliary (liver, gallbladder, pancreas), sarcoma (bone and soft tissue), melanoma, nonmelanoma skin cancer, breast cancer, genitourinary (prostate, kidney, bladder), hematologic, and brain.

Two primary outcomes were assessed: overall distress, and each individual problem indicator. Overall distress was assessed using the thermometer visual analog rating (the thermometer rating of the NCCN screening tool) where possible values range from 0 (no distress) to 10 (extreme distress). The overall distress score was categorized into low distress (<4) and high distress (≥4) for analysis. The response options for individual stressors on the problem list are Yes or No for each of 17 discrete stressors: child care, housing, insurance/financial, transportation, work/school, treatment decisions, dealing with children, dealing with partner, ability to have children, family health issues, depression, fears, nervousness, sadness, worry, loss of interest, and spiritual/religious concerns. Physical complaints were not assessed in this study. Comparisons were made between white and black patients on overall distress score as well as for each individual psychosocial stressor.
 

Data analysis

Descriptive statistics (counts and proportions or means and standard deviations) were calculated stratified by race. Categorical variables were compared by race using chi-square or Fisher exact test. Logistic regression was used to predict high distress by race adjusting for sex, age, and cancer type. All analyses were conducted using SAS 9.4 (Cary, NJ).

This study was reviewed and approved by the Saint Louis University Institutional Review Board (protocol number 26269).
 

Results

A total of 933 patients with cancer completed the NCCN distress screening tool. Of that total, 45 patients did not complete the overall distress score thermometer, but did complete the checklist of individual stressors. Those 45 patients were excluded from the logistic regression analysis for overall distress score, but included on comparisons of individual stressors. The distribution of overall distress scores by race can be seen in the Figure.

Table 2 presents bivariate comparisons on overall distress and individual stressors between black and white patients. There was no difference in the high distress between black and white patients in bivariate analysis (31.9% and 36.1%, respectively, P = .30). However, there were differences in the individual stressors identified for each racial group (Table 2). White patients, compared with black patients, more frequently identified treatment decisions (17.6% vs 10.1%, P = .02) and nervousness (26.8% vs 18.4%, P = .02) as sources of distress. Black patients, compared with white patients, more frequently identified housing (5.1% vs 1.7%, P = .009), the ability to have children (2.5% vs 0.4%, P =.02), and loss of interest (15.2% vs 8.9%, P = .02) as sources of distress. Distress scores did not differ between black and white patients for child care, insurance or financial issues, transportation, work or school, dealing with children, dealing with partners, family health issues, depression, fears, sadness, worry, or spiritual or religious concerns.

Discussion

Management of patients with cancer continues to evolve. Although a tremendous amount of importance is still placed on the pathophysiology of cancer and its prescribed treatments, more emphasis is being assigned to the physical and psychosocial effects of cancer on these patients. In 2008, the Institute of Medicine published a report that examined the psychosocial health of patients with cancer.¹⁴ The report recommended that all cancer care should ensure the provision of appropriate psychosocial health services by facilitating effective communication between patients and care providers, identifying each patient’s psychosocial health needs, coordinating referrals for psychosocial services and monitoring efficacy of psychosocial interventions. The inclusion of psychosocial distress screening in all cancer programs accredited by the ACS CoC helped to prioritize the identification and treatment of psychosocial issues for all cancer patients.

The present study is the first of its kind to compare the individual stressors identified through psychosocial distress screening between black and white cancer patients. In our sample, 304 of 933 patients (32%) reported high distress, with a total score of ≥4. Previous research on overall distress difference across race/ethnicity is mixed. VanHoose and colleagues found no difference in overall distress between racial groups,¹⁵ Alcala and colleagues found higher overall distress in black patients with cancer compared with white patients with cancer,⁹ and Culver and colleagues found black women with breast cancer had lower overall distress compared with white women.¹¹ We found no difference in the presence of high distress between black and white patients at our cancer center in either crude or adjusted analysis. Differences in overall distress across studies may be owing to the timing of screening. Given that overall distress may vary across time^16,17 and there is no current information on whether temporal variations in distress differ by race, it is possible that the time of distress assessment may influence demonstrated differences between racial groups. For example, if different stressors affect black and white women differentially, and those stressors are associated with different points across the cancer continuum, then we might see that the magnitude of racial differences in overall stress are time dependent. Alcala and colleagues examined any cancer diagnosis across the lifespan, whereas Culver and colleagues examined multiple time points across treatment for a small group of breast cancer patients. Badr and colleagues, in a sample of head and neck cancer patients, found that distress increased across the course of treatment;¹⁸ however they did not examine variations in type of stressors related to overall distress, nor did they examine racial differences in distress. Differences in results may also be the result of differences in measurement of distress. Culver and colleagues did not examine distress using the NCCN distress thermometer, rather psychological distress was measured by a scale rating a series of “mood-descriptive adjectives” (p. 497).¹¹ Alcala used the K-6 as a measure of psychological distress;⁹ therefore, demonstrated differences in overall distress between white and black women may vary across studies because of differences in measurement of the underlying distress variable. The lack of racial differences in overall distress in our study is consistent with the findings of VanHoose and colleagues,¹⁵ who also examined distress near the start of treatment and also used the NCCN distress thermometer as the measure of psychosocial distress.

We did find differences in the individual stressors between racial groups, indicating that the source of distress does vary between black and white cancer patients. Black patients more frequently reported distress secondary to housing, loss of interest and their ability to have children than did white patients. By comparison, white patients more frequently reported distress secondary to nervousness and treatment decisions than black patients. Identified differences in individual stressors may be attributable to sociocultural differences or differences in external support. It is also possible that black patients are more likely to willingly report distress related to nonpsychological factors, whereas white patients are more willing to report factors, such as nervousness, that are related to psychological disorders. Although it has been suggested that black cancer patients have more concerns about finances and work than do white cancer patients,¹⁹ we did not identify a statistically significant difference in child care, insurance or financial issues, transportation, work, or school between these 2 cohorts. This may be because the psychosocial distress screening score included in this study was performed at the time of initial diagnosis, and not further into their prescribed treatment at which point the financial worries may be more realized. Psychosocial screening scores obtained at subsequent visits were not included in the analysis because they are not routinely collected as part of clinical care in the center where this study took place. Furthermore, it is impossible to identify where a specific patient is in their treatment regimen based on their demographic data or subsequent distress scores in our data extraction tool. Further investigation into the sources of distress at different time points along the continuum of care may shed more light on this topic.
 

Limitations

There are several limitations to this study. First, the method of data extraction from an electronic medical record report limited the capacity to explore possible differences between the patients in our sample, such as insurance status, level of education, available social support, current employment status, stage of disease, overall prognosis and prescribed treatment regimen.

Second, there were likely patients who either did not complete a psychosocial distress screening tool or whose data were not entered into the electronic medical record for inclusion in the analysis. The present study period took place during the implementation of the NCCN tool at the center. Although the policy was to screen all new patients as part of routine care; not all patients seen at the center received the NCCN screening tool at their first visit. Owing to the mechanisms for data entry and abstraction, only information from the patients who had a completed form was able to be accessed for this study, thus a statistical comparison between those who did and did not receive the NCCN tool cannot be made. During the timeframe for this study, the head and neck, breast, genitourinary, and hematologic services completed proportionally more NCCN screening of new patients than other services in the center. This is reflected in the distributional breakdown of cancer in the overall sample of this study. It is possible that the results are more representative of differences between black and white cancer patients in the services that were more likely to properly implement NCCN screening.

Third, our patient population was derived from an urban, academic medical center and the results may not be generalizable to other patient populations.

Fourth, the NCCN distress thermometer is a single-item rating of overall global distress that is not intended to be a diagnostic indicator of psychological comorbidity and, therefore, does not distinguish between common psychological diagnoses such as depression or anxiety. However, the usefulness of the tool is to provide an impetus for referral to services that may then encompass the evaluation and diagnosis of particular psychological conditions. Further, the distress thermometer tool is designed to identify stress relating to the social aspects of cancer diagnosis and treatment and is not limited to psychological distress alone.
 

Strengths

Despite the limitations, there are also significant strengths to this study. The NCCN tool is a widely accepted measure for the assessment of psychosocial distress in patients with cancer. The measure is a common and routine clinical instrument,²⁰ and has also been used widely in research.^18,21-24 Given the urban, academic environment of our clinical practice, our population is more racially diverse than other settings, allowing for initial examination of disparities between white and black cancer patients.
 

Clinical implications

Understanding differences in common psychosocial stressor between black and white cancer patients may allow for clinicians to strategically look for different types of stressors in order to facilitate faster referrals to appropriate services. It has been established in the literature that distress is correlated to cancer-related outcomes and distress screening is now considered standard of care when treating cancer patients. Identifying differences in psychosocial stressors among black and white cancer patients is paramount to ensuring that the appropriate resources are available to assist them through their cancer journey. The differences in type of stressor, may indicate fundamental differences in the way patients perceive their disease or the social and cultural implication of a cancer diagnosis. In this study, white patients were more likely to find distress in the psychological realm (nervousness, decision-making), whereas black patients were more likely to be distressed about social issues (housing, ability to have children, and loss of interest). The referral needs of patients may be quite different, even with similar levels of overall distress. More research is necessary to further characterize sources of distress for cancer patients, how this distress impacts a patient’s physical and emotional well-being and how health care providers can better identify these issues and make the necessary referrals to support the whole patient.

For patients with cancer, acknowledgment of mental and emotional distress is critically important when developing and implementing a treatment plan. The psychosocial distress associated with cancer diagnosis and treatment can have an impact on a patient’s quality of life, influence a patient’s ability to adhere to treatment regimens, and increase cost of care.^1-4 Rates of depression have been reported to range from 8%-36%, with a 29% risk of anxiety in cancer patients.^{5, 6} Emotional distress is linked to increased hopelessness about their cancer diagnosis, increased issues with chronic pain, and negative treatment outcomes.⁷ Timely screening of psychosocial distress at the first clinical visit enables providers to make appropriate referrals to resources early in their course of treatment; however, referrals to psychosocial interventions remain infrequent nationwide in the United States.⁸

There is some evidence of a differential impact of cancer on mental health diagnoses between racial/ethnic groups; however, results are not entirely consistent across studies. Using the Kessler Pyschological Distress Scale (K6) score, Alcala and colleagues found that cancer was more detrimental to mental health for black patients than for non-Hispanic white patients.⁹ Black breast cancer survivors have also been shown to be more likely to stop working during the early phases of their treatment, indicating that they and their physicians need to take steps to minimize long-term employment consequences.¹⁰ However, in a study of women with breast cancer, black women reported fewer depressive symptoms than did non-Hispanic whites.¹¹

The American College of Surgeons’ Commission on Cancer (ACS CoC) developed a set of Continuum of Care standards in 2012, including the implementation of psychosocial distress screening for patients with cancer. Since 2015, all accredited cancer programs are now required to evaluate these patients for signs of distress during at least 1 pivotal physician visit.¹² The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology has developed a tool that provides a mechanism for meeting the requirements of the ACS CoC accreditation requirements. The NCCN defines distress in cancer as “a multifactorial unpleasant emotional experience of a psychological (cognitive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment.”¹³ The recommendation of the NCCN is to provide a brief screening for psychosocial distress to identify individuals in need of additional support and to provide referrals for patients at high risk of psychosocial distress. The NCCN Distress Thermometer screening tool has been widely accepted as an effective method of identifying and characterizing distress. The NCCN tool provides a visual analogue scale for patients to rate their current distress on a scale of 1-10, as well as a problem checklist. The problem checklist includes 22 stressors addressing the practical, spiritual/religious, emotional, and physical concerns of patients. Although the NCCN tool is used widely, differences in distress scores between black and white cancer patients have not been previously described. The purpose of the study was to compare the global distress screening scores of black and white patients at an academic comprehensive cancer center in the Midwest. A second objective was to examine the distribution of individual stressors between black and white women.
 

Methods

Study sample

The study included all cancer patients from a cancer center in the Midwest who completed the NCCN distress thermometer during January 1, 2015-February 19, 2016. The patient population for this cancer center was primarily non-Hispanic white and non-Hispanic black, therefore, only patients identifying as non-Hispanic white and non-Hispanic black are included in this analysis. As part of routine clinical care, patients are asked to complete the NCCN distress thermometer at their first visit to the center. All patients in this analytic sample were newly diagnosed patients. Some patients also completed the NCCN screening tool at additional appointments; therefore, for patients with more than 1 completed tool, only the first distress screening was used in this analysis. Overall scores and individual stressor scores were entered into the electronic medical record by clinic staff at the time the patients were roomed for their visit. Patient demographics were collected through a reporting mechanism within the electronic medical record that allows for monitoring of the psychosocial screening process.
 

Variables

Race was assessed through self-report and classified as non-Hispanic white and non-Hispanic black. There were not enough patients of any other racial/ethnic group to be included in this analysis. Age was categorized as 18-40 years, 41-60 years, 61-84 years, and 85 years and older. Cancer type was grouped as follows: head and neck cancer, gastrointestinal cancer (esophagus, stomach, small intestine, colon, rectum, anus), hepatobiliary (liver, gallbladder, pancreas), sarcoma (bone and soft tissue), melanoma, nonmelanoma skin cancer, breast cancer, genitourinary (prostate, kidney, bladder), hematologic, and brain.

Two primary outcomes were assessed: overall distress, and each individual problem indicator. Overall distress was assessed using the thermometer visual analog rating (the thermometer rating of the NCCN screening tool) where possible values range from 0 (no distress) to 10 (extreme distress). The overall distress score was categorized into low distress (<4) and high distress (≥4) for analysis. The response options for individual stressors on the problem list are Yes or No for each of 17 discrete stressors: child care, housing, insurance/financial, transportation, work/school, treatment decisions, dealing with children, dealing with partner, ability to have children, family health issues, depression, fears, nervousness, sadness, worry, loss of interest, and spiritual/religious concerns. Physical complaints were not assessed in this study. Comparisons were made between white and black patients on overall distress score as well as for each individual psychosocial stressor.
 

Data analysis

Descriptive statistics (counts and proportions or means and standard deviations) were calculated stratified by race. Categorical variables were compared by race using chi-square or Fisher exact test. Logistic regression was used to predict high distress by race adjusting for sex, age, and cancer type. All analyses were conducted using SAS 9.4 (Cary, NJ).

This study was reviewed and approved by the Saint Louis University Institutional Review Board (protocol number 26269).
 

Results

A total of 933 patients with cancer completed the NCCN distress screening tool. Of that total, 45 patients did not complete the overall distress score thermometer, but did complete the checklist of individual stressors. Those 45 patients were excluded from the logistic regression analysis for overall distress score, but included on comparisons of individual stressors. The distribution of overall distress scores by race can be seen in the Figure.

Table 2 presents bivariate comparisons on overall distress and individual stressors between black and white patients. There was no difference in the high distress between black and white patients in bivariate analysis (31.9% and 36.1%, respectively, P = .30). However, there were differences in the individual stressors identified for each racial group (Table 2). White patients, compared with black patients, more frequently identified treatment decisions (17.6% vs 10.1%, P = .02) and nervousness (26.8% vs 18.4%, P = .02) as sources of distress. Black patients, compared with white patients, more frequently identified housing (5.1% vs 1.7%, P = .009), the ability to have children (2.5% vs 0.4%, P =.02), and loss of interest (15.2% vs 8.9%, P = .02) as sources of distress. Distress scores did not differ between black and white patients for child care, insurance or financial issues, transportation, work or school, dealing with children, dealing with partners, family health issues, depression, fears, sadness, worry, or spiritual or religious concerns.

Discussion

Management of patients with cancer continues to evolve. Although a tremendous amount of importance is still placed on the pathophysiology of cancer and its prescribed treatments, more emphasis is being assigned to the physical and psychosocial effects of cancer on these patients. In 2008, the Institute of Medicine published a report that examined the psychosocial health of patients with cancer.¹⁴ The report recommended that all cancer care should ensure the provision of appropriate psychosocial health services by facilitating effective communication between patients and care providers, identifying each patient’s psychosocial health needs, coordinating referrals for psychosocial services and monitoring efficacy of psychosocial interventions. The inclusion of psychosocial distress screening in all cancer programs accredited by the ACS CoC helped to prioritize the identification and treatment of psychosocial issues for all cancer patients.

The present study is the first of its kind to compare the individual stressors identified through psychosocial distress screening between black and white cancer patients. In our sample, 304 of 933 patients (32%) reported high distress, with a total score of ≥4. Previous research on overall distress difference across race/ethnicity is mixed. VanHoose and colleagues found no difference in overall distress between racial groups,¹⁵ Alcala and colleagues found higher overall distress in black patients with cancer compared with white patients with cancer,⁹ and Culver and colleagues found black women with breast cancer had lower overall distress compared with white women.¹¹ We found no difference in the presence of high distress between black and white patients at our cancer center in either crude or adjusted analysis. Differences in overall distress across studies may be owing to the timing of screening. Given that overall distress may vary across time^16,17 and there is no current information on whether temporal variations in distress differ by race, it is possible that the time of distress assessment may influence demonstrated differences between racial groups. For example, if different stressors affect black and white women differentially, and those stressors are associated with different points across the cancer continuum, then we might see that the magnitude of racial differences in overall stress are time dependent. Alcala and colleagues examined any cancer diagnosis across the lifespan, whereas Culver and colleagues examined multiple time points across treatment for a small group of breast cancer patients. Badr and colleagues, in a sample of head and neck cancer patients, found that distress increased across the course of treatment;¹⁸ however they did not examine variations in type of stressors related to overall distress, nor did they examine racial differences in distress. Differences in results may also be the result of differences in measurement of distress. Culver and colleagues did not examine distress using the NCCN distress thermometer, rather psychological distress was measured by a scale rating a series of “mood-descriptive adjectives” (p. 497).¹¹ Alcala used the K-6 as a measure of psychological distress;⁹ therefore, demonstrated differences in overall distress between white and black women may vary across studies because of differences in measurement of the underlying distress variable. The lack of racial differences in overall distress in our study is consistent with the findings of VanHoose and colleagues,¹⁵ who also examined distress near the start of treatment and also used the NCCN distress thermometer as the measure of psychosocial distress.

We did find differences in the individual stressors between racial groups, indicating that the source of distress does vary between black and white cancer patients. Black patients more frequently reported distress secondary to housing, loss of interest and their ability to have children than did white patients. By comparison, white patients more frequently reported distress secondary to nervousness and treatment decisions than black patients. Identified differences in individual stressors may be attributable to sociocultural differences or differences in external support. It is also possible that black patients are more likely to willingly report distress related to nonpsychological factors, whereas white patients are more willing to report factors, such as nervousness, that are related to psychological disorders. Although it has been suggested that black cancer patients have more concerns about finances and work than do white cancer patients,¹⁹ we did not identify a statistically significant difference in child care, insurance or financial issues, transportation, work, or school between these 2 cohorts. This may be because the psychosocial distress screening score included in this study was performed at the time of initial diagnosis, and not further into their prescribed treatment at which point the financial worries may be more realized. Psychosocial screening scores obtained at subsequent visits were not included in the analysis because they are not routinely collected as part of clinical care in the center where this study took place. Furthermore, it is impossible to identify where a specific patient is in their treatment regimen based on their demographic data or subsequent distress scores in our data extraction tool. Further investigation into the sources of distress at different time points along the continuum of care may shed more light on this topic.
 

Limitations

There are several limitations to this study. First, the method of data extraction from an electronic medical record report limited the capacity to explore possible differences between the patients in our sample, such as insurance status, level of education, available social support, current employment status, stage of disease, overall prognosis and prescribed treatment regimen.

Second, there were likely patients who either did not complete a psychosocial distress screening tool or whose data were not entered into the electronic medical record for inclusion in the analysis. The present study period took place during the implementation of the NCCN tool at the center. Although the policy was to screen all new patients as part of routine care; not all patients seen at the center received the NCCN screening tool at their first visit. Owing to the mechanisms for data entry and abstraction, only information from the patients who had a completed form was able to be accessed for this study, thus a statistical comparison between those who did and did not receive the NCCN tool cannot be made. During the timeframe for this study, the head and neck, breast, genitourinary, and hematologic services completed proportionally more NCCN screening of new patients than other services in the center. This is reflected in the distributional breakdown of cancer in the overall sample of this study. It is possible that the results are more representative of differences between black and white cancer patients in the services that were more likely to properly implement NCCN screening.

Third, our patient population was derived from an urban, academic medical center and the results may not be generalizable to other patient populations.

Fourth, the NCCN distress thermometer is a single-item rating of overall global distress that is not intended to be a diagnostic indicator of psychological comorbidity and, therefore, does not distinguish between common psychological diagnoses such as depression or anxiety. However, the usefulness of the tool is to provide an impetus for referral to services that may then encompass the evaluation and diagnosis of particular psychological conditions. Further, the distress thermometer tool is designed to identify stress relating to the social aspects of cancer diagnosis and treatment and is not limited to psychological distress alone.
 

Strengths

Despite the limitations, there are also significant strengths to this study. The NCCN tool is a widely accepted measure for the assessment of psychosocial distress in patients with cancer. The measure is a common and routine clinical instrument,²⁰ and has also been used widely in research.^18,21-24 Given the urban, academic environment of our clinical practice, our population is more racially diverse than other settings, allowing for initial examination of disparities between white and black cancer patients.
 

Clinical implications

Understanding differences in common psychosocial stressor between black and white cancer patients may allow for clinicians to strategically look for different types of stressors in order to facilitate faster referrals to appropriate services. It has been established in the literature that distress is correlated to cancer-related outcomes and distress screening is now considered standard of care when treating cancer patients. Identifying differences in psychosocial stressors among black and white cancer patients is paramount to ensuring that the appropriate resources are available to assist them through their cancer journey. The differences in type of stressor, may indicate fundamental differences in the way patients perceive their disease or the social and cultural implication of a cancer diagnosis. In this study, white patients were more likely to find distress in the psychological realm (nervousness, decision-making), whereas black patients were more likely to be distressed about social issues (housing, ability to have children, and loss of interest). The referral needs of patients may be quite different, even with similar levels of overall distress. More research is necessary to further characterize sources of distress for cancer patients, how this distress impacts a patient’s physical and emotional well-being and how health care providers can better identify these issues and make the necessary referrals to support the whole patient.

For patients with cancer, acknowledgment of mental and emotional distress is critically important when developing and implementing a treatment plan. The psychosocial distress associated with cancer diagnosis and treatment can have an impact on a patient’s quality of life, influence a patient’s ability to adhere to treatment regimens, and increase cost of care.^1-4 Rates of depression have been reported to range from 8%-36%, with a 29% risk of anxiety in cancer patients.^{5, 6} Emotional distress is linked to increased hopelessness about their cancer diagnosis, increased issues with chronic pain, and negative treatment outcomes.⁷ Timely screening of psychosocial distress at the first clinical visit enables providers to make appropriate referrals to resources early in their course of treatment; however, referrals to psychosocial interventions remain infrequent nationwide in the United States.⁸

There is some evidence of a differential impact of cancer on mental health diagnoses between racial/ethnic groups; however, results are not entirely consistent across studies. Using the Kessler Pyschological Distress Scale (K6) score, Alcala and colleagues found that cancer was more detrimental to mental health for black patients than for non-Hispanic white patients.⁹ Black breast cancer survivors have also been shown to be more likely to stop working during the early phases of their treatment, indicating that they and their physicians need to take steps to minimize long-term employment consequences.¹⁰ However, in a study of women with breast cancer, black women reported fewer depressive symptoms than did non-Hispanic whites.¹¹

The American College of Surgeons’ Commission on Cancer (ACS CoC) developed a set of Continuum of Care standards in 2012, including the implementation of psychosocial distress screening for patients with cancer. Since 2015, all accredited cancer programs are now required to evaluate these patients for signs of distress during at least 1 pivotal physician visit.¹² The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology has developed a tool that provides a mechanism for meeting the requirements of the ACS CoC accreditation requirements. The NCCN defines distress in cancer as “a multifactorial unpleasant emotional experience of a psychological (cognitive, behavioral, emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms and its treatment.”¹³ The recommendation of the NCCN is to provide a brief screening for psychosocial distress to identify individuals in need of additional support and to provide referrals for patients at high risk of psychosocial distress. The NCCN Distress Thermometer screening tool has been widely accepted as an effective method of identifying and characterizing distress. The NCCN tool provides a visual analogue scale for patients to rate their current distress on a scale of 1-10, as well as a problem checklist. The problem checklist includes 22 stressors addressing the practical, spiritual/religious, emotional, and physical concerns of patients. Although the NCCN tool is used widely, differences in distress scores between black and white cancer patients have not been previously described. The purpose of the study was to compare the global distress screening scores of black and white patients at an academic comprehensive cancer center in the Midwest. A second objective was to examine the distribution of individual stressors between black and white women.
 

Methods

Study sample

The study included all cancer patients from a cancer center in the Midwest who completed the NCCN distress thermometer during January 1, 2015-February 19, 2016. The patient population for this cancer center was primarily non-Hispanic white and non-Hispanic black, therefore, only patients identifying as non-Hispanic white and non-Hispanic black are included in this analysis. As part of routine clinical care, patients are asked to complete the NCCN distress thermometer at their first visit to the center. All patients in this analytic sample were newly diagnosed patients. Some patients also completed the NCCN screening tool at additional appointments; therefore, for patients with more than 1 completed tool, only the first distress screening was used in this analysis. Overall scores and individual stressor scores were entered into the electronic medical record by clinic staff at the time the patients were roomed for their visit. Patient demographics were collected through a reporting mechanism within the electronic medical record that allows for monitoring of the psychosocial screening process.
 

Variables

Race was assessed through self-report and classified as non-Hispanic white and non-Hispanic black. There were not enough patients of any other racial/ethnic group to be included in this analysis. Age was categorized as 18-40 years, 41-60 years, 61-84 years, and 85 years and older. Cancer type was grouped as follows: head and neck cancer, gastrointestinal cancer (esophagus, stomach, small intestine, colon, rectum, anus), hepatobiliary (liver, gallbladder, pancreas), sarcoma (bone and soft tissue), melanoma, nonmelanoma skin cancer, breast cancer, genitourinary (prostate, kidney, bladder), hematologic, and brain.

Two primary outcomes were assessed: overall distress, and each individual problem indicator. Overall distress was assessed using the thermometer visual analog rating (the thermometer rating of the NCCN screening tool) where possible values range from 0 (no distress) to 10 (extreme distress). The overall distress score was categorized into low distress (<4) and high distress (≥4) for analysis. The response options for individual stressors on the problem list are Yes or No for each of 17 discrete stressors: child care, housing, insurance/financial, transportation, work/school, treatment decisions, dealing with children, dealing with partner, ability to have children, family health issues, depression, fears, nervousness, sadness, worry, loss of interest, and spiritual/religious concerns. Physical complaints were not assessed in this study. Comparisons were made between white and black patients on overall distress score as well as for each individual psychosocial stressor.
 

Data analysis

Descriptive statistics (counts and proportions or means and standard deviations) were calculated stratified by race. Categorical variables were compared by race using chi-square or Fisher exact test. Logistic regression was used to predict high distress by race adjusting for sex, age, and cancer type. All analyses were conducted using SAS 9.4 (Cary, NJ).

This study was reviewed and approved by the Saint Louis University Institutional Review Board (protocol number 26269).
 

Results

A total of 933 patients with cancer completed the NCCN distress screening tool. Of that total, 45 patients did not complete the overall distress score thermometer, but did complete the checklist of individual stressors. Those 45 patients were excluded from the logistic regression analysis for overall distress score, but included on comparisons of individual stressors. The distribution of overall distress scores by race can be seen in the Figure.

Table 2 presents bivariate comparisons on overall distress and individual stressors between black and white patients. There was no difference in the high distress between black and white patients in bivariate analysis (31.9% and 36.1%, respectively, P = .30). However, there were differences in the individual stressors identified for each racial group (Table 2). White patients, compared with black patients, more frequently identified treatment decisions (17.6% vs 10.1%, P = .02) and nervousness (26.8% vs 18.4%, P = .02) as sources of distress. Black patients, compared with white patients, more frequently identified housing (5.1% vs 1.7%, P = .009), the ability to have children (2.5% vs 0.4%, P =.02), and loss of interest (15.2% vs 8.9%, P = .02) as sources of distress. Distress scores did not differ between black and white patients for child care, insurance or financial issues, transportation, work or school, dealing with children, dealing with partners, family health issues, depression, fears, sadness, worry, or spiritual or religious concerns.

Discussion

Management of patients with cancer continues to evolve. Although a tremendous amount of importance is still placed on the pathophysiology of cancer and its prescribed treatments, more emphasis is being assigned to the physical and psychosocial effects of cancer on these patients. In 2008, the Institute of Medicine published a report that examined the psychosocial health of patients with cancer.¹⁴ The report recommended that all cancer care should ensure the provision of appropriate psychosocial health services by facilitating effective communication between patients and care providers, identifying each patient’s psychosocial health needs, coordinating referrals for psychosocial services and monitoring efficacy of psychosocial interventions. The inclusion of psychosocial distress screening in all cancer programs accredited by the ACS CoC helped to prioritize the identification and treatment of psychosocial issues for all cancer patients.

The present study is the first of its kind to compare the individual stressors identified through psychosocial distress screening between black and white cancer patients. In our sample, 304 of 933 patients (32%) reported high distress, with a total score of ≥4. Previous research on overall distress difference across race/ethnicity is mixed. VanHoose and colleagues found no difference in overall distress between racial groups,¹⁵ Alcala and colleagues found higher overall distress in black patients with cancer compared with white patients with cancer,⁹ and Culver and colleagues found black women with breast cancer had lower overall distress compared with white women.¹¹ We found no difference in the presence of high distress between black and white patients at our cancer center in either crude or adjusted analysis. Differences in overall distress across studies may be owing to the timing of screening. Given that overall distress may vary across time^16,17 and there is no current information on whether temporal variations in distress differ by race, it is possible that the time of distress assessment may influence demonstrated differences between racial groups. For example, if different stressors affect black and white women differentially, and those stressors are associated with different points across the cancer continuum, then we might see that the magnitude of racial differences in overall stress are time dependent. Alcala and colleagues examined any cancer diagnosis across the lifespan, whereas Culver and colleagues examined multiple time points across treatment for a small group of breast cancer patients. Badr and colleagues, in a sample of head and neck cancer patients, found that distress increased across the course of treatment;¹⁸ however they did not examine variations in type of stressors related to overall distress, nor did they examine racial differences in distress. Differences in results may also be the result of differences in measurement of distress. Culver and colleagues did not examine distress using the NCCN distress thermometer, rather psychological distress was measured by a scale rating a series of “mood-descriptive adjectives” (p. 497).¹¹ Alcala used the K-6 as a measure of psychological distress;⁹ therefore, demonstrated differences in overall distress between white and black women may vary across studies because of differences in measurement of the underlying distress variable. The lack of racial differences in overall distress in our study is consistent with the findings of VanHoose and colleagues,¹⁵ who also examined distress near the start of treatment and also used the NCCN distress thermometer as the measure of psychosocial distress.

We did find differences in the individual stressors between racial groups, indicating that the source of distress does vary between black and white cancer patients. Black patients more frequently reported distress secondary to housing, loss of interest and their ability to have children than did white patients. By comparison, white patients more frequently reported distress secondary to nervousness and treatment decisions than black patients. Identified differences in individual stressors may be attributable to sociocultural differences or differences in external support. It is also possible that black patients are more likely to willingly report distress related to nonpsychological factors, whereas white patients are more willing to report factors, such as nervousness, that are related to psychological disorders. Although it has been suggested that black cancer patients have more concerns about finances and work than do white cancer patients,¹⁹ we did not identify a statistically significant difference in child care, insurance or financial issues, transportation, work, or school between these 2 cohorts. This may be because the psychosocial distress screening score included in this study was performed at the time of initial diagnosis, and not further into their prescribed treatment at which point the financial worries may be more realized. Psychosocial screening scores obtained at subsequent visits were not included in the analysis because they are not routinely collected as part of clinical care in the center where this study took place. Furthermore, it is impossible to identify where a specific patient is in their treatment regimen based on their demographic data or subsequent distress scores in our data extraction tool. Further investigation into the sources of distress at different time points along the continuum of care may shed more light on this topic.
 

Limitations

There are several limitations to this study. First, the method of data extraction from an electronic medical record report limited the capacity to explore possible differences between the patients in our sample, such as insurance status, level of education, available social support, current employment status, stage of disease, overall prognosis and prescribed treatment regimen.

Second, there were likely patients who either did not complete a psychosocial distress screening tool or whose data were not entered into the electronic medical record for inclusion in the analysis. The present study period took place during the implementation of the NCCN tool at the center. Although the policy was to screen all new patients as part of routine care; not all patients seen at the center received the NCCN screening tool at their first visit. Owing to the mechanisms for data entry and abstraction, only information from the patients who had a completed form was able to be accessed for this study, thus a statistical comparison between those who did and did not receive the NCCN tool cannot be made. During the timeframe for this study, the head and neck, breast, genitourinary, and hematologic services completed proportionally more NCCN screening of new patients than other services in the center. This is reflected in the distributional breakdown of cancer in the overall sample of this study. It is possible that the results are more representative of differences between black and white cancer patients in the services that were more likely to properly implement NCCN screening.

Third, our patient population was derived from an urban, academic medical center and the results may not be generalizable to other patient populations.

Fourth, the NCCN distress thermometer is a single-item rating of overall global distress that is not intended to be a diagnostic indicator of psychological comorbidity and, therefore, does not distinguish between common psychological diagnoses such as depression or anxiety. However, the usefulness of the tool is to provide an impetus for referral to services that may then encompass the evaluation and diagnosis of particular psychological conditions. Further, the distress thermometer tool is designed to identify stress relating to the social aspects of cancer diagnosis and treatment and is not limited to psychological distress alone.
 

Strengths

Despite the limitations, there are also significant strengths to this study. The NCCN tool is a widely accepted measure for the assessment of psychosocial distress in patients with cancer. The measure is a common and routine clinical instrument,²⁰ and has also been used widely in research.^18,21-24 Given the urban, academic environment of our clinical practice, our population is more racially diverse than other settings, allowing for initial examination of disparities between white and black cancer patients.
 

Clinical implications

Understanding differences in common psychosocial stressor between black and white cancer patients may allow for clinicians to strategically look for different types of stressors in order to facilitate faster referrals to appropriate services. It has been established in the literature that distress is correlated to cancer-related outcomes and distress screening is now considered standard of care when treating cancer patients. Identifying differences in psychosocial stressors among black and white cancer patients is paramount to ensuring that the appropriate resources are available to assist them through their cancer journey. The differences in type of stressor, may indicate fundamental differences in the way patients perceive their disease or the social and cultural implication of a cancer diagnosis. In this study, white patients were more likely to find distress in the psychological realm (nervousness, decision-making), whereas black patients were more likely to be distressed about social issues (housing, ability to have children, and loss of interest). The referral needs of patients may be quite different, even with similar levels of overall distress. More research is necessary to further characterize sources of distress for cancer patients, how this distress impacts a patient’s physical and emotional well-being and how health care providers can better identify these issues and make the necessary referrals to support the whole patient.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related death in men. ¹ Treatment choices for prostate cancer are perhaps more varied than for many other cancers, with surgery, external beam radiation therapy, and brachytherapy all widely used, a number of adjuvant and nonstandard therapy options available, as well as the possibility of not immediately treating the cancer – the “active surveillance” option.

Biochemical failure rates do not differ between the 3 main treatments,² but each exposes patients to the risk of side effects, including impotence, incontinence, rectal injury, and operative mortality. Recovery can be gradual and will not always involve a return to baseline functioning.³ Quality-of-life comparisons observed covariate-controlled decreases in varying specific aspects of quality of life for each of the treatments.⁴

Surgery, brachytherapy, and external beam radiation therapy have each shown advantages over other treatments on at least some specific aspect, but disadvantages on others.⁴ Ongoing surveillance of a cancer left in place has become a more common option in part because of the disadvantages of traditional treatment and because of the growing recognition that sensitive diagnosis techniques often locate cancers that might not be life threatening. Recent reviews and reasonably long-term trials portray active surveillance as a valid alternative to surgery and radiation in many cases, with little difference in life expectancy and cancer-related quality of life, and possibly some reduction in health system cost.^5-7

Prostate cancer patients cope with these uncertainties and decisions in many ways,⁸ often using multiple coping behaviors,⁹ but coping almost always includes seeking information and social support, as well as active problem-solving, to make informed treatment decisions consistent with their values.

Unfortunately, prostate patients often do not receive or use needed information. McGregor¹⁰ reported that patients were aware of their incomplete understanding of their disease and treatment options. Findings from several studies suggest that patients often perceive that clinicians inform them about the disease and treatment options but then send them home unprepared to deal with such things as incontinence or difficulties with sexual functioning.¹¹

Similarly, previous research demonstrates the benefits of social support for prostate cancer patients who receive it, but also that overall they are underserved.^12,13 Male cancer patients are generally far less likely to seek support and health information than are female patients. And when patients with prostate cancer do participate in online cancer support groups, they are more likely to exchange information, whereas breast cancer patients provide support for each other.¹⁴

Mentoring

Some responses to these knowledge and support gaps pair newly diagnosed patients with survivors willing to be a guide, coach, and a source of information, as in the American Cancer Society’s (ACS’s) Man-to-Man support groups.¹⁵ Peer mentors may have a sophisticated level of understanding from their own experiences with medical literature and the health care system, but this cannot be assumed. Another mentoring model is expert-based, exemplified by the National Cancer Institute’s (NCI’s) cancer information specialist at the Cancer Information Service (CIS) and a similar system at the ACS. These telephone services allow for responsiveness to the caller’s needs, existing knowledge, and the caller’s readiness for information. The CIS specialist can also introduce important information the caller might not have known to ask about.¹⁶

However, not all problems presented by callers can be solved in a single conversation. Callers are encouraged to call back with additional questions or when their situation changes, but speaking with the same specialist is not facilitated, so it is hard for a second call to build upon the first. Combining the expertise of the cancer information specialist with the ongoing and proactive contact and support typical of the lay guide/mentor/navigator could be more effective. Here a CIS-trained information specialist called prostate patients multiple times over the intervention period to help them deal with information seeking and interpretation. In a previous study with breast cancer patients, a mentor of this sort improved patient information competence and emotional processing.¹⁷

Interactive resources

Online resources allow cancer patients self-paced and self-directed access to information and support anonymously and at any time. However, this can be more complicated than it might at first seem. With the complexities of the prostate cancer diagnosis, the multiple treatment options, and the uncertain but potentially serious effects of the treatments themselves, the amount of potentially relevant information is quite large. Then, because individuals will value differentially the attributes of treatments, their consequences, or even notions of risk and gain, a system must be able to respond appropriately to a range of very different people. Beyond this, as prostate cancer patients move from the shock of a cancer diagnosis to the problems of interpreting its details, to making treatment decisions, to dealing with problems of recovery, and then re-establishing what is a “new normal” for them, an individual’s demands on a system vary as well. Comprehensive and integrated systems of services meet the varying needs of their users at different times and different situations.^18,19 The systems approach not only makes it far easier for users to find what they need, it may also encourage them to see connections between physical, emotional, and social aspects of their illness. Versions of the system used in the present study – CHESS, or Comprehensive Health Enhancement Support System – have been effective supporting patients with AIDS and breast and lung cancers, and teens with asthma.^16,20

Study goals and hypotheses

Given the success of the 2 aforementioned approaches, we wanted to compare how CHESS and ongoing contact with a human cancer information mentor in patients with prostate cancer would affect both several general aspects of quality of life and 1 specific to prostate cancer. We also examined differences in the patients’ information competence, quality of life, and social support. There was no a priori expectation that one intervention would be superior to the other, but any differences found could be important to policy decisions, given their quite-different cost and scalability.

More importantly, the primary hypothesis of the study was that patients with access to both CHESS and a mentor would experience substantially better outcomes than those with access to either intervention alone, because each had the potential to enhance the other’s benefits. For example, a patient could read CHESS material and come to the mentor much better prepared. By referring the user to specific parts of CHESS for basic information, the mentor could use calls to address more complex issues, or help interpret and evaluate difficult issues. In addition, because CHESS provides the mentor information about changes in the patient’s treatments, symptoms, and CHESS use, in the combined condition the cancer information mentor can know much more about the patient than when working alone. We also expected that the mentor would stimulate the kind of diverse use of CHESS services we have found to be most effective for improving quality of life.²¹ A previous study of CHESS for women with breast cancer concluded that a combined condition benefitted patients more than either CHESS or a cancer mentor alone,¹⁷ and we sought to determine whether we would have similar results with men with prostate cancer.

Because both mentoring and CHESS have consistently produced positive quality of life effects on their own, compared to controls, there is no reasonable expectation that negative effects of a combined condition could occur and should be tested for. Thus, the study was powered for 1-tailed significance in the comparison between the combined condition and either intervention alone, a procedure used consistently in previous studies of CHESS components or combined conditions. However, since the research question comparing the 2 interventions alone had no such strong history it was tested 2-tailed.
 

Methods

Recruitment

Study recruitment was conducted from January 1, 2007 to September 30, 2008 at the University of Wisconsin’s Paul P Carbone Comprehensive Cancer Center in Madison, Hartford Hospital’s Helen and Harry Gray Cancer Center in Hartford, Connecticut, and The University of Texas MD Anderson Cancer Center in Houston.

A total of 461 patients were invited to participate in the study. Of those patients, 147 declined to participate, 4 were excluded, and 310 were randomized to access to CHESS only, access to a human mentor only, or access to CHESS and a mentor (CHESS+Mentor) during the 6-month intervention period, which provided adequate power (>.80) for effects of moderate size (Figure 1). Randomization was done with a computer-generated list that site study managers accessed on a patient-by-patient basis, with experimental conditions blocked within sites.

Interventions

To provide an equal baseline, all of the participants were given access to the Internet, which is becoming a de facto standard for information access. Internet access charges were paid for all participants during the 6-month intervention period, and computers were loaned to those who did not have a personal computer. All of the participants were offered training on using the computer, particularly with Google search procedures so that they could access resources on prostate cancer.

Participants assigned to the CHESS or CHESS+Mentor conditions were also offered training in using CHESS (basically a guided tour), which typically took about 30 minutes on the telephone but was occasionally done in-person.

CHESS intervention. In creating CHESS for prostate cancer patients, a combination of patient needs assessments, focus groups with patients and family members, and clinician expertise helped us identify the needs, coping mechanisms, and relevant medical information to help patients respond to the disease. An article describing development of the CHESS Prostate Cancer Module²² presents how those different services address patient needs for information, communication, and support, or build skills.

Most of these services were present in CHESS for other diseases, but several were newly created to meet needs of prostate cancer patients and partners, such as a decision map tool and a module on managing sexual problems.²² Also, patients expressed frustration at being overwhelmed by the volume of information and said they would prefer to focus only on what was most relevant, so we created an alternative navigation structure on the CHESS homepage. Using terms suggested by focus groups of prostate cancer survivors and their spouses, we devised a navigation structure called Step-by-Step that identified 6 typical sequential steps of men’s experience with prostate cancer. Clicking on a step would take a patient to a menu focused on actions and considerations specific to that disease step, links to information most relevant at that step, and suggested questions to ask oneself and one’s doctor.

Mentor intervention. The cancer information mentor who made most of the calls to patients was an experienced information specialist with the Cancer Information Service and had served as the expert for the CHESS Ask an Expert service for 6 years. She was highly knowledgeable about prostate cancer and patient information needs. Her additional training for this study focused on taking advantage of repeated contacts with the participants and how to set limits to avoid any semblance of psychological counseling. At recruitment, we made clear that a male mentor was also available if the participant would prefer to discuss sensitive topics with another man. The male mentor was experienced in the Man-to-Man program and received additional training for this role, but he was used for only 1% of all contacts.

During calls, the mentor had Internet access to a range of NCI, ACS, and other resources. She could help interpret information the participant already possessed as well as refer him to other public resources, including those on the Internet. CHESS software designers created an additional interface for the mentor that handled call scheduling and allowed her to record the topics of conversations, her responses and recommendations, and her overall ratings of patient preparedness and satisfaction. Using this interface allowed the mentor to quickly review a participant’s status and focus the conversation on issues raised by past conversations or scheduled treatment events. The mentor calls were audiorecorded and reviewed frequently by the project director during the early months of intervention and less frequently thereafter to ensure adherence to the protocol.

The mentor telephoned weekly during the first month of intervention, then twice during the second month, and once a month during the final 4 months of the intervention (ie, 10 scheduled calls, though patients could also initiate additional calls). Calls were scheduled through a combination of telephone contact and e-mail according to the patient’s preference. Call length ranged from 5 minutes to an hour, with the average about 12 minutes (the first call tended to be considerably longer, and was scheduled for 45 minutes). About 10%-15% of participants in the Mentor conditions initiated calls to the mentor to obtain additional support, and about 15% of scheduled calls in fact took place as e-mail exchanges. A few calls were missed because of scheduling difficulties, and some participants stopped scheduling the last few calls, but the average number of full calls or e-mails was 6.41 per participant.

CHESS+Mentor intervention. For the CHESS+Mentor condition, the interactions and resources used were similar to those of the Mentor-only condition, but the interface also provided the mentor with a summary of the participant’s recent CHESS use and any concerns reported to CHESS, which helped the mentor assess knowledge and make tailored recommendations. The mentor could also refer participants to specific resources within CHESS, aided by knowledge of what parts of CHESS had or had not been used.

Assessment methods

Patients were given surveys at the baseline visit to complete and mail back to research staff before randomization. Follow-up surveys were mailed to patients at 2, 6, 12, and 24 weeks post intervention access, and patients returned the surveys by mail. Patient withdrawal rates were about 3%.

Measures

Outcomes. This study included 4 measures of quality of life (an average of relevant portions of the World Health Organization’s Quality of Life (WHOQOL) measure, Emotional and Functional Well-being, and a prostate-cancer specific index, the Expanded Prostate Cancer Index Composite (EPIC). We also tested group differences on 5 more specific outcomes that were likely to be proximal rather than distal effects of the interventions: Cancer Information Competence, Health care Competence, Social Support, Bonding (with other patients), and Positive Coping.



Quality of life. Quality of life was measured by combining the psychological, social, and overall dimensions of the WHOQOL measures.²³ Each of the 11 items was assessed with a 5-point scale, and the mean of those answers was the overall score.



Emotional well-being. Respondents answered 6 items of the Functional Assessment of Cancer Therapy – Prostate (FACT-P)²⁴ describing emotional aspects of reactions to cancer.



Functional well-being. Respondents indicated how often they experienced each of the seven functional well-being subscale items of the FACT-Prostate.²⁴



Prostate cancer patient functioning. We used the EPIC to measure of 3 of 4 domains of prostate cancer patient functioning: urinary, bowel, and sexual (omitting hormonal).²⁵ The EPIC measures frequency and subjective degree of being a problem of several aspects in each domain. We then summed scores across the domains and transformed linearly to a 0-100 scale, with higher scores representing better functioning.



Cancer information competence. Five cancer information competence items, measured on a 5-point scale, assessed a participant’s perception about whether he could find and effectively and use health information, and were summed to create a single score.²⁰



Social support. Six 5-point social support items assessed the informational and emotional support provided by friends, family, coworkers, and others, and were summed to create a single score.²⁰



Health care competence. Five 5-point health care competence items assessed a patient’s comfort and activation level dealing with physicians and health care situations, and were summed to create a single score.²⁰



Positive coping. Coping strategies were measured with the Brief Cope, a shorter version of the original 60-item COPE scale.²⁶ Positive coping strategy, a predictor of positive adaptation in numerous coping contexts, was measured with the mean score of 4 scales (8 items in all): active coping, planning, positive reframing, and humor.



Bonding. Bonding with other prostate cancer patients was measured with five 5-point items about how frequently participants connected with and got information and support from other men with prostate cancer.²⁷



User vs nonuser. Intent-to-treat analyses compared the assigned conditions. However, because CHESS use was self-selected and available at any time whereas mentor calls were scheduled and initiated by another person, the proportion actually using the interventions was quite different.

Since a participant assigned access to CHESS had to select the URL, even a single entry to the system was counted as use. Of 198 participants assigned to either the CHESS or CHESS+Mentor conditions, 43 (22%) never logged in and were classified as nonusers.

Because the mentor scheduled calls and attempted repeatedly to complete scheduled calls, the patient was in a reactive position, and the decision not to use the mentor’s services could come at the earliest at the end of a first completed call. However, after examining call notes and consulting with the mentors, it was clear that opting not to receive mentoring typically occurred at the second call. Furthermore, much (though not all) of the first call was typically taken up with getting acquainted and scheduling issues, so that defining “nonuse” as 2 or fewer completed calls was most faithful to what actually happened. Of 202 participants assigned access to a mentor, 16 (8%) were thus defined as nonusers.

Results

Overall, the participants were about 60 years of age and had some college education and middle-class incomes (Table 1). Only about 10% were minorities or lived alone, and their comfort using computers and the Internet was at or above the “quite comfortable” level. None of groups differed significantly from any other.

The 2 primary hypotheses of the study were that participants in the combined condition would manifest higher outcome scores than those with either intervention alone. Table 2 displays group means at 3 posttest intervals, controlling for theoretically chosen covariates (age, education, and minority status) and pretest levels of the dependent variable. The table also summarizes tests examining the hypotheses and the comparison of CHESS and Mentor conditions. The 4 quality-of-life scores appear first, followed by 5 more specific outcomes that are perhaps more proximal effects of these interventions.

Discussion

We used a randomized control design to test whether combining computer-based and human interventions would provide greater benefits to prostate cancer patients than either alone, as previous research had shown for breast cancer patients.¹⁸ The computer-based resource was CHESS, a repeatedly evaluated integrated system combining information, social support, and interactive tools to help patients manage their response to disease. The human cancer information mentor intervention combined the expertise of NCI’s Cancer Information Service with the repeated contact more typical of peer mentoring. Previous research with breast cancer patients had shown both interventions to provide greater information, support, and quality-of-life benefits than Internet access alone.¹⁴ This study also compared outcomes obtained by the separate CHESS and Mentor conditions, but without predicting a direction of difference.

Tests at 6 weeks, 3 months and 6 months after intervention found instances in which prostate cancer patients assigned to the combined CHESS+Mentor condition experienced more positive quality of life or other outcomes than those assigned to CHESS or Mentor alone, but those differences were scattered rather than consistent. In the direct comparisons of the separate CHESS and Mentor conditions, significance was even rarer, but outcome scores tended to be higher in the Mentor condition than in the CHESS condition.

We noted that differential uptake of the 2 interventions (92% for Mentor vs 78% for CHESS) made interpreting the intent-to-treat analyses problematic, as the mentor’s control of the call schedule meant that far more patients in that condition actually received at least some intervention than in the CHESS condition, where patients used or did not use CHESS entirely at their own volition. This could have biased results in several ways, such as by underestimating the efficacy of the CHESS condition alone and thus inflating the contrast between CHESS alone and CHESS+Mentor. Or the combined condition might have been less different than the Mentor-only condition than intended, thus making for a conservative test of that comparison. However, post hoc analyses of only those participants who had actually used their assigned interventions (and this led to some reclassification of those originally assigned to the CHESS+Mentor condition) produced results that were little different than the intent-to-treat analysis.

Thus, although the combined condition produced some small advantages over either intervention alone, these advantages did not live up to expectations or to previous experience with breast cancer patients.¹⁷ We expected the mentor to be able to reinforce and help interpret what the participants learned from CHESS and their clinicians, and also to advise and direct these patients to be much more effective users of CHESS and other resources. Similarly, we expected that CHESS would make patients much better prepared for mentoring, so that instead of dealing with routine information matters, the mentor could go into greater detail or deal with more complex issues. Their combined effect should have been much larger than each alone, and that was not the case. Perhaps from the prostate cancer patients’ perspective, the 2 interventions seemed to offer similar resources, and a patient benefitted from one or the other but expected no additional gain from attending to both.

The 2 interventions themselves seemed nearly equally effective. The Mentor intervention was significantly stronger than CHESS in only 1 of 27 tests in the intent-to-treat analysis and 2 in the analysis limited to intervention users.

These results for prostate cancer patients are somewhat weaker than those previously reported with breast cancer patients.¹⁷ It is possible that prostate cancer patients (or men in general) are less inclined to seek health information, support, and health self-management than breast cancer patients (or women in general), perhaps because many men perceive decision-making to end with initial treatment, whereas women typically deal with follow-up treatments as well. Use of CHESS and the mentor was modestly lower for the men here than for the women in the previous studies. It is also possible that the CHESS Prostate Cancer module was not as good as the Breast Cancer module, although we are doubtful of that, given the additional tools and improvements added here in response to quite good focus group participants.²²It may also be true that as time goes on, the relative advantage of these interventions over support generally available over the Internet is simply waning – other websites are getting richer and more sophisticated, and users are getting better at searching them out (and avoiding weak or commercially motivated sites).

Although these interventions were experienced by prostate cancer patients in their homes in natural and familiar ways, any experimental manipulation must acknowledge possible problems with external validity. More important here, our recruitment procedures may have produced self-selection to enter or not enter the study in 2 ways that limit its applicability. First, although we thought that offering Internet access to all participants would make participation more likely, the most frequent reason men gave in declining to join the study was “not a computer person.” Our participants were certainly very comfortable with computers and the Internet, and most used them frequently even before the study. Second, it seems that, except for their prostate cancer, our sample was healthy in other respects, as indicated by the low number of other health care visits or surgeries/hospitalization they reported (and “overwhelmed” and “too busy,” 2 common reasons for declining study participations could also be coming from men with more comorbidities). Thus, our sample was probably more computer literate and healthier than the general population of prostate cancer patients.

Nonetheless, for policymakers deciding what information and support interventions to put in place for prostate cancer patients (or more generally for other cancer patients as well), these results have 2 implications. First, since the combination of the mentor and CHESS produced only small advantages over either alone, the extra effort of doing both seems clearly unwarranted for prostate cancer patients. The somewhat larger advantage of the combined intervention shown for breast cancer patients in previous studiesmight warrant using the combination in some circumstances, but even that is not clear-cut.

Finding that CHESS and the cancer information mentor separately provided essentially equal benefits might seem to suggest that they can be regarded as alternatives. However, computer-based services can be provided much more cheaply and scaled up far more readily than services dependent on one-on-one contacts by a highly trained professional. This may direct health care decision makers first toward computer-based services.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related death in men. ¹ Treatment choices for prostate cancer are perhaps more varied than for many other cancers, with surgery, external beam radiation therapy, and brachytherapy all widely used, a number of adjuvant and nonstandard therapy options available, as well as the possibility of not immediately treating the cancer – the “active surveillance” option.

Biochemical failure rates do not differ between the 3 main treatments,² but each exposes patients to the risk of side effects, including impotence, incontinence, rectal injury, and operative mortality. Recovery can be gradual and will not always involve a return to baseline functioning.³ Quality-of-life comparisons observed covariate-controlled decreases in varying specific aspects of quality of life for each of the treatments.⁴

Surgery, brachytherapy, and external beam radiation therapy have each shown advantages over other treatments on at least some specific aspect, but disadvantages on others.⁴ Ongoing surveillance of a cancer left in place has become a more common option in part because of the disadvantages of traditional treatment and because of the growing recognition that sensitive diagnosis techniques often locate cancers that might not be life threatening. Recent reviews and reasonably long-term trials portray active surveillance as a valid alternative to surgery and radiation in many cases, with little difference in life expectancy and cancer-related quality of life, and possibly some reduction in health system cost.^5-7

Prostate cancer patients cope with these uncertainties and decisions in many ways,⁸ often using multiple coping behaviors,⁹ but coping almost always includes seeking information and social support, as well as active problem-solving, to make informed treatment decisions consistent with their values.

Unfortunately, prostate patients often do not receive or use needed information. McGregor¹⁰ reported that patients were aware of their incomplete understanding of their disease and treatment options. Findings from several studies suggest that patients often perceive that clinicians inform them about the disease and treatment options but then send them home unprepared to deal with such things as incontinence or difficulties with sexual functioning.¹¹

Similarly, previous research demonstrates the benefits of social support for prostate cancer patients who receive it, but also that overall they are underserved.^12,13 Male cancer patients are generally far less likely to seek support and health information than are female patients. And when patients with prostate cancer do participate in online cancer support groups, they are more likely to exchange information, whereas breast cancer patients provide support for each other.¹⁴

Mentoring

Some responses to these knowledge and support gaps pair newly diagnosed patients with survivors willing to be a guide, coach, and a source of information, as in the American Cancer Society’s (ACS’s) Man-to-Man support groups.¹⁵ Peer mentors may have a sophisticated level of understanding from their own experiences with medical literature and the health care system, but this cannot be assumed. Another mentoring model is expert-based, exemplified by the National Cancer Institute’s (NCI’s) cancer information specialist at the Cancer Information Service (CIS) and a similar system at the ACS. These telephone services allow for responsiveness to the caller’s needs, existing knowledge, and the caller’s readiness for information. The CIS specialist can also introduce important information the caller might not have known to ask about.¹⁶

However, not all problems presented by callers can be solved in a single conversation. Callers are encouraged to call back with additional questions or when their situation changes, but speaking with the same specialist is not facilitated, so it is hard for a second call to build upon the first. Combining the expertise of the cancer information specialist with the ongoing and proactive contact and support typical of the lay guide/mentor/navigator could be more effective. Here a CIS-trained information specialist called prostate patients multiple times over the intervention period to help them deal with information seeking and interpretation. In a previous study with breast cancer patients, a mentor of this sort improved patient information competence and emotional processing.¹⁷

Interactive resources

Online resources allow cancer patients self-paced and self-directed access to information and support anonymously and at any time. However, this can be more complicated than it might at first seem. With the complexities of the prostate cancer diagnosis, the multiple treatment options, and the uncertain but potentially serious effects of the treatments themselves, the amount of potentially relevant information is quite large. Then, because individuals will value differentially the attributes of treatments, their consequences, or even notions of risk and gain, a system must be able to respond appropriately to a range of very different people. Beyond this, as prostate cancer patients move from the shock of a cancer diagnosis to the problems of interpreting its details, to making treatment decisions, to dealing with problems of recovery, and then re-establishing what is a “new normal” for them, an individual’s demands on a system vary as well. Comprehensive and integrated systems of services meet the varying needs of their users at different times and different situations.^18,19 The systems approach not only makes it far easier for users to find what they need, it may also encourage them to see connections between physical, emotional, and social aspects of their illness. Versions of the system used in the present study – CHESS, or Comprehensive Health Enhancement Support System – have been effective supporting patients with AIDS and breast and lung cancers, and teens with asthma.^16,20

Study goals and hypotheses

Given the success of the 2 aforementioned approaches, we wanted to compare how CHESS and ongoing contact with a human cancer information mentor in patients with prostate cancer would affect both several general aspects of quality of life and 1 specific to prostate cancer. We also examined differences in the patients’ information competence, quality of life, and social support. There was no a priori expectation that one intervention would be superior to the other, but any differences found could be important to policy decisions, given their quite-different cost and scalability.

More importantly, the primary hypothesis of the study was that patients with access to both CHESS and a mentor would experience substantially better outcomes than those with access to either intervention alone, because each had the potential to enhance the other’s benefits. For example, a patient could read CHESS material and come to the mentor much better prepared. By referring the user to specific parts of CHESS for basic information, the mentor could use calls to address more complex issues, or help interpret and evaluate difficult issues. In addition, because CHESS provides the mentor information about changes in the patient’s treatments, symptoms, and CHESS use, in the combined condition the cancer information mentor can know much more about the patient than when working alone. We also expected that the mentor would stimulate the kind of diverse use of CHESS services we have found to be most effective for improving quality of life.²¹ A previous study of CHESS for women with breast cancer concluded that a combined condition benefitted patients more than either CHESS or a cancer mentor alone,¹⁷ and we sought to determine whether we would have similar results with men with prostate cancer.

Because both mentoring and CHESS have consistently produced positive quality of life effects on their own, compared to controls, there is no reasonable expectation that negative effects of a combined condition could occur and should be tested for. Thus, the study was powered for 1-tailed significance in the comparison between the combined condition and either intervention alone, a procedure used consistently in previous studies of CHESS components or combined conditions. However, since the research question comparing the 2 interventions alone had no such strong history it was tested 2-tailed.
 

Methods

Recruitment

Study recruitment was conducted from January 1, 2007 to September 30, 2008 at the University of Wisconsin’s Paul P Carbone Comprehensive Cancer Center in Madison, Hartford Hospital’s Helen and Harry Gray Cancer Center in Hartford, Connecticut, and The University of Texas MD Anderson Cancer Center in Houston.

A total of 461 patients were invited to participate in the study. Of those patients, 147 declined to participate, 4 were excluded, and 310 were randomized to access to CHESS only, access to a human mentor only, or access to CHESS and a mentor (CHESS+Mentor) during the 6-month intervention period, which provided adequate power (>.80) for effects of moderate size (Figure 1). Randomization was done with a computer-generated list that site study managers accessed on a patient-by-patient basis, with experimental conditions blocked within sites.

Interventions

To provide an equal baseline, all of the participants were given access to the Internet, which is becoming a de facto standard for information access. Internet access charges were paid for all participants during the 6-month intervention period, and computers were loaned to those who did not have a personal computer. All of the participants were offered training on using the computer, particularly with Google search procedures so that they could access resources on prostate cancer.

Participants assigned to the CHESS or CHESS+Mentor conditions were also offered training in using CHESS (basically a guided tour), which typically took about 30 minutes on the telephone but was occasionally done in-person.

CHESS intervention. In creating CHESS for prostate cancer patients, a combination of patient needs assessments, focus groups with patients and family members, and clinician expertise helped us identify the needs, coping mechanisms, and relevant medical information to help patients respond to the disease. An article describing development of the CHESS Prostate Cancer Module²² presents how those different services address patient needs for information, communication, and support, or build skills.

Most of these services were present in CHESS for other diseases, but several were newly created to meet needs of prostate cancer patients and partners, such as a decision map tool and a module on managing sexual problems.²² Also, patients expressed frustration at being overwhelmed by the volume of information and said they would prefer to focus only on what was most relevant, so we created an alternative navigation structure on the CHESS homepage. Using terms suggested by focus groups of prostate cancer survivors and their spouses, we devised a navigation structure called Step-by-Step that identified 6 typical sequential steps of men’s experience with prostate cancer. Clicking on a step would take a patient to a menu focused on actions and considerations specific to that disease step, links to information most relevant at that step, and suggested questions to ask oneself and one’s doctor.

Mentor intervention. The cancer information mentor who made most of the calls to patients was an experienced information specialist with the Cancer Information Service and had served as the expert for the CHESS Ask an Expert service for 6 years. She was highly knowledgeable about prostate cancer and patient information needs. Her additional training for this study focused on taking advantage of repeated contacts with the participants and how to set limits to avoid any semblance of psychological counseling. At recruitment, we made clear that a male mentor was also available if the participant would prefer to discuss sensitive topics with another man. The male mentor was experienced in the Man-to-Man program and received additional training for this role, but he was used for only 1% of all contacts.

During calls, the mentor had Internet access to a range of NCI, ACS, and other resources. She could help interpret information the participant already possessed as well as refer him to other public resources, including those on the Internet. CHESS software designers created an additional interface for the mentor that handled call scheduling and allowed her to record the topics of conversations, her responses and recommendations, and her overall ratings of patient preparedness and satisfaction. Using this interface allowed the mentor to quickly review a participant’s status and focus the conversation on issues raised by past conversations or scheduled treatment events. The mentor calls were audiorecorded and reviewed frequently by the project director during the early months of intervention and less frequently thereafter to ensure adherence to the protocol.

The mentor telephoned weekly during the first month of intervention, then twice during the second month, and once a month during the final 4 months of the intervention (ie, 10 scheduled calls, though patients could also initiate additional calls). Calls were scheduled through a combination of telephone contact and e-mail according to the patient’s preference. Call length ranged from 5 minutes to an hour, with the average about 12 minutes (the first call tended to be considerably longer, and was scheduled for 45 minutes). About 10%-15% of participants in the Mentor conditions initiated calls to the mentor to obtain additional support, and about 15% of scheduled calls in fact took place as e-mail exchanges. A few calls were missed because of scheduling difficulties, and some participants stopped scheduling the last few calls, but the average number of full calls or e-mails was 6.41 per participant.

CHESS+Mentor intervention. For the CHESS+Mentor condition, the interactions and resources used were similar to those of the Mentor-only condition, but the interface also provided the mentor with a summary of the participant’s recent CHESS use and any concerns reported to CHESS, which helped the mentor assess knowledge and make tailored recommendations. The mentor could also refer participants to specific resources within CHESS, aided by knowledge of what parts of CHESS had or had not been used.

Assessment methods

Patients were given surveys at the baseline visit to complete and mail back to research staff before randomization. Follow-up surveys were mailed to patients at 2, 6, 12, and 24 weeks post intervention access, and patients returned the surveys by mail. Patient withdrawal rates were about 3%.

Measures

Outcomes. This study included 4 measures of quality of life (an average of relevant portions of the World Health Organization’s Quality of Life (WHOQOL) measure, Emotional and Functional Well-being, and a prostate-cancer specific index, the Expanded Prostate Cancer Index Composite (EPIC). We also tested group differences on 5 more specific outcomes that were likely to be proximal rather than distal effects of the interventions: Cancer Information Competence, Health care Competence, Social Support, Bonding (with other patients), and Positive Coping.



Quality of life. Quality of life was measured by combining the psychological, social, and overall dimensions of the WHOQOL measures.²³ Each of the 11 items was assessed with a 5-point scale, and the mean of those answers was the overall score.



Emotional well-being. Respondents answered 6 items of the Functional Assessment of Cancer Therapy – Prostate (FACT-P)²⁴ describing emotional aspects of reactions to cancer.



Functional well-being. Respondents indicated how often they experienced each of the seven functional well-being subscale items of the FACT-Prostate.²⁴



Prostate cancer patient functioning. We used the EPIC to measure of 3 of 4 domains of prostate cancer patient functioning: urinary, bowel, and sexual (omitting hormonal).²⁵ The EPIC measures frequency and subjective degree of being a problem of several aspects in each domain. We then summed scores across the domains and transformed linearly to a 0-100 scale, with higher scores representing better functioning.



Cancer information competence. Five cancer information competence items, measured on a 5-point scale, assessed a participant’s perception about whether he could find and effectively and use health information, and were summed to create a single score.²⁰



Social support. Six 5-point social support items assessed the informational and emotional support provided by friends, family, coworkers, and others, and were summed to create a single score.²⁰



Health care competence. Five 5-point health care competence items assessed a patient’s comfort and activation level dealing with physicians and health care situations, and were summed to create a single score.²⁰



Positive coping. Coping strategies were measured with the Brief Cope, a shorter version of the original 60-item COPE scale.²⁶ Positive coping strategy, a predictor of positive adaptation in numerous coping contexts, was measured with the mean score of 4 scales (8 items in all): active coping, planning, positive reframing, and humor.



Bonding. Bonding with other prostate cancer patients was measured with five 5-point items about how frequently participants connected with and got information and support from other men with prostate cancer.²⁷



User vs nonuser. Intent-to-treat analyses compared the assigned conditions. However, because CHESS use was self-selected and available at any time whereas mentor calls were scheduled and initiated by another person, the proportion actually using the interventions was quite different.

Since a participant assigned access to CHESS had to select the URL, even a single entry to the system was counted as use. Of 198 participants assigned to either the CHESS or CHESS+Mentor conditions, 43 (22%) never logged in and were classified as nonusers.

Because the mentor scheduled calls and attempted repeatedly to complete scheduled calls, the patient was in a reactive position, and the decision not to use the mentor’s services could come at the earliest at the end of a first completed call. However, after examining call notes and consulting with the mentors, it was clear that opting not to receive mentoring typically occurred at the second call. Furthermore, much (though not all) of the first call was typically taken up with getting acquainted and scheduling issues, so that defining “nonuse” as 2 or fewer completed calls was most faithful to what actually happened. Of 202 participants assigned access to a mentor, 16 (8%) were thus defined as nonusers.

Results

Overall, the participants were about 60 years of age and had some college education and middle-class incomes (Table 1). Only about 10% were minorities or lived alone, and their comfort using computers and the Internet was at or above the “quite comfortable” level. None of groups differed significantly from any other.

The 2 primary hypotheses of the study were that participants in the combined condition would manifest higher outcome scores than those with either intervention alone. Table 2 displays group means at 3 posttest intervals, controlling for theoretically chosen covariates (age, education, and minority status) and pretest levels of the dependent variable. The table also summarizes tests examining the hypotheses and the comparison of CHESS and Mentor conditions. The 4 quality-of-life scores appear first, followed by 5 more specific outcomes that are perhaps more proximal effects of these interventions.

Discussion

We used a randomized control design to test whether combining computer-based and human interventions would provide greater benefits to prostate cancer patients than either alone, as previous research had shown for breast cancer patients.¹⁸ The computer-based resource was CHESS, a repeatedly evaluated integrated system combining information, social support, and interactive tools to help patients manage their response to disease. The human cancer information mentor intervention combined the expertise of NCI’s Cancer Information Service with the repeated contact more typical of peer mentoring. Previous research with breast cancer patients had shown both interventions to provide greater information, support, and quality-of-life benefits than Internet access alone.¹⁴ This study also compared outcomes obtained by the separate CHESS and Mentor conditions, but without predicting a direction of difference.

Tests at 6 weeks, 3 months and 6 months after intervention found instances in which prostate cancer patients assigned to the combined CHESS+Mentor condition experienced more positive quality of life or other outcomes than those assigned to CHESS or Mentor alone, but those differences were scattered rather than consistent. In the direct comparisons of the separate CHESS and Mentor conditions, significance was even rarer, but outcome scores tended to be higher in the Mentor condition than in the CHESS condition.

We noted that differential uptake of the 2 interventions (92% for Mentor vs 78% for CHESS) made interpreting the intent-to-treat analyses problematic, as the mentor’s control of the call schedule meant that far more patients in that condition actually received at least some intervention than in the CHESS condition, where patients used or did not use CHESS entirely at their own volition. This could have biased results in several ways, such as by underestimating the efficacy of the CHESS condition alone and thus inflating the contrast between CHESS alone and CHESS+Mentor. Or the combined condition might have been less different than the Mentor-only condition than intended, thus making for a conservative test of that comparison. However, post hoc analyses of only those participants who had actually used their assigned interventions (and this led to some reclassification of those originally assigned to the CHESS+Mentor condition) produced results that were little different than the intent-to-treat analysis.

Thus, although the combined condition produced some small advantages over either intervention alone, these advantages did not live up to expectations or to previous experience with breast cancer patients.¹⁷ We expected the mentor to be able to reinforce and help interpret what the participants learned from CHESS and their clinicians, and also to advise and direct these patients to be much more effective users of CHESS and other resources. Similarly, we expected that CHESS would make patients much better prepared for mentoring, so that instead of dealing with routine information matters, the mentor could go into greater detail or deal with more complex issues. Their combined effect should have been much larger than each alone, and that was not the case. Perhaps from the prostate cancer patients’ perspective, the 2 interventions seemed to offer similar resources, and a patient benefitted from one or the other but expected no additional gain from attending to both.

The 2 interventions themselves seemed nearly equally effective. The Mentor intervention was significantly stronger than CHESS in only 1 of 27 tests in the intent-to-treat analysis and 2 in the analysis limited to intervention users.

These results for prostate cancer patients are somewhat weaker than those previously reported with breast cancer patients.¹⁷ It is possible that prostate cancer patients (or men in general) are less inclined to seek health information, support, and health self-management than breast cancer patients (or women in general), perhaps because many men perceive decision-making to end with initial treatment, whereas women typically deal with follow-up treatments as well. Use of CHESS and the mentor was modestly lower for the men here than for the women in the previous studies. It is also possible that the CHESS Prostate Cancer module was not as good as the Breast Cancer module, although we are doubtful of that, given the additional tools and improvements added here in response to quite good focus group participants.²²It may also be true that as time goes on, the relative advantage of these interventions over support generally available over the Internet is simply waning – other websites are getting richer and more sophisticated, and users are getting better at searching them out (and avoiding weak or commercially motivated sites).

Although these interventions were experienced by prostate cancer patients in their homes in natural and familiar ways, any experimental manipulation must acknowledge possible problems with external validity. More important here, our recruitment procedures may have produced self-selection to enter or not enter the study in 2 ways that limit its applicability. First, although we thought that offering Internet access to all participants would make participation more likely, the most frequent reason men gave in declining to join the study was “not a computer person.” Our participants were certainly very comfortable with computers and the Internet, and most used them frequently even before the study. Second, it seems that, except for their prostate cancer, our sample was healthy in other respects, as indicated by the low number of other health care visits or surgeries/hospitalization they reported (and “overwhelmed” and “too busy,” 2 common reasons for declining study participations could also be coming from men with more comorbidities). Thus, our sample was probably more computer literate and healthier than the general population of prostate cancer patients.

Nonetheless, for policymakers deciding what information and support interventions to put in place for prostate cancer patients (or more generally for other cancer patients as well), these results have 2 implications. First, since the combination of the mentor and CHESS produced only small advantages over either alone, the extra effort of doing both seems clearly unwarranted for prostate cancer patients. The somewhat larger advantage of the combined intervention shown for breast cancer patients in previous studiesmight warrant using the combination in some circumstances, but even that is not clear-cut.

Finding that CHESS and the cancer information mentor separately provided essentially equal benefits might seem to suggest that they can be regarded as alternatives. However, computer-based services can be provided much more cheaply and scaled up far more readily than services dependent on one-on-one contacts by a highly trained professional. This may direct health care decision makers first toward computer-based services.

Prostate cancer is the most common cancer among men and the second leading cause of cancer-related death in men. ¹ Treatment choices for prostate cancer are perhaps more varied than for many other cancers, with surgery, external beam radiation therapy, and brachytherapy all widely used, a number of adjuvant and nonstandard therapy options available, as well as the possibility of not immediately treating the cancer – the “active surveillance” option.

Biochemical failure rates do not differ between the 3 main treatments,² but each exposes patients to the risk of side effects, including impotence, incontinence, rectal injury, and operative mortality. Recovery can be gradual and will not always involve a return to baseline functioning.³ Quality-of-life comparisons observed covariate-controlled decreases in varying specific aspects of quality of life for each of the treatments.⁴

Surgery, brachytherapy, and external beam radiation therapy have each shown advantages over other treatments on at least some specific aspect, but disadvantages on others.⁴ Ongoing surveillance of a cancer left in place has become a more common option in part because of the disadvantages of traditional treatment and because of the growing recognition that sensitive diagnosis techniques often locate cancers that might not be life threatening. Recent reviews and reasonably long-term trials portray active surveillance as a valid alternative to surgery and radiation in many cases, with little difference in life expectancy and cancer-related quality of life, and possibly some reduction in health system cost.^5-7

Prostate cancer patients cope with these uncertainties and decisions in many ways,⁸ often using multiple coping behaviors,⁹ but coping almost always includes seeking information and social support, as well as active problem-solving, to make informed treatment decisions consistent with their values.

Unfortunately, prostate patients often do not receive or use needed information. McGregor¹⁰ reported that patients were aware of their incomplete understanding of their disease and treatment options. Findings from several studies suggest that patients often perceive that clinicians inform them about the disease and treatment options but then send them home unprepared to deal with such things as incontinence or difficulties with sexual functioning.¹¹

Similarly, previous research demonstrates the benefits of social support for prostate cancer patients who receive it, but also that overall they are underserved.^12,13 Male cancer patients are generally far less likely to seek support and health information than are female patients. And when patients with prostate cancer do participate in online cancer support groups, they are more likely to exchange information, whereas breast cancer patients provide support for each other.¹⁴

Mentoring

Some responses to these knowledge and support gaps pair newly diagnosed patients with survivors willing to be a guide, coach, and a source of information, as in the American Cancer Society’s (ACS’s) Man-to-Man support groups.¹⁵ Peer mentors may have a sophisticated level of understanding from their own experiences with medical literature and the health care system, but this cannot be assumed. Another mentoring model is expert-based, exemplified by the National Cancer Institute’s (NCI’s) cancer information specialist at the Cancer Information Service (CIS) and a similar system at the ACS. These telephone services allow for responsiveness to the caller’s needs, existing knowledge, and the caller’s readiness for information. The CIS specialist can also introduce important information the caller might not have known to ask about.¹⁶

However, not all problems presented by callers can be solved in a single conversation. Callers are encouraged to call back with additional questions or when their situation changes, but speaking with the same specialist is not facilitated, so it is hard for a second call to build upon the first. Combining the expertise of the cancer information specialist with the ongoing and proactive contact and support typical of the lay guide/mentor/navigator could be more effective. Here a CIS-trained information specialist called prostate patients multiple times over the intervention period to help them deal with information seeking and interpretation. In a previous study with breast cancer patients, a mentor of this sort improved patient information competence and emotional processing.¹⁷

Interactive resources

Online resources allow cancer patients self-paced and self-directed access to information and support anonymously and at any time. However, this can be more complicated than it might at first seem. With the complexities of the prostate cancer diagnosis, the multiple treatment options, and the uncertain but potentially serious effects of the treatments themselves, the amount of potentially relevant information is quite large. Then, because individuals will value differentially the attributes of treatments, their consequences, or even notions of risk and gain, a system must be able to respond appropriately to a range of very different people. Beyond this, as prostate cancer patients move from the shock of a cancer diagnosis to the problems of interpreting its details, to making treatment decisions, to dealing with problems of recovery, and then re-establishing what is a “new normal” for them, an individual’s demands on a system vary as well. Comprehensive and integrated systems of services meet the varying needs of their users at different times and different situations.^18,19 The systems approach not only makes it far easier for users to find what they need, it may also encourage them to see connections between physical, emotional, and social aspects of their illness. Versions of the system used in the present study – CHESS, or Comprehensive Health Enhancement Support System – have been effective supporting patients with AIDS and breast and lung cancers, and teens with asthma.^16,20

Study goals and hypotheses

Given the success of the 2 aforementioned approaches, we wanted to compare how CHESS and ongoing contact with a human cancer information mentor in patients with prostate cancer would affect both several general aspects of quality of life and 1 specific to prostate cancer. We also examined differences in the patients’ information competence, quality of life, and social support. There was no a priori expectation that one intervention would be superior to the other, but any differences found could be important to policy decisions, given their quite-different cost and scalability.

More importantly, the primary hypothesis of the study was that patients with access to both CHESS and a mentor would experience substantially better outcomes than those with access to either intervention alone, because each had the potential to enhance the other’s benefits. For example, a patient could read CHESS material and come to the mentor much better prepared. By referring the user to specific parts of CHESS for basic information, the mentor could use calls to address more complex issues, or help interpret and evaluate difficult issues. In addition, because CHESS provides the mentor information about changes in the patient’s treatments, symptoms, and CHESS use, in the combined condition the cancer information mentor can know much more about the patient than when working alone. We also expected that the mentor would stimulate the kind of diverse use of CHESS services we have found to be most effective for improving quality of life.²¹ A previous study of CHESS for women with breast cancer concluded that a combined condition benefitted patients more than either CHESS or a cancer mentor alone,¹⁷ and we sought to determine whether we would have similar results with men with prostate cancer.

Because both mentoring and CHESS have consistently produced positive quality of life effects on their own, compared to controls, there is no reasonable expectation that negative effects of a combined condition could occur and should be tested for. Thus, the study was powered for 1-tailed significance in the comparison between the combined condition and either intervention alone, a procedure used consistently in previous studies of CHESS components or combined conditions. However, since the research question comparing the 2 interventions alone had no such strong history it was tested 2-tailed.
 

Methods

Recruitment

Study recruitment was conducted from January 1, 2007 to September 30, 2008 at the University of Wisconsin’s Paul P Carbone Comprehensive Cancer Center in Madison, Hartford Hospital’s Helen and Harry Gray Cancer Center in Hartford, Connecticut, and The University of Texas MD Anderson Cancer Center in Houston.

A total of 461 patients were invited to participate in the study. Of those patients, 147 declined to participate, 4 were excluded, and 310 were randomized to access to CHESS only, access to a human mentor only, or access to CHESS and a mentor (CHESS+Mentor) during the 6-month intervention period, which provided adequate power (>.80) for effects of moderate size (Figure 1). Randomization was done with a computer-generated list that site study managers accessed on a patient-by-patient basis, with experimental conditions blocked within sites.

Interventions

To provide an equal baseline, all of the participants were given access to the Internet, which is becoming a de facto standard for information access. Internet access charges were paid for all participants during the 6-month intervention period, and computers were loaned to those who did not have a personal computer. All of the participants were offered training on using the computer, particularly with Google search procedures so that they could access resources on prostate cancer.

Participants assigned to the CHESS or CHESS+Mentor conditions were also offered training in using CHESS (basically a guided tour), which typically took about 30 minutes on the telephone but was occasionally done in-person.

CHESS intervention. In creating CHESS for prostate cancer patients, a combination of patient needs assessments, focus groups with patients and family members, and clinician expertise helped us identify the needs, coping mechanisms, and relevant medical information to help patients respond to the disease. An article describing development of the CHESS Prostate Cancer Module²² presents how those different services address patient needs for information, communication, and support, or build skills.

Most of these services were present in CHESS for other diseases, but several were newly created to meet needs of prostate cancer patients and partners, such as a decision map tool and a module on managing sexual problems.²² Also, patients expressed frustration at being overwhelmed by the volume of information and said they would prefer to focus only on what was most relevant, so we created an alternative navigation structure on the CHESS homepage. Using terms suggested by focus groups of prostate cancer survivors and their spouses, we devised a navigation structure called Step-by-Step that identified 6 typical sequential steps of men’s experience with prostate cancer. Clicking on a step would take a patient to a menu focused on actions and considerations specific to that disease step, links to information most relevant at that step, and suggested questions to ask oneself and one’s doctor.

Mentor intervention. The cancer information mentor who made most of the calls to patients was an experienced information specialist with the Cancer Information Service and had served as the expert for the CHESS Ask an Expert service for 6 years. She was highly knowledgeable about prostate cancer and patient information needs. Her additional training for this study focused on taking advantage of repeated contacts with the participants and how to set limits to avoid any semblance of psychological counseling. At recruitment, we made clear that a male mentor was also available if the participant would prefer to discuss sensitive topics with another man. The male mentor was experienced in the Man-to-Man program and received additional training for this role, but he was used for only 1% of all contacts.

During calls, the mentor had Internet access to a range of NCI, ACS, and other resources. She could help interpret information the participant already possessed as well as refer him to other public resources, including those on the Internet. CHESS software designers created an additional interface for the mentor that handled call scheduling and allowed her to record the topics of conversations, her responses and recommendations, and her overall ratings of patient preparedness and satisfaction. Using this interface allowed the mentor to quickly review a participant’s status and focus the conversation on issues raised by past conversations or scheduled treatment events. The mentor calls were audiorecorded and reviewed frequently by the project director during the early months of intervention and less frequently thereafter to ensure adherence to the protocol.

The mentor telephoned weekly during the first month of intervention, then twice during the second month, and once a month during the final 4 months of the intervention (ie, 10 scheduled calls, though patients could also initiate additional calls). Calls were scheduled through a combination of telephone contact and e-mail according to the patient’s preference. Call length ranged from 5 minutes to an hour, with the average about 12 minutes (the first call tended to be considerably longer, and was scheduled for 45 minutes). About 10%-15% of participants in the Mentor conditions initiated calls to the mentor to obtain additional support, and about 15% of scheduled calls in fact took place as e-mail exchanges. A few calls were missed because of scheduling difficulties, and some participants stopped scheduling the last few calls, but the average number of full calls or e-mails was 6.41 per participant.

CHESS+Mentor intervention. For the CHESS+Mentor condition, the interactions and resources used were similar to those of the Mentor-only condition, but the interface also provided the mentor with a summary of the participant’s recent CHESS use and any concerns reported to CHESS, which helped the mentor assess knowledge and make tailored recommendations. The mentor could also refer participants to specific resources within CHESS, aided by knowledge of what parts of CHESS had or had not been used.

Assessment methods

Patients were given surveys at the baseline visit to complete and mail back to research staff before randomization. Follow-up surveys were mailed to patients at 2, 6, 12, and 24 weeks post intervention access, and patients returned the surveys by mail. Patient withdrawal rates were about 3%.

Measures

Outcomes. This study included 4 measures of quality of life (an average of relevant portions of the World Health Organization’s Quality of Life (WHOQOL) measure, Emotional and Functional Well-being, and a prostate-cancer specific index, the Expanded Prostate Cancer Index Composite (EPIC). We also tested group differences on 5 more specific outcomes that were likely to be proximal rather than distal effects of the interventions: Cancer Information Competence, Health care Competence, Social Support, Bonding (with other patients), and Positive Coping.



Quality of life. Quality of life was measured by combining the psychological, social, and overall dimensions of the WHOQOL measures.²³ Each of the 11 items was assessed with a 5-point scale, and the mean of those answers was the overall score.



Emotional well-being. Respondents answered 6 items of the Functional Assessment of Cancer Therapy – Prostate (FACT-P)²⁴ describing emotional aspects of reactions to cancer.



Functional well-being. Respondents indicated how often they experienced each of the seven functional well-being subscale items of the FACT-Prostate.²⁴



Prostate cancer patient functioning. We used the EPIC to measure of 3 of 4 domains of prostate cancer patient functioning: urinary, bowel, and sexual (omitting hormonal).²⁵ The EPIC measures frequency and subjective degree of being a problem of several aspects in each domain. We then summed scores across the domains and transformed linearly to a 0-100 scale, with higher scores representing better functioning.



Cancer information competence. Five cancer information competence items, measured on a 5-point scale, assessed a participant’s perception about whether he could find and effectively and use health information, and were summed to create a single score.²⁰



Social support. Six 5-point social support items assessed the informational and emotional support provided by friends, family, coworkers, and others, and were summed to create a single score.²⁰



Health care competence. Five 5-point health care competence items assessed a patient’s comfort and activation level dealing with physicians and health care situations, and were summed to create a single score.²⁰



Positive coping. Coping strategies were measured with the Brief Cope, a shorter version of the original 60-item COPE scale.²⁶ Positive coping strategy, a predictor of positive adaptation in numerous coping contexts, was measured with the mean score of 4 scales (8 items in all): active coping, planning, positive reframing, and humor.



Bonding. Bonding with other prostate cancer patients was measured with five 5-point items about how frequently participants connected with and got information and support from other men with prostate cancer.²⁷



User vs nonuser. Intent-to-treat analyses compared the assigned conditions. However, because CHESS use was self-selected and available at any time whereas mentor calls were scheduled and initiated by another person, the proportion actually using the interventions was quite different.

Since a participant assigned access to CHESS had to select the URL, even a single entry to the system was counted as use. Of 198 participants assigned to either the CHESS or CHESS+Mentor conditions, 43 (22%) never logged in and were classified as nonusers.

Because the mentor scheduled calls and attempted repeatedly to complete scheduled calls, the patient was in a reactive position, and the decision not to use the mentor’s services could come at the earliest at the end of a first completed call. However, after examining call notes and consulting with the mentors, it was clear that opting not to receive mentoring typically occurred at the second call. Furthermore, much (though not all) of the first call was typically taken up with getting acquainted and scheduling issues, so that defining “nonuse” as 2 or fewer completed calls was most faithful to what actually happened. Of 202 participants assigned access to a mentor, 16 (8%) were thus defined as nonusers.

Results

Overall, the participants were about 60 years of age and had some college education and middle-class incomes (Table 1). Only about 10% were minorities or lived alone, and their comfort using computers and the Internet was at or above the “quite comfortable” level. None of groups differed significantly from any other.

The 2 primary hypotheses of the study were that participants in the combined condition would manifest higher outcome scores than those with either intervention alone. Table 2 displays group means at 3 posttest intervals, controlling for theoretically chosen covariates (age, education, and minority status) and pretest levels of the dependent variable. The table also summarizes tests examining the hypotheses and the comparison of CHESS and Mentor conditions. The 4 quality-of-life scores appear first, followed by 5 more specific outcomes that are perhaps more proximal effects of these interventions.

Discussion

We used a randomized control design to test whether combining computer-based and human interventions would provide greater benefits to prostate cancer patients than either alone, as previous research had shown for breast cancer patients.¹⁸ The computer-based resource was CHESS, a repeatedly evaluated integrated system combining information, social support, and interactive tools to help patients manage their response to disease. The human cancer information mentor intervention combined the expertise of NCI’s Cancer Information Service with the repeated contact more typical of peer mentoring. Previous research with breast cancer patients had shown both interventions to provide greater information, support, and quality-of-life benefits than Internet access alone.¹⁴ This study also compared outcomes obtained by the separate CHESS and Mentor conditions, but without predicting a direction of difference.

Tests at 6 weeks, 3 months and 6 months after intervention found instances in which prostate cancer patients assigned to the combined CHESS+Mentor condition experienced more positive quality of life or other outcomes than those assigned to CHESS or Mentor alone, but those differences were scattered rather than consistent. In the direct comparisons of the separate CHESS and Mentor conditions, significance was even rarer, but outcome scores tended to be higher in the Mentor condition than in the CHESS condition.

We noted that differential uptake of the 2 interventions (92% for Mentor vs 78% for CHESS) made interpreting the intent-to-treat analyses problematic, as the mentor’s control of the call schedule meant that far more patients in that condition actually received at least some intervention than in the CHESS condition, where patients used or did not use CHESS entirely at their own volition. This could have biased results in several ways, such as by underestimating the efficacy of the CHESS condition alone and thus inflating the contrast between CHESS alone and CHESS+Mentor. Or the combined condition might have been less different than the Mentor-only condition than intended, thus making for a conservative test of that comparison. However, post hoc analyses of only those participants who had actually used their assigned interventions (and this led to some reclassification of those originally assigned to the CHESS+Mentor condition) produced results that were little different than the intent-to-treat analysis.

Thus, although the combined condition produced some small advantages over either intervention alone, these advantages did not live up to expectations or to previous experience with breast cancer patients.¹⁷ We expected the mentor to be able to reinforce and help interpret what the participants learned from CHESS and their clinicians, and also to advise and direct these patients to be much more effective users of CHESS and other resources. Similarly, we expected that CHESS would make patients much better prepared for mentoring, so that instead of dealing with routine information matters, the mentor could go into greater detail or deal with more complex issues. Their combined effect should have been much larger than each alone, and that was not the case. Perhaps from the prostate cancer patients’ perspective, the 2 interventions seemed to offer similar resources, and a patient benefitted from one or the other but expected no additional gain from attending to both.

The 2 interventions themselves seemed nearly equally effective. The Mentor intervention was significantly stronger than CHESS in only 1 of 27 tests in the intent-to-treat analysis and 2 in the analysis limited to intervention users.

These results for prostate cancer patients are somewhat weaker than those previously reported with breast cancer patients.¹⁷ It is possible that prostate cancer patients (or men in general) are less inclined to seek health information, support, and health self-management than breast cancer patients (or women in general), perhaps because many men perceive decision-making to end with initial treatment, whereas women typically deal with follow-up treatments as well. Use of CHESS and the mentor was modestly lower for the men here than for the women in the previous studies. It is also possible that the CHESS Prostate Cancer module was not as good as the Breast Cancer module, although we are doubtful of that, given the additional tools and improvements added here in response to quite good focus group participants.²²It may also be true that as time goes on, the relative advantage of these interventions over support generally available over the Internet is simply waning – other websites are getting richer and more sophisticated, and users are getting better at searching them out (and avoiding weak or commercially motivated sites).

Although these interventions were experienced by prostate cancer patients in their homes in natural and familiar ways, any experimental manipulation must acknowledge possible problems with external validity. More important here, our recruitment procedures may have produced self-selection to enter or not enter the study in 2 ways that limit its applicability. First, although we thought that offering Internet access to all participants would make participation more likely, the most frequent reason men gave in declining to join the study was “not a computer person.” Our participants were certainly very comfortable with computers and the Internet, and most used them frequently even before the study. Second, it seems that, except for their prostate cancer, our sample was healthy in other respects, as indicated by the low number of other health care visits or surgeries/hospitalization they reported (and “overwhelmed” and “too busy,” 2 common reasons for declining study participations could also be coming from men with more comorbidities). Thus, our sample was probably more computer literate and healthier than the general population of prostate cancer patients.

Nonetheless, for policymakers deciding what information and support interventions to put in place for prostate cancer patients (or more generally for other cancer patients as well), these results have 2 implications. First, since the combination of the mentor and CHESS produced only small advantages over either alone, the extra effort of doing both seems clearly unwarranted for prostate cancer patients. The somewhat larger advantage of the combined intervention shown for breast cancer patients in previous studiesmight warrant using the combination in some circumstances, but even that is not clear-cut.

Finding that CHESS and the cancer information mentor separately provided essentially equal benefits might seem to suggest that they can be regarded as alternatives. However, computer-based services can be provided much more cheaply and scaled up far more readily than services dependent on one-on-one contacts by a highly trained professional. This may direct health care decision makers first toward computer-based services.

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

Skin adnexal tumors (SAT) are rare tumors that make up about 1%-2% of all cutaneous malignancies. They represent a various group of benign and malignant tumors that arise from skin adnexal epithelial structures: hair follicle, pilosebaceous unit, and apocrine or eccrine sweat glands. Although this derivation provides a practical basis for classification, some tumors may exhibit a mixed or more than one line of differentiation, rendering precise classification of those neoplasms difficult, and such cases should be categorized according to prevailing phenotype. In this report, we present a patient with metastatic eccrine carcinoma. Clinical experience for metastatic disease treatment is derived from a few reports, and there are no universal treatment guidelines. Given the few reported cases and the absence of randomized clinical trials for these patients, it is important to collect clinical experiences.

Case presentation and summary

A 56-year-old African man presented with a 5-week history of multiple nontender subcutaneous skin nodules all over his body except for his palms and soles, and associated with generalized itching. He had a mass in the sole of his right foot 35 years previously in another country. The mass had recurred 15 years later and was excised again. The exact etiology of the mass was unknown to the patient. He had no other medical problems. He was on no medications and did not smoke, drink, or use recreational drugs.

His vital signs on admission were normal. Examination was significant for innumerable superficial skin nodules in the scalp, back, torso, and abdomen. The largest was in the neck and measured 4 x 2 cm. A firm right inguinal mass of 7 x 4 cm was palpable. An abdominal exam revealed large ascites but no organomegaly.

The results of laboratory tests were significant for hyponatremia 126 mEq/L (normal, 135-145), hypercalcemia of 12.2 mg/dL (8.5-10.5), with normal phosphorous of 2.5 mg/dL (2.5-4.5), parathyroid of 11.5 pg/ml (6-65), and low vitamin D level of <7 ng/ml (30-100). Other test results were: carcinoembryonic antigen (CEA), 4.36 ng/ml (0.00-2.99); alpha fetoprotein, 2.39 IU/ml (0.00-9.0); calcium 11.6 mg/dL (8.5-10.2); lactate dehydrogenase, 325 U/L (85-210); aspartate aminotransferase, 59 U/L (0-40); alanine aminotransferase 43 U/L (5-35); alkaline phosphatase, 65 u/L (50-120); albumin, 2.7 g/dL (3.8-5.2); white blood cell count, 14.1 k/uL (4.4-10.6); hemoglobin, 12.6 g/dL; and platelets, 339 k/uL (161-369).

A chest and abdomen computed-tomography scan on presentation showed presence of innumerable subcutaneous and intramuscular nodules throughout the chest, abdomen, and pelvis (Figure 1).

Discussion

Sweat gland carcinomas are very rare malignant tumors of the adnexal epithelial structures of the skin, sebaceous, hair follicle, apocrine or eccrine glands that were first described by Cornil in 1865.¹ They occur primarily in adult patients, with a peak incidence in fifth and sixth decades of life.^2,3 The etiology is unknown, but some cases have been reported to be a consequence of radiation therapy.⁴ They are almost always an incidental histologic diagnosis.^2,5 The tumors usually appear as single nodule, and multinodularity usually associated with both local and metastatic disease.⁶ There are no characteristic findings to suggest that a particular nodule may represent sweat gland carcinoma, and even if sweat gland tumor is suspected, benign counterparts are more common.

Eccrine carcinoma is the most aggressive among skin adnexal tumors. They can arise on the lower limbs, trunk, head and neck, scalp and ears, upper extremities, abdomen, and genital sites.⁷

The cells of eccrine sweat glands express low molecular weight keratin, epithelial membrane antigen, carcinoembryonic antigen, as well as S100 protein, smooth muscle actin, p63, calponin, cytokeratin 14, and bcl-2.⁸ Skin tumors with eccrine differentiation may stain for estrogen and progesterone, which has important clinical implications because those patients can be treated with hormonal therapy.⁹ Positivity for estrogen receptors does not differentiate cutaneous eccrine tumors from cutaneous metastases of breast cancers.^8,9 Androgen receptor evaluation in these cases can help distinguish between the two.¹⁰ Human epidermal growth factor receptor 2 (HER-2) is expressed in 3.5% of skin adnexal tumors.¹¹

The molecular pathogenesis of malignant adnexal tumors is not clear, but overexpression of tumor suppressor protein p16 has been described as a common feature in eccrine carcinomas.¹²

Prognostic factors for sweat gland carcinoma are difficult to identify, because of the small number of reported cases. The likely prognostic factors include size, histological type, lymph node involvement, and presence of distant metastasis. Absent of lymph node involvement correlates with 10-year disease-free survival rate of 56%, which falls to 9% if nodes are involved.¹³

There are no uniform guidelines for the treatment sweat gland carcinomas, and the clinical experience described in the literature is the only source of available information.

The treatment of choice of all subtypes of localized sweat gland carcinomas is wide surgical excision with broad tumor margins, given the propensity for local recurrences along with regional lymph node dissection in the presence of clinically positive nodes. Prophylactic lymph node resection does not seem to improve survival or decrease recurrence rates.⁷ The use of adjuvant radiotherapy to prevent local recurrence also is not well established. One report suggested radiosensitivity of these tumors, and adjuvant radiation was therefore recommended in high-risk cases (ie, large tumors of 5 cm and positive surgical margins of 1 cm) and moderate to poorly differentiated tumors with lymphovascular invasion.¹⁴ Adjuvant radiation to the involved lymph node basin is suggested in the setting of extranodal extension or extensive involvement, that is, 4 lymph nodes.¹⁵ The role of lymphadenectomy has not been adequately addressed in the literature.

The role of chemotherapy in metastatic disease is not clear, but sweat gland carcinomas are considered chemoresistant (Table). Several combinations have been used with short-term responses. In one case treated with doxorubicin, mitomycin, vincristine, and 5-FU followed by maintenance therapy, the patient achieved a complete response that lasted for 16 months.¹⁶ In another report, the treatment response was 2 years with treatment consisted of anthracyclin, cyclophosphamide, vincristine, and bloemycin.¹⁷ Other combinations used in the literature include carboplatin and paclitaxel, which led to prolonged remission.¹⁴ Cisplatin and 5-FU, or cisplatin plus cetuximab have been reported but with discouraging results.¹⁸ Results to taxanes showed conflicting results.^19,20

Autoimmune hemolytic anemia (AIHA) is characterized by the temperature at which the auto-antibody has the greatest avidity for the target red cell antigen, either warm or cold forms. It is detected by a positive direct antiglobulin test (DAT) also known as the direct Coombs test. DAT is used to determine if red cells have been coated in vivo with immunoglobulin, complement, or both.¹ Some causes of a positive DAT include hemolytic transfusion reactions, hemolytic disease of the fetus and newborn, AIHA, and drug-induced immune hemolysis.

Case presentation and summary

A 58-year-old woman from Brazil with past medical history only significant for cholecystectomy and cesarean section had been visiting in United States for 2 months when she presented to an outside hospital with fever, shortness of breath, and syncope that had resulted in a foot injury. She reported she had been feeling short of breath and had a nonproductive cough and malaise for about 2 weeks before presentation with sick contacts at home. On admission it was noted that she had a hemoglobin level of 7.7 g/dL (normal, 12.0-15.5 g/dL; MCV, 94 fL), total bilirubin of 2.14 mg/dL (normal, 0.2-1.0 mg/dL), and lactate dehydrogenase of 523 U/L (normal, 81-234 U/L). There were no signs of bleeding on her examination. Her DAT was positive and moderate red blood cell agglutination was reported. During the first admission at the outside hospital she was diagnosed with influenza A and completed a full course of oseltamivir (75 mg po twice daily for 5 days). A chest X-ray was negative for infiltrates and showed that the patient’s lung fields were clear. She was transfused 2 units of packed red blood cells with response in hemoglobin up to 9.8 g/dL. The patient was treated with dexamethasone (4 mg IV Q8) as an inpatient and was discharged on a prednisone taper (40 mg, with taper by 10 mg every 3 days) with hemoglobin of 8.1 g/dL.

The patient continued to have nonproductive cough, dyspnea, fevers, chills, and generalized weakness, when she returned to the same outside hospital’s emergency department 2 days after her discharge. At that time, it was noted that she had leucocytosis (white blood cell count, 34.6 x 10⁹ per L), a hemoglobin level of 6.8 g/dL, and her total bilirubin level was 6.9 mg/dL. Her hemodynamics were unstable and she was admitted to their intensive care unit. The results of a chest X-ray revealed right lung consolidation.

The day after this admission, her hemoglobin level fell to 4.7 g/dL, and she was transfused 2 units of packed red blood cells before being transferred to our hospital. A chest X-ray at our hospital confirmed a right lung infiltrate. Vancomycin (1,250 mg IV Q12), levaquin (750 mg IV Q24), and maxipime (1 g IV Q12) were initiated for pneumonia and the patient was transferred to our hospital’s intensive care unit. She was afebrile at 98.3°F, her pulse rate was 84 beats per minute, she was tachypneic with respiratory rate of 26 breaths per minute, her blood pressure was 98/51 mmHg, and she had an oxygen saturation of 99% on 2L oxygen via nasal cannula.

On physical examination she was noted to have scleral icterus and was in mild respiratory distress. A chest X-ray revealed a patchy opacity in the right mid to lower lung. Her initial complete blood panel revealed anemia, with hemoglobin, 6.3 g/dL; white blood cell count, 27 x 10⁹ per L; and platelets, 533 x 10⁹ per L. The patient was then transfused another 2 units of packed red blood cells. She was given intravenous hydration, acetaminophen, and albuterol nebulizer treatments as supportive care. She was provided with blankets to keep warm. In addition to her antibiotics, she was also given prednisone 70 mg for her respiratory symptoms.

Further tests revealed haptoglobin, <30 mg/dL (normal, 36-195 mg/dL); lactate dehydrogenase, 371 U/L (normal, 98-192 U/L); and complements C3, 90 mg/dL (normal, 79-152 mg/dL) and C4, <8 mg/dL (normal, 18-55 mg/dL). Her DAT was positive, and agglutination was seen on peripheral smear (Figure 1). This was her second positive DAT as she had positive one at the outside hospital initially. Her tests for mycoplasma pneumonia, the PCR and IgM, were negative, as were the Monospot for mononucleosis and the ANA for autoimmune disorders. Her cold agglutinin titer was 1:256 (normal, no agglutination <1:64). The patient’s repeat respiratory viral panel was negative given recent full treatment for her influenza A at the previous hospital. Her blood and urine cultures were negative.

Figures 2 and 3 illustrate her hemoglobin and reticulocyte trend during her admission at our hospital.

Discussion

The incidence of cold AIHA or cold agglutinin disease (CAD) occurs about 4 per 1 million people and commonly affects women more often than men.² The cause of CAD can be subdivided into primary, idiopathic, or secondary causes, which can include infections, malignancies, or benign diseases.^3,4 Primary CAD is a chronic disorder that is generally seen in older women. Secondary CAD can be associated with B-cell lymphoproliferative disorders, such as Waldenstrom macroglobulinemia or chronic lymphocytic leukemia, and infectious agents such as Mycoplasma pneumoniae and mononucleosis caused by Epstein-Barr virus.

Mild hemolysis or acrocyanosis may occur with exposure to cold. The blood smear in CAD demonstrates red blood cell agglutination or clumping, polychromasia, and an absence of spherocytosis. In general, most cases require no treatment, but cytotoxic agents or rituximab can be used to treat more severe cases. Appropriate treatment for infectious causes of CAD includes supportive care aimed at the underlying disease process. In addition, it is helpful to keep the patient warm. There is no role for steroid therapy in CAD unlike in warm AIHA. However, our patient was symptomatic from her pneumonia, so we added steroids to help with her pulmonary insult.

The patient had a cold agglutinin titer of 1:256. Titers of 1:32 or higher are considered elevated by this technique. Elevated titers are generally rarely seen except in primary atypical pneumonia due to either M. pneumoniae, influenza A, influenza B, parainfluenza, and adenovirus, and in certain hemolytic anemias. Low titers of cold agglutinins have been demonstrated in malaria, peripheral vascular disease, and common respiratory diseases.

Warm AIHA is caused by IgG antibody activities at body temperature or at 98.6°F. They may or may not bind complement and are removed from circulation by the spleen. Cold AIHA is due to IgM antibodies coating red cells at lower temperatures. They bind complement and lead to red blood cell destruction of agglutinated cells. If the antibody is active at temperatures approaching 98.6°F, clinically significant intravascular and sometimes extravascular complement-mediated hemolysis occur in the liver.⁵

The incidence of warm AIHA occurs about 10 per 1 million people and affects women twice often as men.² It can be primary or idiopathic, or associated with various underlying conditions, including autoimmune disorders, immunodeficiency syndromes, lymphoproliferative disorders, other malignancies, and certain drugs. In more severe cases, jaundice and splenomegaly may occur. The blood smear in warm AIHA demonstrates variable spherocytosis, polychromasia, and rare erythrophagocytosis. Treatment usually includes steroids, cytotoxic agents, and splenectomy in severe cases.

There have been few case reports describing influenza as a cause of cold agglutinin hemolytic anemia. Chen and colleagues reported a case of influenza A infection in a 22-month-old boy.⁶Schoindre and colleagues reported the case of a 60-year-old woman infected with influenza A H1N1 virus who died from CAD.⁷ Shizuma reported the case of a 67-year-old man with alcoholic cirrhosis who developed a mixed hemolytic anemia and was positive for influenza A.⁸Our patient presented with influenza A, which had been diagnosed by respiratory virus panel at a different hospital, and she was anemic at the time of presentation to the outside hospital, with a positive DAT test. She was treated for influenza A with a full course of osltamivir and then returned with complaints of worsening fatigue and was again noted to be anemic with the development of patchy opacities on chest X-ray. The patient was subsequently transferred to our hospital and remained anemic during the course of her treatment. She received supportive care for her underlying influenza A and had symptomatic improvement. She ultimately decided the she would like to pursue further treatment in her native country and was discharged.

In conclusion, this case represents a rare complication of a common illness. Few cases of influenza causing hemolytic anemia have been reported in the literature. There have been reports of oseltamivir causing hemolytic anemia, but our patient presented with evidence of hemolytic anemia before initiation of the medication. In all the aforementioned cases, the patients died as a result of comorbid conditions. Our patient was stable enough to be discharged from the hospital after treatment of her comorbid conditions.

Acknowledgment
The authors thank David Henry, MD, at Pennsylvania Hospital, Philadelphia, for sharing this case and for his guidance during this patient’s treatment.

Autoimmune hemolytic anemia (AIHA) is characterized by the temperature at which the auto-antibody has the greatest avidity for the target red cell antigen, either warm or cold forms. It is detected by a positive direct antiglobulin test (DAT) also known as the direct Coombs test. DAT is used to determine if red cells have been coated in vivo with immunoglobulin, complement, or both.¹ Some causes of a positive DAT include hemolytic transfusion reactions, hemolytic disease of the fetus and newborn, AIHA, and drug-induced immune hemolysis.

Case presentation and summary

A 58-year-old woman from Brazil with past medical history only significant for cholecystectomy and cesarean section had been visiting in United States for 2 months when she presented to an outside hospital with fever, shortness of breath, and syncope that had resulted in a foot injury. She reported she had been feeling short of breath and had a nonproductive cough and malaise for about 2 weeks before presentation with sick contacts at home. On admission it was noted that she had a hemoglobin level of 7.7 g/dL (normal, 12.0-15.5 g/dL; MCV, 94 fL), total bilirubin of 2.14 mg/dL (normal, 0.2-1.0 mg/dL), and lactate dehydrogenase of 523 U/L (normal, 81-234 U/L). There were no signs of bleeding on her examination. Her DAT was positive and moderate red blood cell agglutination was reported. During the first admission at the outside hospital she was diagnosed with influenza A and completed a full course of oseltamivir (75 mg po twice daily for 5 days). A chest X-ray was negative for infiltrates and showed that the patient’s lung fields were clear. She was transfused 2 units of packed red blood cells with response in hemoglobin up to 9.8 g/dL. The patient was treated with dexamethasone (4 mg IV Q8) as an inpatient and was discharged on a prednisone taper (40 mg, with taper by 10 mg every 3 days) with hemoglobin of 8.1 g/dL.

The patient continued to have nonproductive cough, dyspnea, fevers, chills, and generalized weakness, when she returned to the same outside hospital’s emergency department 2 days after her discharge. At that time, it was noted that she had leucocytosis (white blood cell count, 34.6 x 10⁹ per L), a hemoglobin level of 6.8 g/dL, and her total bilirubin level was 6.9 mg/dL. Her hemodynamics were unstable and she was admitted to their intensive care unit. The results of a chest X-ray revealed right lung consolidation.

The day after this admission, her hemoglobin level fell to 4.7 g/dL, and she was transfused 2 units of packed red blood cells before being transferred to our hospital. A chest X-ray at our hospital confirmed a right lung infiltrate. Vancomycin (1,250 mg IV Q12), levaquin (750 mg IV Q24), and maxipime (1 g IV Q12) were initiated for pneumonia and the patient was transferred to our hospital’s intensive care unit. She was afebrile at 98.3°F, her pulse rate was 84 beats per minute, she was tachypneic with respiratory rate of 26 breaths per minute, her blood pressure was 98/51 mmHg, and she had an oxygen saturation of 99% on 2L oxygen via nasal cannula.

On physical examination she was noted to have scleral icterus and was in mild respiratory distress. A chest X-ray revealed a patchy opacity in the right mid to lower lung. Her initial complete blood panel revealed anemia, with hemoglobin, 6.3 g/dL; white blood cell count, 27 x 10⁹ per L; and platelets, 533 x 10⁹ per L. The patient was then transfused another 2 units of packed red blood cells. She was given intravenous hydration, acetaminophen, and albuterol nebulizer treatments as supportive care. She was provided with blankets to keep warm. In addition to her antibiotics, she was also given prednisone 70 mg for her respiratory symptoms.

Further tests revealed haptoglobin, <30 mg/dL (normal, 36-195 mg/dL); lactate dehydrogenase, 371 U/L (normal, 98-192 U/L); and complements C3, 90 mg/dL (normal, 79-152 mg/dL) and C4, <8 mg/dL (normal, 18-55 mg/dL). Her DAT was positive, and agglutination was seen on peripheral smear (Figure 1). This was her second positive DAT as she had positive one at the outside hospital initially. Her tests for mycoplasma pneumonia, the PCR and IgM, were negative, as were the Monospot for mononucleosis and the ANA for autoimmune disorders. Her cold agglutinin titer was 1:256 (normal, no agglutination <1:64). The patient’s repeat respiratory viral panel was negative given recent full treatment for her influenza A at the previous hospital. Her blood and urine cultures were negative.

Figures 2 and 3 illustrate her hemoglobin and reticulocyte trend during her admission at our hospital.

Discussion

The incidence of cold AIHA or cold agglutinin disease (CAD) occurs about 4 per 1 million people and commonly affects women more often than men.² The cause of CAD can be subdivided into primary, idiopathic, or secondary causes, which can include infections, malignancies, or benign diseases.^3,4 Primary CAD is a chronic disorder that is generally seen in older women. Secondary CAD can be associated with B-cell lymphoproliferative disorders, such as Waldenstrom macroglobulinemia or chronic lymphocytic leukemia, and infectious agents such as Mycoplasma pneumoniae and mononucleosis caused by Epstein-Barr virus.

Mild hemolysis or acrocyanosis may occur with exposure to cold. The blood smear in CAD demonstrates red blood cell agglutination or clumping, polychromasia, and an absence of spherocytosis. In general, most cases require no treatment, but cytotoxic agents or rituximab can be used to treat more severe cases. Appropriate treatment for infectious causes of CAD includes supportive care aimed at the underlying disease process. In addition, it is helpful to keep the patient warm. There is no role for steroid therapy in CAD unlike in warm AIHA. However, our patient was symptomatic from her pneumonia, so we added steroids to help with her pulmonary insult.

The patient had a cold agglutinin titer of 1:256. Titers of 1:32 or higher are considered elevated by this technique. Elevated titers are generally rarely seen except in primary atypical pneumonia due to either M. pneumoniae, influenza A, influenza B, parainfluenza, and adenovirus, and in certain hemolytic anemias. Low titers of cold agglutinins have been demonstrated in malaria, peripheral vascular disease, and common respiratory diseases.

Warm AIHA is caused by IgG antibody activities at body temperature or at 98.6°F. They may or may not bind complement and are removed from circulation by the spleen. Cold AIHA is due to IgM antibodies coating red cells at lower temperatures. They bind complement and lead to red blood cell destruction of agglutinated cells. If the antibody is active at temperatures approaching 98.6°F, clinically significant intravascular and sometimes extravascular complement-mediated hemolysis occur in the liver.⁵

The incidence of warm AIHA occurs about 10 per 1 million people and affects women twice often as men.² It can be primary or idiopathic, or associated with various underlying conditions, including autoimmune disorders, immunodeficiency syndromes, lymphoproliferative disorders, other malignancies, and certain drugs. In more severe cases, jaundice and splenomegaly may occur. The blood smear in warm AIHA demonstrates variable spherocytosis, polychromasia, and rare erythrophagocytosis. Treatment usually includes steroids, cytotoxic agents, and splenectomy in severe cases.

There have been few case reports describing influenza as a cause of cold agglutinin hemolytic anemia. Chen and colleagues reported a case of influenza A infection in a 22-month-old boy.⁶Schoindre and colleagues reported the case of a 60-year-old woman infected with influenza A H1N1 virus who died from CAD.⁷ Shizuma reported the case of a 67-year-old man with alcoholic cirrhosis who developed a mixed hemolytic anemia and was positive for influenza A.⁸Our patient presented with influenza A, which had been diagnosed by respiratory virus panel at a different hospital, and she was anemic at the time of presentation to the outside hospital, with a positive DAT test. She was treated for influenza A with a full course of osltamivir and then returned with complaints of worsening fatigue and was again noted to be anemic with the development of patchy opacities on chest X-ray. The patient was subsequently transferred to our hospital and remained anemic during the course of her treatment. She received supportive care for her underlying influenza A and had symptomatic improvement. She ultimately decided the she would like to pursue further treatment in her native country and was discharged.

In conclusion, this case represents a rare complication of a common illness. Few cases of influenza causing hemolytic anemia have been reported in the literature. There have been reports of oseltamivir causing hemolytic anemia, but our patient presented with evidence of hemolytic anemia before initiation of the medication. In all the aforementioned cases, the patients died as a result of comorbid conditions. Our patient was stable enough to be discharged from the hospital after treatment of her comorbid conditions.

Acknowledgment
The authors thank David Henry, MD, at Pennsylvania Hospital, Philadelphia, for sharing this case and for his guidance during this patient’s treatment.

Autoimmune hemolytic anemia (AIHA) is characterized by the temperature at which the auto-antibody has the greatest avidity for the target red cell antigen, either warm or cold forms. It is detected by a positive direct antiglobulin test (DAT) also known as the direct Coombs test. DAT is used to determine if red cells have been coated in vivo with immunoglobulin, complement, or both.¹ Some causes of a positive DAT include hemolytic transfusion reactions, hemolytic disease of the fetus and newborn, AIHA, and drug-induced immune hemolysis.

Case presentation and summary

A 58-year-old woman from Brazil with past medical history only significant for cholecystectomy and cesarean section had been visiting in United States for 2 months when she presented to an outside hospital with fever, shortness of breath, and syncope that had resulted in a foot injury. She reported she had been feeling short of breath and had a nonproductive cough and malaise for about 2 weeks before presentation with sick contacts at home. On admission it was noted that she had a hemoglobin level of 7.7 g/dL (normal, 12.0-15.5 g/dL; MCV, 94 fL), total bilirubin of 2.14 mg/dL (normal, 0.2-1.0 mg/dL), and lactate dehydrogenase of 523 U/L (normal, 81-234 U/L). There were no signs of bleeding on her examination. Her DAT was positive and moderate red blood cell agglutination was reported. During the first admission at the outside hospital she was diagnosed with influenza A and completed a full course of oseltamivir (75 mg po twice daily for 5 days). A chest X-ray was negative for infiltrates and showed that the patient’s lung fields were clear. She was transfused 2 units of packed red blood cells with response in hemoglobin up to 9.8 g/dL. The patient was treated with dexamethasone (4 mg IV Q8) as an inpatient and was discharged on a prednisone taper (40 mg, with taper by 10 mg every 3 days) with hemoglobin of 8.1 g/dL.

The patient continued to have nonproductive cough, dyspnea, fevers, chills, and generalized weakness, when she returned to the same outside hospital’s emergency department 2 days after her discharge. At that time, it was noted that she had leucocytosis (white blood cell count, 34.6 x 10⁹ per L), a hemoglobin level of 6.8 g/dL, and her total bilirubin level was 6.9 mg/dL. Her hemodynamics were unstable and she was admitted to their intensive care unit. The results of a chest X-ray revealed right lung consolidation.

The day after this admission, her hemoglobin level fell to 4.7 g/dL, and she was transfused 2 units of packed red blood cells before being transferred to our hospital. A chest X-ray at our hospital confirmed a right lung infiltrate. Vancomycin (1,250 mg IV Q12), levaquin (750 mg IV Q24), and maxipime (1 g IV Q12) were initiated for pneumonia and the patient was transferred to our hospital’s intensive care unit. She was afebrile at 98.3°F, her pulse rate was 84 beats per minute, she was tachypneic with respiratory rate of 26 breaths per minute, her blood pressure was 98/51 mmHg, and she had an oxygen saturation of 99% on 2L oxygen via nasal cannula.

On physical examination she was noted to have scleral icterus and was in mild respiratory distress. A chest X-ray revealed a patchy opacity in the right mid to lower lung. Her initial complete blood panel revealed anemia, with hemoglobin, 6.3 g/dL; white blood cell count, 27 x 10⁹ per L; and platelets, 533 x 10⁹ per L. The patient was then transfused another 2 units of packed red blood cells. She was given intravenous hydration, acetaminophen, and albuterol nebulizer treatments as supportive care. She was provided with blankets to keep warm. In addition to her antibiotics, she was also given prednisone 70 mg for her respiratory symptoms.

Further tests revealed haptoglobin, <30 mg/dL (normal, 36-195 mg/dL); lactate dehydrogenase, 371 U/L (normal, 98-192 U/L); and complements C3, 90 mg/dL (normal, 79-152 mg/dL) and C4, <8 mg/dL (normal, 18-55 mg/dL). Her DAT was positive, and agglutination was seen on peripheral smear (Figure 1). This was her second positive DAT as she had positive one at the outside hospital initially. Her tests for mycoplasma pneumonia, the PCR and IgM, were negative, as were the Monospot for mononucleosis and the ANA for autoimmune disorders. Her cold agglutinin titer was 1:256 (normal, no agglutination <1:64). The patient’s repeat respiratory viral panel was negative given recent full treatment for her influenza A at the previous hospital. Her blood and urine cultures were negative.

Figures 2 and 3 illustrate her hemoglobin and reticulocyte trend during her admission at our hospital.

Discussion

The incidence of cold AIHA or cold agglutinin disease (CAD) occurs about 4 per 1 million people and commonly affects women more often than men.² The cause of CAD can be subdivided into primary, idiopathic, or secondary causes, which can include infections, malignancies, or benign diseases.^3,4 Primary CAD is a chronic disorder that is generally seen in older women. Secondary CAD can be associated with B-cell lymphoproliferative disorders, such as Waldenstrom macroglobulinemia or chronic lymphocytic leukemia, and infectious agents such as Mycoplasma pneumoniae and mononucleosis caused by Epstein-Barr virus.

Mild hemolysis or acrocyanosis may occur with exposure to cold. The blood smear in CAD demonstrates red blood cell agglutination or clumping, polychromasia, and an absence of spherocytosis. In general, most cases require no treatment, but cytotoxic agents or rituximab can be used to treat more severe cases. Appropriate treatment for infectious causes of CAD includes supportive care aimed at the underlying disease process. In addition, it is helpful to keep the patient warm. There is no role for steroid therapy in CAD unlike in warm AIHA. However, our patient was symptomatic from her pneumonia, so we added steroids to help with her pulmonary insult.

The patient had a cold agglutinin titer of 1:256. Titers of 1:32 or higher are considered elevated by this technique. Elevated titers are generally rarely seen except in primary atypical pneumonia due to either M. pneumoniae, influenza A, influenza B, parainfluenza, and adenovirus, and in certain hemolytic anemias. Low titers of cold agglutinins have been demonstrated in malaria, peripheral vascular disease, and common respiratory diseases.

Warm AIHA is caused by IgG antibody activities at body temperature or at 98.6°F. They may or may not bind complement and are removed from circulation by the spleen. Cold AIHA is due to IgM antibodies coating red cells at lower temperatures. They bind complement and lead to red blood cell destruction of agglutinated cells. If the antibody is active at temperatures approaching 98.6°F, clinically significant intravascular and sometimes extravascular complement-mediated hemolysis occur in the liver.⁵

The incidence of warm AIHA occurs about 10 per 1 million people and affects women twice often as men.² It can be primary or idiopathic, or associated with various underlying conditions, including autoimmune disorders, immunodeficiency syndromes, lymphoproliferative disorders, other malignancies, and certain drugs. In more severe cases, jaundice and splenomegaly may occur. The blood smear in warm AIHA demonstrates variable spherocytosis, polychromasia, and rare erythrophagocytosis. Treatment usually includes steroids, cytotoxic agents, and splenectomy in severe cases.

There have been few case reports describing influenza as a cause of cold agglutinin hemolytic anemia. Chen and colleagues reported a case of influenza A infection in a 22-month-old boy.⁶Schoindre and colleagues reported the case of a 60-year-old woman infected with influenza A H1N1 virus who died from CAD.⁷ Shizuma reported the case of a 67-year-old man with alcoholic cirrhosis who developed a mixed hemolytic anemia and was positive for influenza A.⁸Our patient presented with influenza A, which had been diagnosed by respiratory virus panel at a different hospital, and she was anemic at the time of presentation to the outside hospital, with a positive DAT test. She was treated for influenza A with a full course of osltamivir and then returned with complaints of worsening fatigue and was again noted to be anemic with the development of patchy opacities on chest X-ray. The patient was subsequently transferred to our hospital and remained anemic during the course of her treatment. She received supportive care for her underlying influenza A and had symptomatic improvement. She ultimately decided the she would like to pursue further treatment in her native country and was discharged.

In conclusion, this case represents a rare complication of a common illness. Few cases of influenza causing hemolytic anemia have been reported in the literature. There have been reports of oseltamivir causing hemolytic anemia, but our patient presented with evidence of hemolytic anemia before initiation of the medication. In all the aforementioned cases, the patients died as a result of comorbid conditions. Our patient was stable enough to be discharged from the hospital after treatment of her comorbid conditions.

Acknowledgment
The authors thank David Henry, MD, at Pennsylvania Hospital, Philadelphia, for sharing this case and for his guidance during this patient’s treatment.

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

The United States Food and Drug Administration’s approval earlier this year of pembrolizumab marks the first tumor agnostic indication for a cancer drug.^1,2 Accelerated approval was granted for the treatment of adult and pediatric patients with any unresectable or metastatic solid tumor that displays mismatch repair deficiencies (dMMR) or high levels of microsatellite instability (MSI-H) and who have progressed after previous treatment and have no satisfactory alternatives. It is also approved specifically for patients with MSI-H or dMMR colorectal cancer (CRC) that has progressed after treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.

Pembrolizumab is a programmed cell death protein-1 (PD-1) receptor inhibitor that blocks the interaction between PD-1 and its ligand, PD-L1, restoring the activity of tumor-infiltrating T cells and boosting the anti-tumor immune response. It is thought to be particularly effective in dMMR/MSI-H tumors because they have a high mutational load and therefore display an abundance of antigens on their surfaces to provoke an immune response.

Approval for the drug was based on the demonstration of durable responses in 149 patients with MSI-H or dMMR cancers across 5 uncontrolled, multicohort, multicenter, single-arm trials. In all, 90 of the patients had CRC, and the remaining 59 patients had 1 of 14 other cancer types that included endometrial, biliary, gastric or gastroesophageal, pancreatic, and breast cancers.

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.

The accelerated approval by the United States Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK) inhibitor brigatinib, marked the fourth approved drug in this class.¹ The most recent approval expands the available treatment options for patients with metastatic ALK-positive non–small-cell lung cancer (NSCLC) whose disease is no longer responding to the first-line ALK inhibitor crizotinib. The FDA based its decision on the results of the phase 2 ALTA trial, in which a significant proportion of patients experienced tumor shrinkage.²

The pivotal trial was a noncomparative, 2-arm, open-label, multicenter study that was carried out during June 2014-September 2015 at 71 centers across 18 countries. Eligible patients were 18 years or older, with locally advanced or metastatic ALK-positive NSCLC, disease progression while taking crizotinib, at least 1 measurable lesion, adequate organ and hematologic function, and Eastern Cooperative Oncology Group (ECOG) performance status of ≤2 (range, 0-5, where 0 means the patient is fully active, and 2, ambulatory and capable of all self-care but not able to carry out any work activities).

Patients were excluded from the trial if they had received previous ALK inhibitor therapy, other than crizotinib, or had received crizotinib within 3 days of the first dose of brigatinib, or they had received chemotherapy, radiation therapy, or investigational drugs within 14 days or monoclonal antibody therapy within 30 days of the first dose of the study drug. Anyone with a history or the presence of pulmonary interstitial disease or drug-related pneumonitis or symptomatic central nervous system (CNS) metastases that were neurologically unstable or required an increasing dose of corticosteroids was also ineligible.

A total of 222 patients were randomized to receive one of two brigatinib doses, either 90 mg daily or 180 mg daily after a 7-day lead-in at 90 mg (the latter to help mitigate pulmonary adverse events observed in previous studies). Randomization was stratified according to baseline brain metastases (present or absent) and best investigator-assessed response to crizotinib (complete response [CR] or partial response [PR] vs other or unknown)

Chest and abdomen imaging by computed-tomography (CT) or magnetic resonance imaging (MRI) with contrast were performed to assess disease at screening and every 8 weeks through cycle 15, and then every 12 weeks until disease progression. Contrast-enhanced brain MRI was carried out at screening and repeated after baseline for the 68% of patients who had CNS metastases at the time of enrollment.

The primary endpoint was confirmed investigator-assessed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1), and secondary endpoints included CNS response, duration of response (DoR), progression-free and overall survival (PFS and OS, respectively). ORRs for the 90-mg and 180-mg doses were 48% and 53%, respectively. Responses occurred quickly and were durable in both arms; after a median follow-up of 8 months, median DoR was 13.8 months for both doses. Among the patients with brain metastases, the intracranial response rates for the two doses were 42% and 67%, respectively, notable because of the poor ability of crizotinib to penetrate the blood-brain barrier.

Other secondary outcomes also favored the 180-mg dose. Investigator-assessed PFS for the 90-mg and 180-mg doses were 9.2 months and 12.9 months, respectively, and estimated 1-year OS was 71% and 80%, respectively, the latter representing a nonstatistically significant 43% reduction in the risk of death with the 180 mg dose. There were 4 confirmed CRs in the 180-mg arm and 1 in the 90-mg arm.

The safety of brigatinib was evaluated in 219 patients who received at least 1 dose of brigatinib. Treatment was discontinued in 8% of patients in the 180-mg arm and 3% in the 90-mg arm because of adverse events (AEs). The most common AEs were nausea, diarrhea, fatigue, cough, and headache, and visual disturbances also occurred. The most common serious AEs were pneumonia and interstitial lung disease/pneumonitis.

The prescribing information details warnings and precautions about these and other potential toxicities, including hypertension, bradycardia, creatine phosphokinase (CPK) and pancreatic enzyme elevation, and hyperglycemia.³ Patients should be monitored for new or worsening respiratory symptoms, especially during the first week of initiating brigatinib treatment; blood pressure should be controlled before treatment initiation and monitored after 2 weeks and at least monthly thereafter; heart rate and blood pressure should be monitored frequently; patients should be advised to report any visual symptoms, or any unexplained muscle pain, tenderness or weakness; CPK, lipase, and amylase levels should be monitored during treatment, and fasting glucose tested before starting treatment and periodically thereafter.

Brigatinib should be withheld in any patient with new or worsening respiratory symptoms, for grade 3 hypertension despite optimal antihypertensive therapy, for symptomatic bradycardia, for patients with new or worsening visual symptoms of grade 2 or above, for grade 3 or 4 CPK or pancreatic enzyme elevation, or if adequate hyperglycemia control cannot be achieved. Treatment should be permanently discontinued for grade 3 or 4 or recurrent interstitial lung disease/pneumonitis, grade 4 or recurrent grade 3 hypertension, life-threatening bradycardia, and grade 4 visual disturbance.

Based on its mechanism of action, brigatinib can cause fetal harm and patients of reproductive potential should be advised of the risks and necessary precautions. Brigatinib is marketed as Alunbrig. It was discovered by Ariad Pharmaceuticals Inc, which was acquired by Takeda in February 2017.