Introduction

Exocrine pancreatic cancer refers to pancreatic adenocarcinomas that arise from ductal epithelial cells. Pancreatic ductal adenocarcinoma is a highly lethal malignancy, ranking as the fourth most common cause of cancer-related death in the United States¹ and the eighth most common worldwide.² In the United States, the pancreas is the second most common site of gastrointestinal malignancy after the colon.¹ The only potentially curative modality for pancreatic adenocarcinomas is complete resection, followed by adjuvant therapy; unfortunately, only around 20% of patients are surgical candidates at the time of presentation due to delayed development of symptoms and consequently diagnosis.³ Most symptomatic patients with pancreatic cancer have locally advanced disease at diagnosis, and only a select group of patients with good performance status and borderline resectable disease can be offered neoadjuvant therapy. Adjuvant chemotherapy is typically recommended for patients who undergo potentially curative resection for pancreatic cancer.

Epidemiology

In the United States, pancreatic cancer has an annual estimated incidence of 55,440 new cases.¹ It causes an estimated 44,330 deaths per year, with a 5-year overall survival (OS) rate of 8.2%.¹ Worldwide an estimated 138,100 men and 127,900 women die of pancreatic cancer each year.² In general, pancreatic cancers occur more commonly in persons living in Western/industrialized countries, older persons (age > 60 years), males (ratio 1.3:1 female), and African-Americans and native Hawaiians.⁴

Etiology

The major preventable environmental risk factor for pancreatic cancer is cigarette smoking, which accounts for 25% of all cases.⁵ A prospective study that estimated the excess incidence of pancreatic cancer among cigarette smokers and assessed the influence of smoking cessation on the risk for pancreatic cancer showed that persons who quit smoking reduced their risk of pancreatic cancer by 48% after 2 years of cessation, compared with smokers who did not quit, and reduced their risk to near the level of a never smoker after 10 years of cessation.⁵ Risk is higher for heavy smokers and those with homozygous deletions of the glutathione S-transferase theta 1 gene (GSTT1), which results in the absence of the carcinogen-metabolizing function of the glutathione S-transferase enzyme. High body mass index and sedentary lifestyle have been linked to pancreatic cancer.⁶ Data regarding aspirin, diet, coffee, and excess alcohol consumption are insufficient, inconclusive, and even conflicting, and thus the effect of these factors on risk for pancreatic cancer remains unclear. Infectious risk factors such as Helicobacter pylori and hepatitis B and C virus have weak associations with pancreatic cancer. Chronic pancreatitis and pancreatic cysts (eg, intraductal papillary mucinous neoplasm [IPMN] of the pancreas) carry a risk for malignant transformation, and hence may require surveillance. Multiple epidemiologic studies have shown a strong association between pancreatic cancer and recently diagnosed diabetes mellitus (relative risk [RR] 1.97 [95% confidence interval {CI} 1.78 to 2.18]); the presence of diabetes also may be a long-term predisposing factor for pancreatic cancer, and cancer screening needs to be considered for selected patients.⁷

A predisposing genetic anomaly accounts for 15% of all cases of pancreatic cancer.⁸ Hereditary risk factors are divided into 2 broad categories: defined genetic syndromes and familial pancreatic cancer. Familial predispositions that do not meet genetic syndrome criteria account for approximately 5% to 10% of all cases associated with hereditary factors; in one study, 29% of tested kindreds with an incident pancreatic cancer had a germline BRCA2 mutation.⁹ Other predisposing genetic syndromes that have been linked to pancreatic cancer include:

• Peutz-Jeghers syndrome with germline STK11 mutations (RR 132);
• Hereditary pancreatitis with germline PRSS1, SPINK1, and CFTR mutations (RR 26–87);
• Familial atypical multiple mole melanoma syndrome with CDKN2A mutations (RR 20–40);
• Familial breast and ovarian cancer with BRCA2 (RR 10) and BRCA1 (RR 2.8) mutations;
• Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch II syndrome) with MLH1, MSH2, MSH6, and PMS2 mutations (RR 9–11); and
• Familial adenomatous polyposis with APC mutations (RR 5).¹⁰

Other gene mutations with unknown relative risk for pancreatic cancer include mutations affecting PALB2, ATM, and TP53.

The International Cancer of the Pancreas Screening consortium consensus on screening for pancreatic cancer in patients with increased risk for familial pancreatic cancer recommends screening those at high risk: first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic kindred with at least 2 affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2, and HNPCC mutation carriers with 1 or more affected FDRs and hereditary pancreatitis. The guidelines emphasize that screening should be done only in those who are surgical candidates and are evaluated at an experienced multidisciplinary center.⁸

Deleterious germline mutations in pancreatic cancer can account for 33% of patients with apparent sporadic cancers and no hereditary risk. These include germline mutations affecting BRCA1/2, PALB2, ATM, MLH1, CHK-2, CDKN2A, and TP53.¹¹

Pathogenesis

Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.¹² It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.¹³ This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.

Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).¹⁴ Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.¹⁵ Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.¹⁴ Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.¹⁶

Diagnosis and Staging

Case Presentation

A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.

• What is the typical presentation of pancreatic cancer?

The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).¹⁷ The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).¹⁷ The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.¹⁸ Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.

• What is the approach to diagnosis and staging?

History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.¹⁹ Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).²⁰ Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.

If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,²¹ but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.

The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.²² CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.²³

The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1). 

Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.

Neoadjuvant Therapy

Case Continued

The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.

• What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?

Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.³ Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),²⁸ the NCCN,²⁶ and the European Society for Medical Oncology (ESMO),²⁹ particularly for patients with borderline resectable tumors (Table 3). 

Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.²⁶ Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.

Case Continued

A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.

• What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?

There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,³² and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,²⁶ although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.²⁸ The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.

The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.^26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.

Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.³³ Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m²/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m²/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m² for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).³⁴ Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.³⁵ Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m² days 1, 8, and 15 and capecitabine 830 mg/m² days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m² twice daily on weekdays only) or gemcitabine (300 mg/m² weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).

The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m²/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m²/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m² weekly for 7 weeks) followed by maintenance gemcitabine in both arms.³⁶ Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.³⁷ LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m²) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.^26,28,29

Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial³⁸) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial³⁹) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.⁴⁰ A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.⁴¹ In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.⁴¹

The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.⁴² A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.⁴³ The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.

There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.³⁹ An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.²⁶ Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.²⁶ A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).

Summary

Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).

Adjuvant Therapy

Case Continued

Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.

• Would the patient benefit from adjuvant therapy?

Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.²⁸ Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.²⁸ Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.

The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m² and leucovorin 20 mg/m² daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m² intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.⁴⁴ The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. ⁴⁵ Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.

The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m² days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.³⁰ A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.³¹

Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.³² This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m² weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m² followed by fluorouracil 425 mg/m² intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).⁴⁶ Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.

The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m² daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.⁴⁷

The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.⁴⁸ Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m²/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m²/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,²⁸ but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,^26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.

Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.

Follow-Up and Surveillance

Case Conclusion

After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.

• What is the recommended duration of surveillance following curative resection?

Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.²⁶ However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.^26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.

Conclusion

Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.

Introduction

Exocrine pancreatic cancer refers to pancreatic adenocarcinomas that arise from ductal epithelial cells. Pancreatic ductal adenocarcinoma is a highly lethal malignancy, ranking as the fourth most common cause of cancer-related death in the United States¹ and the eighth most common worldwide.² In the United States, the pancreas is the second most common site of gastrointestinal malignancy after the colon.¹ The only potentially curative modality for pancreatic adenocarcinomas is complete resection, followed by adjuvant therapy; unfortunately, only around 20% of patients are surgical candidates at the time of presentation due to delayed development of symptoms and consequently diagnosis.³ Most symptomatic patients with pancreatic cancer have locally advanced disease at diagnosis, and only a select group of patients with good performance status and borderline resectable disease can be offered neoadjuvant therapy. Adjuvant chemotherapy is typically recommended for patients who undergo potentially curative resection for pancreatic cancer.

Epidemiology

In the United States, pancreatic cancer has an annual estimated incidence of 55,440 new cases.¹ It causes an estimated 44,330 deaths per year, with a 5-year overall survival (OS) rate of 8.2%.¹ Worldwide an estimated 138,100 men and 127,900 women die of pancreatic cancer each year.² In general, pancreatic cancers occur more commonly in persons living in Western/industrialized countries, older persons (age > 60 years), males (ratio 1.3:1 female), and African-Americans and native Hawaiians.⁴

Etiology

The major preventable environmental risk factor for pancreatic cancer is cigarette smoking, which accounts for 25% of all cases.⁵ A prospective study that estimated the excess incidence of pancreatic cancer among cigarette smokers and assessed the influence of smoking cessation on the risk for pancreatic cancer showed that persons who quit smoking reduced their risk of pancreatic cancer by 48% after 2 years of cessation, compared with smokers who did not quit, and reduced their risk to near the level of a never smoker after 10 years of cessation.⁵ Risk is higher for heavy smokers and those with homozygous deletions of the glutathione S-transferase theta 1 gene (GSTT1), which results in the absence of the carcinogen-metabolizing function of the glutathione S-transferase enzyme. High body mass index and sedentary lifestyle have been linked to pancreatic cancer.⁶ Data regarding aspirin, diet, coffee, and excess alcohol consumption are insufficient, inconclusive, and even conflicting, and thus the effect of these factors on risk for pancreatic cancer remains unclear. Infectious risk factors such as Helicobacter pylori and hepatitis B and C virus have weak associations with pancreatic cancer. Chronic pancreatitis and pancreatic cysts (eg, intraductal papillary mucinous neoplasm [IPMN] of the pancreas) carry a risk for malignant transformation, and hence may require surveillance. Multiple epidemiologic studies have shown a strong association between pancreatic cancer and recently diagnosed diabetes mellitus (relative risk [RR] 1.97 [95% confidence interval {CI} 1.78 to 2.18]); the presence of diabetes also may be a long-term predisposing factor for pancreatic cancer, and cancer screening needs to be considered for selected patients.⁷

A predisposing genetic anomaly accounts for 15% of all cases of pancreatic cancer.⁸ Hereditary risk factors are divided into 2 broad categories: defined genetic syndromes and familial pancreatic cancer. Familial predispositions that do not meet genetic syndrome criteria account for approximately 5% to 10% of all cases associated with hereditary factors; in one study, 29% of tested kindreds with an incident pancreatic cancer had a germline BRCA2 mutation.⁹ Other predisposing genetic syndromes that have been linked to pancreatic cancer include:

• Peutz-Jeghers syndrome with germline STK11 mutations (RR 132);
• Hereditary pancreatitis with germline PRSS1, SPINK1, and CFTR mutations (RR 26–87);
• Familial atypical multiple mole melanoma syndrome with CDKN2A mutations (RR 20–40);
• Familial breast and ovarian cancer with BRCA2 (RR 10) and BRCA1 (RR 2.8) mutations;
• Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch II syndrome) with MLH1, MSH2, MSH6, and PMS2 mutations (RR 9–11); and
• Familial adenomatous polyposis with APC mutations (RR 5).¹⁰

Other gene mutations with unknown relative risk for pancreatic cancer include mutations affecting PALB2, ATM, and TP53.

The International Cancer of the Pancreas Screening consortium consensus on screening for pancreatic cancer in patients with increased risk for familial pancreatic cancer recommends screening those at high risk: first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic kindred with at least 2 affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2, and HNPCC mutation carriers with 1 or more affected FDRs and hereditary pancreatitis. The guidelines emphasize that screening should be done only in those who are surgical candidates and are evaluated at an experienced multidisciplinary center.⁸

Deleterious germline mutations in pancreatic cancer can account for 33% of patients with apparent sporadic cancers and no hereditary risk. These include germline mutations affecting BRCA1/2, PALB2, ATM, MLH1, CHK-2, CDKN2A, and TP53.¹¹

Pathogenesis

Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.¹² It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.¹³ This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.

Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).¹⁴ Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.¹⁵ Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.¹⁴ Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.¹⁶

Diagnosis and Staging

Case Presentation

A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.

• What is the typical presentation of pancreatic cancer?

The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).¹⁷ The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).¹⁷ The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.¹⁸ Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.

• What is the approach to diagnosis and staging?

History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.¹⁹ Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).²⁰ Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.

If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,²¹ but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.

The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.²² CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.²³

The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1). 

Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.

Neoadjuvant Therapy

Case Continued

The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.

• What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?

Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.³ Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),²⁸ the NCCN,²⁶ and the European Society for Medical Oncology (ESMO),²⁹ particularly for patients with borderline resectable tumors (Table 3). 

Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.²⁶ Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.

Case Continued

A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.

• What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?

There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,³² and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,²⁶ although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.²⁸ The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.

The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.^26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.

Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.³³ Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m²/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m²/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m² for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).³⁴ Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.³⁵ Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m² days 1, 8, and 15 and capecitabine 830 mg/m² days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m² twice daily on weekdays only) or gemcitabine (300 mg/m² weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).

The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m²/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m²/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m² weekly for 7 weeks) followed by maintenance gemcitabine in both arms.³⁶ Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.³⁷ LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m²) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.^26,28,29

Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial³⁸) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial³⁹) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.⁴⁰ A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.⁴¹ In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.⁴¹

The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.⁴² A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.⁴³ The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.

There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.³⁹ An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.²⁶ Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.²⁶ A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).

Summary

Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).

Adjuvant Therapy

Case Continued

Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.

• Would the patient benefit from adjuvant therapy?

Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.²⁸ Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.²⁸ Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.

The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m² and leucovorin 20 mg/m² daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m² intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.⁴⁴ The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. ⁴⁵ Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.

The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m² days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.³⁰ A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.³¹

Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.³² This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m² weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m² followed by fluorouracil 425 mg/m² intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).⁴⁶ Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.

The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m² daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.⁴⁷

The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.⁴⁸ Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m²/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m²/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,²⁸ but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,^26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.

Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.

Follow-Up and Surveillance

Case Conclusion

After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.

• What is the recommended duration of surveillance following curative resection?

Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.²⁶ However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.^26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.

Conclusion

Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.

Introduction

Exocrine pancreatic cancer refers to pancreatic adenocarcinomas that arise from ductal epithelial cells. Pancreatic ductal adenocarcinoma is a highly lethal malignancy, ranking as the fourth most common cause of cancer-related death in the United States¹ and the eighth most common worldwide.² In the United States, the pancreas is the second most common site of gastrointestinal malignancy after the colon.¹ The only potentially curative modality for pancreatic adenocarcinomas is complete resection, followed by adjuvant therapy; unfortunately, only around 20% of patients are surgical candidates at the time of presentation due to delayed development of symptoms and consequently diagnosis.³ Most symptomatic patients with pancreatic cancer have locally advanced disease at diagnosis, and only a select group of patients with good performance status and borderline resectable disease can be offered neoadjuvant therapy. Adjuvant chemotherapy is typically recommended for patients who undergo potentially curative resection for pancreatic cancer.

Epidemiology

In the United States, pancreatic cancer has an annual estimated incidence of 55,440 new cases.¹ It causes an estimated 44,330 deaths per year, with a 5-year overall survival (OS) rate of 8.2%.¹ Worldwide an estimated 138,100 men and 127,900 women die of pancreatic cancer each year.² In general, pancreatic cancers occur more commonly in persons living in Western/industrialized countries, older persons (age > 60 years), males (ratio 1.3:1 female), and African-Americans and native Hawaiians.⁴

Etiology

The major preventable environmental risk factor for pancreatic cancer is cigarette smoking, which accounts for 25% of all cases.⁵ A prospective study that estimated the excess incidence of pancreatic cancer among cigarette smokers and assessed the influence of smoking cessation on the risk for pancreatic cancer showed that persons who quit smoking reduced their risk of pancreatic cancer by 48% after 2 years of cessation, compared with smokers who did not quit, and reduced their risk to near the level of a never smoker after 10 years of cessation.⁵ Risk is higher for heavy smokers and those with homozygous deletions of the glutathione S-transferase theta 1 gene (GSTT1), which results in the absence of the carcinogen-metabolizing function of the glutathione S-transferase enzyme. High body mass index and sedentary lifestyle have been linked to pancreatic cancer.⁶ Data regarding aspirin, diet, coffee, and excess alcohol consumption are insufficient, inconclusive, and even conflicting, and thus the effect of these factors on risk for pancreatic cancer remains unclear. Infectious risk factors such as Helicobacter pylori and hepatitis B and C virus have weak associations with pancreatic cancer. Chronic pancreatitis and pancreatic cysts (eg, intraductal papillary mucinous neoplasm [IPMN] of the pancreas) carry a risk for malignant transformation, and hence may require surveillance. Multiple epidemiologic studies have shown a strong association between pancreatic cancer and recently diagnosed diabetes mellitus (relative risk [RR] 1.97 [95% confidence interval {CI} 1.78 to 2.18]); the presence of diabetes also may be a long-term predisposing factor for pancreatic cancer, and cancer screening needs to be considered for selected patients.⁷

A predisposing genetic anomaly accounts for 15% of all cases of pancreatic cancer.⁸ Hereditary risk factors are divided into 2 broad categories: defined genetic syndromes and familial pancreatic cancer. Familial predispositions that do not meet genetic syndrome criteria account for approximately 5% to 10% of all cases associated with hereditary factors; in one study, 29% of tested kindreds with an incident pancreatic cancer had a germline BRCA2 mutation.⁹ Other predisposing genetic syndromes that have been linked to pancreatic cancer include:

• Peutz-Jeghers syndrome with germline STK11 mutations (RR 132);
• Hereditary pancreatitis with germline PRSS1, SPINK1, and CFTR mutations (RR 26–87);
• Familial atypical multiple mole melanoma syndrome with CDKN2A mutations (RR 20–40);
• Familial breast and ovarian cancer with BRCA2 (RR 10) and BRCA1 (RR 2.8) mutations;
• Hereditary nonpolyposis colorectal cancer (HNPCC, Lynch II syndrome) with MLH1, MSH2, MSH6, and PMS2 mutations (RR 9–11); and
• Familial adenomatous polyposis with APC mutations (RR 5).¹⁰

Other gene mutations with unknown relative risk for pancreatic cancer include mutations affecting PALB2, ATM, and TP53.

The International Cancer of the Pancreas Screening consortium consensus on screening for pancreatic cancer in patients with increased risk for familial pancreatic cancer recommends screening those at high risk: first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic kindred with at least 2 affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2, and HNPCC mutation carriers with 1 or more affected FDRs and hereditary pancreatitis. The guidelines emphasize that screening should be done only in those who are surgical candidates and are evaluated at an experienced multidisciplinary center.⁸

Deleterious germline mutations in pancreatic cancer can account for 33% of patients with apparent sporadic cancers and no hereditary risk. These include germline mutations affecting BRCA1/2, PALB2, ATM, MLH1, CHK-2, CDKN2A, and TP53.¹¹

Pathogenesis

Pancreatic neoplasms can be benign or malignant and thus a tissue histologic diagnosis is paramount. Pancreatic adenocarcinomas with exocrine features represent more than 95% of all pancreatic neoplasms, with only 5% arising from the endocrine pancreas (ie, neuroendocrine tumors). Pancreatic neuroendocrine tumors and pancreatic adenocarcinoma must be distinguished histologically because treatment of the 2 neoplasms is completely different. Other malignant pancreatic tumors are signet ring cell carcinoma, adenosquamous carcinoma, undifferentiated (anaplastic) carcinoma, and mucinous noncystic (colloid) carcinoma; the latter tumor has a better prognosis.¹² It is essential to characterize and distinguish among benign cystic neoplasms, as some require surgical resection due to the risk of malignant transformation. IPMN, pancreatic intraepithelial neoplasia, and mucinous cystic neoplasms are thought to be premalignant lesions of invasive ductal adenocarcinomas, and the pathological report should highlight the degree of dysplasia for adequate risk stratification.¹³ This information could be the deciding factor in whether a pancreatectomy is recommended by a multidisciplinary team.

Most pancreatic cancers harbor activating or silencing genetic mutations, and multiple combinations of altered genes can be detected by next-generation sequencing (average of 63 genetic alterations per cancer).¹⁴ Mutational activated KRAS is the most frequent (> 90%) genetic alteration in pancreatic cancer, even in early neoplastic precursors (IPMN > 75%). KRAS is a highly complex, dynamic proto-oncogene involved in signaling of various receptor kinases such as the epidermal growth factor receptor and the insulin-like growth factor receptor-I. It also engages in canonical downstream effector pathways, mainly Raf/MEK/ERK, PI3K/PDK1/Akt, and the Ral guanine nucleotide exchange factor pathway, which drive much of the pathogenesis of malignancy. These pathways lead to sustained proliferation, metabolic reprogramming, anti-apoptosis, remodeling of the tumor microenvironment, evasion of the immune response, cell migration, and metastasis. An activating point mutation in codon G12 is the most common (98%) locus of KRAS mutation in pancreatic adenocarcinoma, but all drugs targeting this mutation have failed in clinical practice.¹⁵ Additionally, inactivation of tumor suppressor genes such as p53, DPC4 (SMAD4/MADH4), CDKN2A (p16/MTS1), and BRCA2 can be found in 75%, 30%, 35%, and 4% of pancreatic adenocarcinoma cases, respectively.¹⁴ Another pancreatic cancer hallmark is inactivation of DNA damage repair genes, which include MLH1 and MSH2.¹⁶

Diagnosis and Staging

Case Presentation

A 71-year-old male veteran with no significant past medical history other than hypertension and hyperlipidemia and an excellent performance status presents to the emergency department after noticing a yellowish skin and sclera color. He denies weight loss, abdominal pain, or any other pertinent symptom or sign. Physical examination reveals a healthy developed man with yellowish discoloration of the skin and sclera and a soft, nontender benign abdomen; physical examination is otherwise unremarkable. Laboratory evaluation reveals a direct bilirubin level of 4.5 mg/dL and normal values for complete blood count and renal, liver, and coagulation panels. Abdominal and pelvis computed tomography (CT) with intravenous contrast shows a pancreatic head mass measuring 2.6 × 2.3 cm minimally abutting the anterior surface of the superior mesenteric vein, which remains patent. Follow-up endoscopic ultrasound (EUS) confirms an irregular mass at the head of the pancreas measuring 3.2 × 2.6 cm with sonographic evidence suggesting invasion into the portal vein. During the procedure, the bile duct is successfully stented, the mass is biopsied, and bile duct brushing is performed. Pathology report is consistent with pancreatic adenocarcinoma.

• What is the typical presentation of pancreatic cancer?

The most common symptoms of pancreatic cancer at the time of presentation include weight loss (85%), asthenia/anorexia (86%), and/or abdominal pain (79%).¹⁷ The most frequent signs are jaundice (55%), hepatomegaly (39%), and cachexia (13%). Courvoisier sign, a nontender but palpable distended gallbladder at the right costal margin, is neither sensitive nor specific for pancreatic cancer (13% of cases). Trousseau syndrome, a superficial thrombophlebitis, is another classic sign that reflects the hypercoagulable nature of pancreatic cancer (3% of cases).¹⁷ The pathophysiology of this syndrome is not completely understood, but it may occur secondary to the release of cancer microparticles in the blood stream which in turn stimulate the coagulation cascade. Other nonspecific symptoms are dark urine, nausea, vomiting, diarrhea, steatorrhea, and epigastric and back pain. Because symptoms early in the course of the disease are nonspecific, pancreatic cancer is typically diagnosed late, after the cancer has invaded local structures or metastasized. The initial presentation varies depending on tumor location, with 70% of pancreatic head malignancies presenting with jaundice and pain correlating to an advanced stage.¹⁸ Although data supporting an association between new-onset diabetes mellitus and pancreatic cancer are inconclusive, pancreatic cancer should still be a consideration in patients with new-onset diabetes mellitus and other symptoms such as pain and weight loss. Early signs of incurable disease include a palpable mass, ascites, lymphadenopathy (classic Virchow node), and an umbilical mass (Sister Mary Joseph node). Incidentally discovered pancreatic masses on imaging are rare, but the incidence is increasing due to frequent imaging for other reasons and improved diagnostic techniques.

• What is the approach to diagnosis and staging?

History and physical examination findings are not sufficiently sensitive or specific to diagnose pancreatic cancer. High clinical suspicion in a patient with risk factors can lead to a comprehensive evaluation and potential early diagnosis. In general, an initial diagnostic work-up for suspected pancreatic cancer will include serologic evaluation (liver function test, lipase, tumor markers) and abdominal imaging (ultrasound, CT scans, or magnetic resonance imaging [MRI]). Ultrasound is a first-line diagnostic tool with a sensitivity of 90% and specificity of 98.8% for pancreatic cancer, but it is investigator-dependent and is less accurate in detecting tumors smaller than 3 cm in diameter.¹⁹ Multiphasic helical CT of the abdomen has better sensitivity (100%) and specificity (100%) for detecting tumors larger than 2 cm, but this modality is less accurate in detecting pancreatic masses smaller than 2 cm (77%).²⁰ Percutaneous fine-needle aspiration (FNA) performed by ultrasound or CT guidance is avoided due to theoretical concerns about intraperitoneal seeding and bleeding.

If a pancreatic mass is detected by ultrasound or CT, additional interventions may be indicated depending on the clinical scenario. EUS-guided biopsy can provide histological confirmation and is currently utilized frequently for diagnosis and early resectability staging. Endoscopic retrograde cholangiopancreatography (ERCP) is indicated for patients with biliary obstruction requiring stent placement, and this procedure may provide tissue confirmation by forceps biopsy or brush cytology (lower accuracy than EUS). In a meta-analysis that evaluated the diagnostic value of tests for pancreatic cancer, ERCP had the highest sensitivity (92%) and specificity (96%) compared to ultrasound and CT,²¹ but this modality carries a risk for pancreatitis, bleeding, and cholangitis. Magnetic resonance cholangiopancreatography has not replaced ERCP, but it but may be an alternative for patients who cannot undergo ERCP (eg, gastric outlet obstruction, duodenal stenosis, anatomical surgical disruption, unsuccessful ERCP). ERCP is used frequently because many patients present with obstructive jaundice due to pancreatic mass compression, specifically if the mass is located in the head, and must undergo ERCP and stenting of the common bile duct.

The carbohydrate antigen (CA) 19-9 level has variable sensitivity and specificity in pancreatic cancer, as levels can be elevated in many benign pancreaticobiliary disorders. Elevated CA 19-9, in the appropriate clinical scenario (ie, a suspicious pancreatic mass and a value greater than 37 U/mL) demonstrated a sensitivity of 77% and specificity of 87% when differentiating pancreaticobiliary cancer from benign clinical conditions such as acute cholangitis or cholestasis.²² CA 19-9 level has prognostic value, as it may predict occult disease and correlates with survival rates, but no specific cutoff value has been established to guide perioperative therapy for high-risk resectable tumors.²³

The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) system is the preferred method for staging pancreatic cancer (Table 1). 

Positron emission tomography with CT scan is occasionally utilized in practice to assess tumor burden by evaluating anatomical structures and assessing physiologic uptake, which aids in establishing the extent of disease in equivocal cases. Staging laparoscopy with or without peritoneal biopsy is sometimes used to establish appropriate staging in cases that are questionable for occult metastatic disease. This procedure helps avoid unnecessary morbid surgeries.

Neoadjuvant Therapy

Case Continued

The patient is referred to oncology. Blood work reveals a CA 19-9 level of 100 U/mL (reference range < 35 U/mL) and a staging CT scan of the chest reveals a benign-appearing 3-mm nodule (no prior imaging for comparison). CT scan of the abdomen and pelvis does not define venous vasculature involvement appropriately and hence MRI of the abdomen and pelvis is performed. MRI reveals a pancreatic head mass measuring 3.0 × 2.7 cm, without arterial or venous vasculature invasion. However, the mass is abutting the portal vein and superior mesenteric vein and there is a new nonspecific 8-mm aortocaval lymph node.

• What are the current approaches to treating patients with resectable, unresectable, and metastatic disease?

Accurate staging and assessment of surgical resectability in pancreatic cancer are paramount as these steps prevent a futile morbid Whipple procedure in patients with advanced disease and a high risk of recurrence. Conversely, it allows patients with low-volume disease to undergo a potentially curative surgery. Approximately 20% of patients present with resectable disease, 40% present with locally advanced unresectable tumors (eg, involvement of critical vascular structures), and 40% present with metastatic disease.³ Treatment for resectable pancreatic cancer continues to be upfront surgery, although neoadjuvant therapy with either chemoradiation, radiation alone, or chemotherapy is an option per guidelines from the American Society of Clinical Oncology (ASCO),²⁸ the NCCN,²⁶ and the European Society for Medical Oncology (ESMO),²⁹ particularly for patients with borderline resectable tumors (Table 3). 

Systemic chemotherapy is recommended for fit candidates with locally advanced unresectable or metastatic disease, with an emphasis on supportive palliative measures. Palliative interventions include biliary stenting, duodenal stent for relieving gastric-outlet obstruction, and celiac axis nerve blocks, when indicated. Routine preoperative biliary stent placement/drainage in patients undergoing subsequent surgery for pancreatic cancer located in the head is associated with an increased risk of surgical complications when compared with up-front surgery without prior biliary drainage, and thus stent placement/drainage is not recommended.²⁶ Aggressive supportive management of symptoms, such as cancer-associated pain, anorexia-cachexia syndromes, and anxiety-depression disorders, should remain a primary palliative focus.

Case Continued

A multidisciplinary tumor board discusses the patient’s case and deems the cancer borderline resectable; neoadjuvant therapy is recommended. The patient is started on treatment with gemcitabine and nab-paclitaxel as first-line neoadjuvant therapy. After 4 cycles, the CA 19-9 level drops to 14 U/mL, and MRI reveals a smaller head mass of 1.3 × 1.4 cm with stable effacement of the superior mesenteric vein and no portal vein involvement; the aortocaval lymph node remains stable. At tumor board, it is evident that the patient has responded to therapy and the recommendation is to treat with gemcitabine chemoradiotherapy before surgery.

• What neoadjuvant therapy strategies are used in the treatment of pancreatic adenocarcinoma?

There are no established evidence-based recommendations for neoadjuvant therapy in patients with borderline resectable pancreatic cancer or patients with unresectable locally advanced pancreatic cancer. However, there are ongoing trials to investigate this treatment approach, and it is offered off-label in specific clinical scenarios, such as in the case patient described here. In patients with borderline resectable disease, preoperative chemotherapy followed by chemoradiation is a routine practice in most cancer centers,³² and ongoing clinical trials are an option for this cohort of patients (eg, Southwest Oncology Group Trial 1505, NCT02562716). The definitions of borderline resectable and unresectable pancreatic cancer have been described by the NCCN,²⁶ although most surgeons consider involvement of the major upper abdominal blood vessels the main unresectability criterion; oncologists also consider other parameters such as suspicious lesions on scans, worsening performance status, and a significantly elevated CA 19-9 level suggestive of disseminated disease.²⁸ The goal of a conversion approach by chemotherapy with or without radiation for borderline and unresectable cancers is to deliver a tolerable regimen leading to tumor downstaging, allowing for surgical resection. No randomized clinical trial has shown a survival advantage of this approach. Enrollment in clinical trials is preferred for patients with borderline and unresectable cancer, and there are trials that are currently enrolling patients.

The main treatment strategies for patients with locally advanced borderline and unresectable pancreatic cancer outside of a clinical trial are primary radiotherapy, systemic chemotherapy, and chemoradiation therapy. Guidelines from ASCO, NCCN, and ESMO recommend induction chemotherapy followed by restaging and consolidation chemoradiotherapy in the absence of progression.^26,28,29 There is no standard chemoradiation regimen and the role of chemotherapy sensitizers, including fluorouracil, gemcitabine, and capecitabine (an oral fluoropyrimidine substitute), and targeted agents in combination with different radiation modalities is now being investigated.

Fluorouracil is a radio-sensitizer that has been used in locally advanced pancreatic cancer based on experience in other gastrointestinal malignancies; data shows conflicting results with this drug. Capecitabine and tegafur/gimeracil/oteracil (S-1) are oral prodrugs that can safely replace infusional fluorouracil. Gemcitabine, a more potent radiation sensitizer, is very toxic, even at low-doses twice weekly, and does not provide a survival benefit, as demonstrated in the Cancer and Leukemia Group B (CALGB) 89805 trial, a phase 2 study of patients with surgically staged locally advanced pancreatic cancer.³³ Gemcitabine-based chemoradiotherapy was also evaluated in the Eastern Cooperative Group (ECOG) E4201 trial, which randomly assigned patients to receive gemcitabine alone (at 1000 mg/m²/wk for weeks 1 through 6, followed by 1 week rest, then weekly for 3 out of 4 weeks) or gemcitabine (600 mg/m²/wk for weeks 1 to 5, then 4 weeks later 1000 mg/m² for 3 out of 4 weeks) plus radiotherapy (starting on day 1, 1.8 Gy/fraction for total of 50.4 Gy).³⁴ Patients with locally advanced unresectable pancreatic cancer had a better OS outcome with gemcitabine in combination with radiation therapy (11.1 months) as compared with patients who received gemcitabine alone (9.2 months). Although there was a greater incidence of grade 4 and 5 treatment-related toxicities in the combination arm, no statistical differences in quality-of-life measurements were reported. Gemcitabine-based and capecitabine-based chemoradiotherapy were compared in the open-label phase 2 multicenter randomized SCALOP trial.³⁵ Patients with locally advanced pancreatic cancer were assigned to receive 3 cycles of induction with gemcitabine 1000 mg/m² days 1, 8, and 15 and capecitabine 830 mg/m² days 1 to 21 every 28 days; patients who had stable or responding disease were randomly assigned to receive a fourth cycle followed by capecitabine (830 mg/m² twice daily on weekdays only) or gemcitabine (300 mg/m² weekly) with radiation (50.4 Gy over 28 fractions). Patients treated with capecitabine-based chemoradiotherapy had higher nonsignificant median OS (17.6 months) and median progression-free survival (12 months) compared to those treated with gemcitabine (14.6 months and 10.4 months, respectively).

The benefit of radiation therapy in the treatment of locally advanced pancreatic cancer was further explored by the Fédération Francophone de Cancérologie Digestive 2000-01 phase 3 trial. This study compared induction chemoradiotherapy (60 Gy, 2 Gy/fraction; concomitant fluorouracil infusion, 300 mg/m²/day, days 1–5 for 6 weeks; cisplatin, 20 mg/m²/day, days 1–5 during weeks 1 and 5) to gemcitabine alone (1000 mg/m² weekly for 7 weeks) followed by maintenance gemcitabine in both arms.³⁶ Unexpectedly, the median OS was significantly shorter in the chemoradiotherapy arm than in the chemotherapy alone arm (8.6 months versus 13 months, respectively, P = 0.03) and the combination arm had more toxicities. The phase 3 open-label LAP07 study explored the role of radiation therapy in patients with locally advanced pancreatic cancer who had controlled disease after 4 months of induction therapy.³⁷ LAP07 had 2 randomizations: first, patients with locally advanced pancreatic cancer were assigned to receive weekly gemcitabine alone (1000 mg/m²) or this same dose of gemcitabine plus erlotinib 100 mg/day; second, patients with progression-free disease (61% of initial cohort) after 4 months of therapy were assigned to receive 2 months of the same chemotherapy or chemoradiotherapy (54 Gy plus capecitabine). This study showed that the addition of erlotinib to gemcitabine did not improve survival and in fact affected survival adversely. Of note, no survival benefit was observed after the first randomization from chemotherapy to consolidating chemoradiotherapy. Chemoradiotherapy achieved better locoregional tumor control with significantly less local tumor progression (32% versus 46%, P < 0.03) and no increase in toxicity. Based on prior moderate-quality evidence, guidelines recommend consolidative chemoradiotherapy only for surgical resection candidates following induction chemotherapy; for those who are not surgical candidates, guidelines recommend continuing systemic therapy.^26,28,29

Gemcitabine and fluorouracil-based chemotherapies were the standard induction regimens until evidence from studies of metastatic systemic treatment protocols with FOLFIRINOX (ACCORD trial³⁸) and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (MPACT trial³⁹) was extrapolated to clinical practice. These regimens were shown to achieve higher objective response rates when compared to single-agent gemcitabine in patients with metastatic pancreatic cancer. Due to the broad heterogeneity of results in small retrospective series with neoadjuvant trials in borderline resectable pancreatic cancer, the quality of the evidence is low and any recommendation is limited. Many individual series have demonstrated improved complete resection rates and promising survival rates. In the largest single-institution retrospective review of patients with borderline resectable pancreatic adenocarcinoma who completed neoadjuvant gemcitabine-based chemoradiotherapy (50 Gy in 28 fractions or 30 Gy in 10 fractions), 94% achieved a margin-negative pancreatectomy; the median OS in those who completed preoperative therapy and had surgery was 40 months, with a 5-year OS of 36%.⁴⁰ A meta-analysis by Andriulli and colleagues included 20 prospective studies of patients with initially resectable (366 lesions) or unresectable (341 lesions) disease who were treated with neoadjuvant/preoperative gemcitabine with or without radiotherapy.⁴¹ In the group with initially unresectable disease, 39% underwent surgery after restaging and 68% of explored patients were resected; the R0 resection rate was 60%. After restaging, 91% of patients with resectable disease underwent surgery, with 82% of explored patients undergoing surgical resection and 89% of these achieving R0 resection. The estimated 1- and 2-year survival probabilities after resection among patients with initially unresectable disease were 86.3% and 54.2%.⁴¹

The largest single-institution retrospective review of FOLFIRINOX (fluorouracil, oxaliplatin, irinotecan, and leucovorin), an alternative to gemcitabine, for neoadjuvant induction therapy for patients with locally advanced unresectable disease was conducted at Memorial Sloan Kettering Cancer Center. In this study (n = 101), 31% of patients initially deemed unresectable who completed FOLFIRINOX induction therapy with or without chemoradiation underwent resection. The R0 resection rate in these patients was 55%, and patients who did not progress during induction FOLFIRINOX therapy had a median OS of 26 months.⁴² A systematic review and meta-analysis of FOLFIRINOX chemotherapy with or without radiotherapy in patients with locally advanced unresectable pancreatic cancer reported that 25.9% of patients underwent resection after FOLFIRINOX therapy, and the R0 resection rate in these patients was 78.4%.⁴³ The median OS in this study was 24.2 months, which was longer than the previously reported median OS rates for gemcitabine.

There is no strong evidence published for the use of combination nab-paclitaxel plus gemcitabine in the neoadjuvant setting, but it is used in clinical practice based on evidence from the MPACT trial, which showed the combination improved OS and progression-free survival in patients with metastatic pancreatic cancer.³⁹ An early-phase 1-arm clinical trial of neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) followed by radiotherapy showed an increased response rate and survival for locally advanced disease; however, the NCCN expert panel has reached a consensus but not a uniform recommendation regarding this regimen due to significant toxicities and low patient accrual.²⁶ Selected patients with pancreatic cancer with BRCA1/2 mutations are more sensitive to platinum-based chemotherapy. Although studies of neoadjuvant platinum-based chemotherapy in this population have not been reported, the NCCN guidelines list it as an alternative option based on extrapolated data.²⁶ A clinical trial of gemcitabine, nab-paclitaxel, and cisplatin in the neoadjuvant setting in patients with resectable pancreatic cancer is currently enrolling patients (NGC triple regimen NCT0339257).

Summary

Chemotherapy alone or followed by chemoradiotherapy may be used as initial treatment for patients with borderline and unresectable pancreatic adenocarcinoma without distant metastases who are potential surgical candidates. Chemoradiotherapy remains a preferred treatment option for patients with poorly controlled pain from local tumor invasion, in view of the well-documented analgesic palliative effect of radiation therapy. FOLFIRINOX with or without radiation therapy may offer the highest documented response rates, but it also results in higher rates of treatment-related toxicities. FOLFIRINOX can be offered to selected fit patients (< 65 years old, no comorbidity contraindication, good functional status [ECOG 0–1]) who can tolerate triple therapy with a more toxic adverse-effect profile. A clinical trial evaluating neoadjuvant FOLFIRINOX with or without preoperative chemoradiotherapy in patients with borderline resectable pancreatic cancer is ongoing (PANDAS-PRODIGE 44, NCT02676349). Gemcitabine with or without radiation therapy is a tolerable combination, although it is potentially more toxic when combined with radiation. The addition of nab-paclitaxel to gemcitabine without radiation may emerge as a preferred neoadjuvant treatment for selected patients; a clinical trial investigating this modality in patients with resectable and borderline resectable disease is ongoing (NCT02723331).

Adjuvant Therapy

Case Continued

Prior to the planned surgical resection and after undergoing chemoradiation therapy, the patient has an excellent performance status and repeat MRI shows a 1.3 × 1.4 cm head mass with no further vasculature involvement, no evidence of lymphadenopathy, and no distant metastasis. The CA 19-9 level is stable at 18 U/mL. The patient undergoes an uncomplicated partial pancreaticoduodenectomy, and analysis of a surgical pathology specimen reveals T3N0 disease with closest margin of 0.1 cm.

• Would the patient benefit from adjuvant therapy?

Adjuvant chemotherapy for 6 months after pancreatic cancer resection should be offered to all patients based on mature data. Gemcitabine and capecitabine are the current standard of care in adjuvant therapy; alternatively, single-agent gemcitabine can be offered to patients with poor performance status or patients who cannot tolerate the toxicities associated with this combination.²⁸ Adjuvant treatment should be initiated within approximately 8 weeks of surgical resection. The value of radiation therapy remains controversial, but it can be offered within the context of a clinical trial or to patients with positive margins after surgical resection and/or lymph node–positive disease. Based on low-quality supportive evidence, it is strongly recommended that patients who receive neoadjuvant therapy complete a total of 6 months of chemotherapy, factoring in the duration of the preoperative regimen.²⁸ Different adjuvant strategies have been investigated, including chemotherapy alone with a fluoropyrimidine and/or gemcitabine with or without combined chemoradiation therapy.

The European Study Group for Pancreatic Cancer 1 (ESPAC)-1 trial was a randomized clinical trial that evaluated several adjuvant strategies in pancreatic cancer treatment. This trial assigned patients who underwent pancreatic adenocarcinoma resection to adjuvant chemotherapy alone (intravenous fluorouracil 425 mg/m² and leucovorin 20 mg/m² daily for 5 days, monthly for 6 months), chemoradiotherapy (20 Gy in 10 daily fractions over 2 weeks with 500 mg/m² intravenous fluorouracil on days 1–3, repeated after 2 weeks), both chemotherapy and chemoradiation, and observation.⁴⁴ The results showed no added benefit for adjuvant chemoradiotherapy, with a median OS of 15.5 months in the chemoradiotherapy cohort, as compared to a median OS of 16.1 months in the chemotherapy-alone cohort (hazard ratio [HR] 1.18 [95% CI 0.90 to 1.55], P = 0.24). In addition, there was evidence of a survival benefit for the chemotherapy-alone arm when compared to the combined modality arm, with a median OS of 19.7 versus 14.0 months, respectively (HR 0.66 [95% CI 0.52 to 0.83], P = 0.0005). Although ESPAC-1 has been criticized for being underpowered to perform statistical comparison, it is still considered a landmark trial demonstrating benefit with single-agent chemotherapy alone. A follow-up analysis of ESPAC-1 showed that adjuvant chemotherapy alone conferred a significant 5-year survival benefit while the combined modality had a deleterious effect on survival. ⁴⁵ Hence, adjuvant chemotherapy alone became the standard of care in the United States following resection.

The results of the multicenter randomized controlled phase 3 CONKO-001 (CharitéOnkologie 001) trial, which were reported in 2007, supported the use of adjuvant gemcitabine for 6 months in patients with resected pancreatic adenocarcinoma. In this study, patients treated with adjuvant gemcitabine (1000 mg/m² days 1, 8, and 15 every 4 weeks for 6 months) had superior disease-free survival compared with those who received surgery alone.³⁰ A long-term outcome update of this study demonstrated a significant improvement in 5-year OS for patients treated with adjuvant gemcitabine (20.7% [95% CI 14.7% to 26.6%]) compared to those who received surgical resection alone (10.4% [95% CI 5.9% to 15.0%]). This benefit persisted at 10-year follow-up, with an OS of 12.2% (95% CI 7.3% to 17.2%) in the adjuvant gemcitabine group, as compared to 7.7% (95% CI 3.6% to 11.8%) in the resection alone group.³¹

Fluorouracil and gemcitabine remained equivalent adjuvant treatment options until the results of the ESPAC-3 trial were reported in 2010.³² This large phase 3 trial, conducted mainly in the United Kingdom, compared weekly gemcitabine (1000 mg/m² weekly for 3 of every 4 weeks) to leucovorin-modulated fluorouracil (Mayo Clinic regimen: leucovorin 20 mg/m² followed by fluorouracil 425 mg/m² intravenous bolus days 1 through 5 every 28 days) as adjuvant therapy in resected pancreatic adenocarcinoma. After a median follow-up of 34.2 months, the median OS was similar in the 2 groups (fluorouracil/leucovorin 23.0 months versus gemcitabine 23.6 months; P = 0.39). However, the fluorouracil/leucovorin group experienced more grade 3/4 treatment-related toxicities (mucositis, stomatitis, diarrhea, and hosptializations; 14% versus 7.5%; P < 0.001).⁴⁶ Following this trial, gemcitabine became the standard of care for adjuvant chemotherapy for resected pancreatic cancer.

The U.S. Radiation Therapy Oncology Group (RTOG) 9704 trial was conducted to investigate the potential benefit of adding radiation therapy to gemcitabine. This trial demonstrated an improved trend among patients with pancreatic head tumors (but not with cancers of the pancreatic body or tail) who received adjuvant gemcitabine followed by chemoradiotherapy (50.4 Gy in 1.8 Gy daily fractions for 5.5 weeks with concurrent infusional fluorouracil 250 mg/m² daily) and subsequent gemcitabine monotherapy compared to postoperative fluorouracil-based chemoradiotherapy. Results showed a 5-year OS of 22% versus 18%, respectively, although this improvement was not statistically significant (P = 0.08). This trial failed to show a benefit of adding radiotherapy to gemcitabine.⁴⁷

The ESPAC-4 trial, reported in 2017, evaluated the combination of gemcitabine and capecitabine compared to gemcitabine alone as adjuvant therapy for resected pancreatic adenocarcinoma.⁴⁸ Patients were randomly assigned after surgical resection, regardless of margin or node status, to 6 months of gemcitabine alone (1000 mg/m²/day on days 1, 8, and 15 of each 28-day cycle) or gemcitabine plus capecitabine (1660 mg/m²/day on days 1 through 21 of each 28-day cycle). Combination therapy had a significant survival benefit compared to single therapy, with median OS durations of 28 months and 25.5 months, respectively (HR for death 0.82 [95% CI 0.68 to 0.98]). The 5-year OS for patients who received combination treatment was 29 months (95% CI 22.9 to 35.2) versus 16 months (95% CI 10.2 to 23.7) for those in the monotherapy group. As expected, grade 3 or 4 treatment-related toxicities (diarrhea, hand-foot syndrome, and neutropenia) were significantly more common with combined therapy, although there were no significant differences in the rates of serious adverse events. The adjuvant combination of gemcitabine and capecitabine became the current and preferred new standard of care following resection of pancreatic ductal adenocarcinoma,²⁸ but single-agent gemcitabine and fluorouracil/leucovorin continue to be viable options,^26,28,29 particularly for elderly patients, patients with borderline performance status, or patients with multiple comorbidities.

Evidence showing that a more intensive regimen can improve outcome in the adjuvant setting remains elusive. The phase 3 APACT study (Adjuvant Therapy for Patients with Resected Pancreatic Cancer, NCT01964430) comparing gemcitabine alone to gemcitabine plus nab-paclitaxel in patients with surgically resected pancreatic adenocarcinoma has concluded, with the results projected to be released in 2018. Another phase 3 trial investigating the efficacy of FOLFIRINOX versus gemcitabine alone as adjuvant therapy is underway in France and Canada (PRODIGE24/ACCORD24, NCT01526135). Other strategies with newer targeted therapies and immunotherapy are in the development phase.

Follow-Up and Surveillance

Case Conclusion

After recovery from surgery, the patient is offered and completes 4 cycles of adjuvant chemotherapy with gemcitabine plus capecitabine. He is started on surveillance at 3 and 6 months, and he maintains an excellent performance status. He develops clinical evidence of pancreatic enzyme insufficiency and is placed on oral replacement therapy. He has no other complaints, and there is no evidence of recurrence on MRI and CA 19-9 levels.

• What is the recommended duration of surveillance following curative resection?

Surveillance after curative resection of pancreatic adenocarcinoma is recommended by NCCN guidelines.²⁶ However, pancreatic adenocarcinoma has a poor prognosis, and surveillance after curative surgical resection with or without perioperative therapy has not been shown to impact survival. Most recurrences will occur within 2 years after treatment. Surveillance recommendations differ among expert groups.^26,28,29 NCCN guidelines recommend evaluating patients by history and physical examination every 3 to 6 months for the first 2 years, then every 6 to 12 months for 3 years. CA 19-9 level and CT scan should be obtained every 3 to 6 months for 2 years and then every 6 to 12 months for 3 years. Follow-up with CA 19-9 levels and CT scans after 5 years is not routinely performed unless guided by signs, symptoms, or laboratory findings that raise suspicion for recurrence. Follow-up visits should also include evaluation of treatment-related toxicities, symptom management, nutrition support of pancreatic insufficiency, and psychosocial support.

Conclusion

Pancreatic cancer is a leading cause of cancer-related death that frequently presents with locally advanced or metastatic disease due to nonspecific symptoms and lack of a screening modality. Histological tissue biopsy confirmation and accurate resectability staging guide treatment planning and prognosis. The only potentially curative therapy is surgical resection plus adjuvant therapy for those with resectable disease. Surgical candidates with borderline resectable and unresectable disease can be offered induction preoperative chemotherapy followed by consolidation chemoradiation, based on clinical consensus practice. Enrollment in clinical trials should be encouraged for all patients, as evidence from clinical trials is essential to making progress in pancreatic cancer treatment.

Women, the VA wants your brains. It sounds a little disconcerting at first, but the National Center for PTSD and the nonprofit PINK Concussions are encouraging women to donate their brains for research.

In the past, says Dr. Carolyn Clancy, executive in charge of Veterans Health Administration, “the focus on TBI and PTSD brain research has primarily been based on male brains, without any active recruitment for women.” There has been almost no postmortem brain tissue available for study of injury in women. The VA also notes a lack of research on chronic traumatic encephalopathy in women. Only 2 peer-reviewed journal articles, both published in the early 1990s, have focused on women.

Women who are interested can take the “PINK Brain Pledge,” a nonbinding promise to leave their brains to science. They do not have to have a history of TBI or PTSD; brains also are needed for controls.

Women, the VA wants your brains. It sounds a little disconcerting at first, but the National Center for PTSD and the nonprofit PINK Concussions are encouraging women to donate their brains for research.

In the past, says Dr. Carolyn Clancy, executive in charge of Veterans Health Administration, “the focus on TBI and PTSD brain research has primarily been based on male brains, without any active recruitment for women.” There has been almost no postmortem brain tissue available for study of injury in women. The VA also notes a lack of research on chronic traumatic encephalopathy in women. Only 2 peer-reviewed journal articles, both published in the early 1990s, have focused on women.

Women who are interested can take the “PINK Brain Pledge,” a nonbinding promise to leave their brains to science. They do not have to have a history of TBI or PTSD; brains also are needed for controls.

Women, the VA wants your brains. It sounds a little disconcerting at first, but the National Center for PTSD and the nonprofit PINK Concussions are encouraging women to donate their brains for research.

In the past, says Dr. Carolyn Clancy, executive in charge of Veterans Health Administration, “the focus on TBI and PTSD brain research has primarily been based on male brains, without any active recruitment for women.” There has been almost no postmortem brain tissue available for study of injury in women. The VA also notes a lack of research on chronic traumatic encephalopathy in women. Only 2 peer-reviewed journal articles, both published in the early 1990s, have focused on women.

Women who are interested can take the “PINK Brain Pledge,” a nonbinding promise to leave their brains to science. They do not have to have a history of TBI or PTSD; brains also are needed for controls.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Photo from Novartis

The Institute for Clinical and Economic Review (ICER) has made policy recommendations intended to ensure affordability and access to chimeric antigen receptor (CAR) T-cell therapies.

ICER released a Final Evidence Report on tisagenlecleucel (Kymriah, Novartis) and axicabtagene ciloleucel (Yescarta, Kite Pharma/Gilead), 2 CAR T-cell therapies approved in the US to treat B-cell acute lymphoblastic leukemia (B-ALL) and non-Hodgkin lymphoma (NHL), respectively.

The report says the pricing of these therapies aligns with patient benefit, but changes will be needed in future pricing, payment, and delivery mechanisms to ensure patient access without threatening health system affordability.

“Given the currently available evidence, these therapies appear to be effective options for those with B-ALL or NHL, though uncertainty in the evidence raised questions around the long-term value for money,” said Dan Ollendorf, PhD, ICER’s chief scientific officer.

Net health benefit

ICER’s report says tisagenlecleucel provides a net health benefit for children with B-ALL, and both tisagenlecleucel and axicabtagene ciloleucel provide a net health benefit for adults with certain types of NHL. (Novartis is seeking approval for tisagenlecleucel in NHL).

The evidence suggests there is at least a small net health benefit of the CAR T-cell therapies compared to other therapies. The benefit may be substantial, but uncertainties remain.

The data show complete remission (CR), disease-free survival (DFS), and overall survival (OS) rates are superior for NHL patients who receive axicabtagene ciloleucel, compared to patients who receive standard chemoimmunotherapy regimens.

Similarly, B-ALL patients treated with tisagenlecleucel have superior CR, DFS, and OS rates to patients treated with standard therapies. CR and OS rates are also superior in NHL patients treated with tisagenlecleucel, but DFS has not been reported in this population.

The report says there is insufficient evidence to distinguish between the 2 CAR T-cell therapies for the treatment of NHL.

Toxicity and uncertainty

The report highlights the fact that cytokine release syndrome, neurological symptoms, and B-cell aplasia have been observed in patients who receive CAR T-cell therapies. However, these sometimes severe adverse events are generally “manageable.”

In addition to toxicity, the report highlights sources of uncertainty. These include the fact that studies of tisagenlecleucel and axicabtagene ciloleucel are small, single-arm trials with short follow-up; comparisons with historical controls may be misleading; and improvements in the CAR T-cell manufacturing process may change outcomes.

Cost-effectiveness

The report states that the cost-effectiveness of each therapy fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime.

For its analyses, ICER used the wholesale acquisition cost (WAC) plus an assumed hospital mark-up. The analyses were also based on the assumption that survival benefits observed in clinical trials would continue after the trials ended.

For tisagenlecleucel in pediatric B-ALL, the WAC is $475,000. The long-term cost-effectiveness compared to clofarabine is $45,871 per QALY gained.

For axicabtagene ciloleucel in adults with NHL, the WAC is $373,000. The long-term cost-effectiveness compared to salvage chemotherapy is $136,078 per QALY gained. The effectiveness assumptions for chemotherapy were based on an average of salvage chemotherapy regimens from the SCHOLAR-1 trial, and the cost assumptions were based on the cost of the R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin) regimen.

The report says tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied.

Meanwhile, axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower threshold ($100,000 per QALY gained).

Tisagenlecleucel, as a treatment for B-ALL, is not expected to cross the $915 million threshold for annual budget impact.

However, the short-term costs of axicabtagene ciloleucel for relapsed/refractory NHL could exceed the threshold. Only 38% of the estimated 5900 eligible patients could receive axicabtagene ciloleucel in a year before crossing the threshold.

Because of these findings, ICER issued an “Affordability and Access Alert” for axicabtagene ciloleucel.

This alert is intended to signal when the added costs associated with a new treatment may be difficult for the healthcare system to absorb over the short-term without displacing other needed services or contributing to unsustainable growth in healthcare insurance costs.

“Based on current evidence, both therapies appear to be priced in alignment with their clinical value, but there are potential short-term affordability concerns—for axicabtagene ciloleucel under its current indication and for both treatments should they receive future approvals for broader patient populations,” Dr Ollendorf said.

Panel voting results

ICER’s report was reviewed at a public meeting of the California Technology Assessment Forum on March 2.

Most of the panel said tisagenlecleucel provides intermediate long-term value for money when treating B-ALL. However, the significant uncertainty surrounding the long-term risks and benefits of the therapy precluded a high-value vote.

After deliberating on the value of axicabtagene ciloleucel to treat NHL, the panel’s votes were split between low-value and intermediate-value, driven by similar concerns about long-term uncertainty.

Policy recommendations

Following the voting session, ICER convened a policy roundtable of experts, including physicians, patient advocates, manufacturer representatives, and payer representatives.

Based on the roundtable discussion, ICER developed recommendations for enhanced stakeholder communication, innovative payment models, generation of additional evidence, settings of care, and patient education.

“With many other potentially transformative therapies in the pipeline, stakeholders must collaborate now to develop payment and delivery systems that can ensure timely patient access, manage short-term affordability for expensive one-time treatments, and continue to reward the innovation that brings these new treatments to market,” Dr Ollendorf said.

Some of ICER’s recommendations include:

• When launching novel therapies approved with limited clinical evidence, such as CAR T-cell therapies, manufacturers and payers should consider using a lower launch price that could be increased if substantial clinical benefits are confirmed or using a higher initial price tied to a requirement for refunds or rebates if real-world evidence fails to confirm high expectations.
• Outcomes-based pricing arrangements must be linked to “meaningful clinical outcomes assessed with sufficient follow up.”
• Hospital mark-up for CAR T-cell therapies “should reflect the expected additional cost for care delivered in the hospital, rather than a percentage of the drug cost to avoid perverse incentives in choosing the treatment location.”
• Initially, CAR T-cell therapies should be delivered in “manufacturer-accredited centers to ensure the quality and appropriateness of care.” Later, “centers of excellence accredited by specialty societies” can administer these therapies, as long as providers have “sufficient expertise” to manage serious side effects.
• Centers should ensure that patients understand what to expect from CAR T-cell therapy, including long-term consequences.
• Because additional evidence on CAR T-cell therapies is needed, all patients who receive these therapies should enter into a registry with planned long-term follow-up.
• Studies should determine the optimal timing of CAR T-cell therapy in the sequence of treatments for B-ALL and NHL.

Additional recommendations and more details are available in ICER’s report.

About ICER

ICER is an independent, non-profit research institute that produces reports analyzing evidence on the effectiveness and value of drugs and other medical services.

ICER’s reports include evidence-based calculations of prices for new drugs that reflect the degree of improvement expected in long-term patient outcomes, while also highlighting price levels that might contribute to unaffordable short-term cost growth for the overall healthcare system.

ICER’s reports incorporate input from stakeholders and are the subject of public hearings through 3 core programs: the California Technology Assessment Forum, the Midwest Comparative Effectiveness Public Advisory Council, and the New England Comparative Effectiveness Public Advisory Council.

These independent panels review ICER’s reports at public meetings to deliberate on the evidence and develop recommendations for how patients, clinicians, insurers, and policymakers can improve the quality and value of healthcare.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

Library of Medicine

James F. Holland, MD, passed away last week, at the age of 92, due to complications of cardiovascular disease.

Dr Holland has been called a pioneer in the field of leukemia research.

He and his colleagues are credited with using combination chemotherapy to transform pediatric acute lymphoblastic leukemia from an incurable illness to one with a high survival rate.

Dr Holland and his colleagues also developed the 7+3 regimen—3 daily injections of daunorubicin and 7 days of intravenous cytarabine—for patients with acute myeloid leukemia.

Dr Holland was born on May 16, 1925, in Morristown, New Jersey. He graduated from Princeton University in 1944 and earned his medical degree from Columbia University College of Physicians and Surgeons in 1947.

Dr Holland was a captain in the US Army Medical Corps from 1949 to 1951. After that, he worked at Francis Delafield Hospital (which closed in 1975) in New York, New York. He joined the National Cancer Institute (NCI) in 1953. Two years later, he began working at Roswell Park Cancer Institute in Buffalo, New York.

Dr Holland became Roswell Park’s chief of medicine and director of the Cancer Clinical Research Center. But he continued to work with the NCI, conducting research as part of Acute Leukemia Group B, which later became Cancer and Leukemia Group B.

After spending a year on an oncology exchange program in the Soviet Union, Dr Holland started at Mount Sinai in New York, New York, in 1973. While there, he established the Department of Neoplastic Diseases at The Tisch Cancer Institute, Icahn School of Medicine.

Most recently, Dr Holland was a distinguished professor of neoplastic diseases at Mount Sinai. He saw patients but also conducted research on the human mammary tumor virus.

Dr Holland collaborated with Emil Frei III to publish the textbook Cancer Medicine, which is now in its ninth edition. Dr Holland served as president of the American Association for Cancer Research and the American Society of Clinical Oncology. He was a co-founder of the African Organization for Research and Training in Cancer as well.

Dr Holland was married to Jimmie C. Holland, MD, who is credited with founding the field of psycho-oncology. Jimmie passed away in December 2017. The couple is survived by 6 children and 9 grandchildren.

Photo from Business Wire

Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved the bispecific factor IXa- and factor X-directed antibody emicizumab (Hemlibra), according to Chugai Pharmaceutical Co., Ltd.

Emicizumab is now approved for use in Japan as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A and factor VIII inhibitors.

There are a few conditions for this approval, including requirements for a risk management plan, early phase post-marketing vigilance, and post-marketing drug use surveillance.

A risk management plan is intended to assess measures for appropriate management of the risks associated with a drug, either at regular intervals or in response to the progress of post-marketing surveillance.

According to Japan’s Pharmaceuticals and Medical Devices Agency, a risk management plan must consist of 3 elements:

1. Safety specification—Important adverse drug reactions and missing information
2. Pharmacovigilance activities—Information collection activities performed in the post-marketing period
3. Risk-minimization activities—Safety measures taken to minimize risks, which consists of providing information to healthcare professionals and setting the terms of use for a drug.

For the early phase post-marketing vigilance requirement, Chugai must provide safety information to healthcare professionals and collect information on adverse reactions to emicizumab in the early post-marketing phase.

Post-marketing drug use surveillance for emicizumab will include all patients receiving the product and is scheduled to continue until data is collected from approximately 100 people. The goal is to understand background information on patients receiving emicizumab, as well as to collect safety and efficacy data on the product and take necessary measures for the appropriate use of emicizumab.

The data collected via this surveillance effort will be reviewed to determine whether new surveillance or further safety measures are needed. Results of the surveillance will be reported to the regulatory authorities, and the data will be presented at scientific meetings, according to Chugai.

Phase 3 studies

The MHLW’s approval of emicizumab is based on data from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs). Three had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved the bispecific factor IXa- and factor X-directed antibody emicizumab (Hemlibra), according to Chugai Pharmaceutical Co., Ltd.

Emicizumab is now approved for use in Japan as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A and factor VIII inhibitors.

There are a few conditions for this approval, including requirements for a risk management plan, early phase post-marketing vigilance, and post-marketing drug use surveillance.

A risk management plan is intended to assess measures for appropriate management of the risks associated with a drug, either at regular intervals or in response to the progress of post-marketing surveillance.

According to Japan’s Pharmaceuticals and Medical Devices Agency, a risk management plan must consist of 3 elements:

1. Safety specification—Important adverse drug reactions and missing information
2. Pharmacovigilance activities—Information collection activities performed in the post-marketing period
3. Risk-minimization activities—Safety measures taken to minimize risks, which consists of providing information to healthcare professionals and setting the terms of use for a drug.

For the early phase post-marketing vigilance requirement, Chugai must provide safety information to healthcare professionals and collect information on adverse reactions to emicizumab in the early post-marketing phase.

Post-marketing drug use surveillance for emicizumab will include all patients receiving the product and is scheduled to continue until data is collected from approximately 100 people. The goal is to understand background information on patients receiving emicizumab, as well as to collect safety and efficacy data on the product and take necessary measures for the appropriate use of emicizumab.

The data collected via this surveillance effort will be reviewed to determine whether new surveillance or further safety measures are needed. Results of the surveillance will be reported to the regulatory authorities, and the data will be presented at scientific meetings, according to Chugai.

Phase 3 studies

The MHLW’s approval of emicizumab is based on data from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs). Three had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo from Business Wire

Japan’s Ministry of Health, Labour and Welfare (MHLW) has approved the bispecific factor IXa- and factor X-directed antibody emicizumab (Hemlibra), according to Chugai Pharmaceutical Co., Ltd.

Emicizumab is now approved for use in Japan as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with hemophilia A and factor VIII inhibitors.

There are a few conditions for this approval, including requirements for a risk management plan, early phase post-marketing vigilance, and post-marketing drug use surveillance.

A risk management plan is intended to assess measures for appropriate management of the risks associated with a drug, either at regular intervals or in response to the progress of post-marketing surveillance.

According to Japan’s Pharmaceuticals and Medical Devices Agency, a risk management plan must consist of 3 elements:

1. Safety specification—Important adverse drug reactions and missing information
2. Pharmacovigilance activities—Information collection activities performed in the post-marketing period
3. Risk-minimization activities—Safety measures taken to minimize risks, which consists of providing information to healthcare professionals and setting the terms of use for a drug.

For the early phase post-marketing vigilance requirement, Chugai must provide safety information to healthcare professionals and collect information on adverse reactions to emicizumab in the early post-marketing phase.

Post-marketing drug use surveillance for emicizumab will include all patients receiving the product and is scheduled to continue until data is collected from approximately 100 people. The goal is to understand background information on patients receiving emicizumab, as well as to collect safety and efficacy data on the product and take necessary measures for the appropriate use of emicizumab.

The data collected via this surveillance effort will be reviewed to determine whether new surveillance or further safety measures are needed. Results of the surveillance will be reported to the regulatory authorities, and the data will be presented at scientific meetings, according to Chugai.

Phase 3 studies

The MHLW’s approval of emicizumab is based on data from a pair of phase 3 studies—HAVEN 1 and HAVEN 2.

Results from HAVEN 1 were published in NEJM and presented at the 26th ISTH Congress in July 2017. Updated results from HAVEN 2 were presented at the 2017 ASH Annual Meeting in December.

HAVEN 1

This study enrolled 109 patients (age 12 and older) with hemophilia A and factor VIII inhibitors who were previously treated with bypassing agents (BPAs) on-demand or as prophylaxis.

The patients were randomized to receive emicizumab prophylaxis or no prophylaxis. On-demand treatment of breakthrough bleeds with BPAs was allowed.

There was a significant reduction in treated bleeds of 87% with emicizumab prophylaxis compared to no prophylaxis (95% CI: 72.3; 94.3, P<0.0001). And there was an 80% reduction in all bleeds with emicizumab (95% CI: 62.5; 89.8, P<0.0001).

Adverse events (AEs) occurring in at least 5% of patients treated with emicizumab were local injection site reactions, headache, fatigue, upper respiratory tract infection, and arthralgia.

Two patients experienced thromboembolic events (TEs). Three had thrombotic microangiopathy (TMA) while receiving emicizumab prophylaxis and more than 100 u/kg/day of activated prothrombin complex concentrate, on average, for 24 hours or more before the event. Two of these patients had also received recombinant factor VIIa.

Neither TE required anticoagulation therapy, and 1 patient restarted emicizumab. The cases of TMA observed were transient, and 1 patient restarted emicizumab.

HAVEN 2

In this single-arm trial, researchers evaluated emicizumab prophylaxis in 60 patients, ages 1 to 17, who had hemophilia A with factor VIII inhibitors.

The efficacy analysis included 57 patients who were younger than 12. The 3 older patients were only included in the safety analysis.

Of the 57 patients, 64.9% had 0 bleeds, 94.7% had 0 treated bleeds, and 98.2% had 0 treated spontaneous bleeds and 0 treated joint bleeds. None of the patients had treated target joint bleeds.

Forty patients had a total of 201 AEs. The most common of these were viral upper respiratory tract infections (16.7%) and injection site reactions (16.7%).

There were no TEs or TMA events, and none of the patients tested positive for anti-drug antibodies. None of the 7 serious AEs in this trial were considered treatment-related.

Photo by Darren Baker

The US Food and Drug Administration (FDA) has granted 510(k) clearance for ORTHO CONNECT V2.0, a software system developed by Ortho Clinical Diagnostics.

ORTHO CONNECT V2.0 is middleware designed to keep large quantities of data accessible and consistent across multiple instruments and laboratory systems.

ORTHO CONNECT V2.0 works with other products Ortho Clinical Diagnostics has developed for immunohematology labs.

The software is now available for purchase in the US.

According to Ortho Clinical Diagnostics, ORTHO CONNECT V2.0 is comprehensive, integrated, and customizable middleware (software that acts as a bridge between an operating system or database and application).

ORTHO CONNECT V2.0 centralizes laboratory operations and workflow across hospitals and networks, allowing blood banks and their data to be managed through one central terminal. The software can link all Ortho Clinical Diagnostics instruments to lab information systems through a single interface.

Acting as an intermediary between instruments and lab information systems, ORTHO CONNECT V2.0 allows labs to exchange data, perform data management, and complete regulatory process tasks that are not easily performed alone. All test results on connected analyzers can be viewed and verified no matter the location.

ORTHO CONNECT V2.0 enables the ORTHO VISION® and ORTHO VISION® Max immunohematology analyzers, which test blood for transfusion compatibility, to integrate with a hospital’s laboratory information systems through a single validated connection to exchange data and simplify processes.

“Ortho [Clinical Diagnostics] is focused on diminishing the complexities of immunohematology testing while improving safety, speed, and efficiency throughout the blood bank,” said Robert Yates, the company’s chief operating officer.

“ORTHO CONNECT does just that, bringing improved functionality to laboratory information systems that are often relatively rigid and outdated. It’s the perfect complement to our ORTHO VISION platform of analyzers.”

Photo by Darren Baker

The US Food and Drug Administration (FDA) has granted 510(k) clearance for ORTHO CONNECT V2.0, a software system developed by Ortho Clinical Diagnostics.

ORTHO CONNECT V2.0 is middleware designed to keep large quantities of data accessible and consistent across multiple instruments and laboratory systems.

ORTHO CONNECT V2.0 works with other products Ortho Clinical Diagnostics has developed for immunohematology labs.

The software is now available for purchase in the US.

According to Ortho Clinical Diagnostics, ORTHO CONNECT V2.0 is comprehensive, integrated, and customizable middleware (software that acts as a bridge between an operating system or database and application).

ORTHO CONNECT V2.0 centralizes laboratory operations and workflow across hospitals and networks, allowing blood banks and their data to be managed through one central terminal. The software can link all Ortho Clinical Diagnostics instruments to lab information systems through a single interface.

Acting as an intermediary between instruments and lab information systems, ORTHO CONNECT V2.0 allows labs to exchange data, perform data management, and complete regulatory process tasks that are not easily performed alone. All test results on connected analyzers can be viewed and verified no matter the location.

ORTHO CONNECT V2.0 enables the ORTHO VISION® and ORTHO VISION® Max immunohematology analyzers, which test blood for transfusion compatibility, to integrate with a hospital’s laboratory information systems through a single validated connection to exchange data and simplify processes.

“Ortho [Clinical Diagnostics] is focused on diminishing the complexities of immunohematology testing while improving safety, speed, and efficiency throughout the blood bank,” said Robert Yates, the company’s chief operating officer.

“ORTHO CONNECT does just that, bringing improved functionality to laboratory information systems that are often relatively rigid and outdated. It’s the perfect complement to our ORTHO VISION platform of analyzers.”

Photo by Darren Baker

The US Food and Drug Administration (FDA) has granted 510(k) clearance for ORTHO CONNECT V2.0, a software system developed by Ortho Clinical Diagnostics.

ORTHO CONNECT V2.0 is middleware designed to keep large quantities of data accessible and consistent across multiple instruments and laboratory systems.

ORTHO CONNECT V2.0 works with other products Ortho Clinical Diagnostics has developed for immunohematology labs.

The software is now available for purchase in the US.

According to Ortho Clinical Diagnostics, ORTHO CONNECT V2.0 is comprehensive, integrated, and customizable middleware (software that acts as a bridge between an operating system or database and application).

ORTHO CONNECT V2.0 centralizes laboratory operations and workflow across hospitals and networks, allowing blood banks and their data to be managed through one central terminal. The software can link all Ortho Clinical Diagnostics instruments to lab information systems through a single interface.

Acting as an intermediary between instruments and lab information systems, ORTHO CONNECT V2.0 allows labs to exchange data, perform data management, and complete regulatory process tasks that are not easily performed alone. All test results on connected analyzers can be viewed and verified no matter the location.

ORTHO CONNECT V2.0 enables the ORTHO VISION® and ORTHO VISION® Max immunohematology analyzers, which test blood for transfusion compatibility, to integrate with a hospital’s laboratory information systems through a single validated connection to exchange data and simplify processes.

“Ortho [Clinical Diagnostics] is focused on diminishing the complexities of immunohematology testing while improving safety, speed, and efficiency throughout the blood bank,” said Robert Yates, the company’s chief operating officer.

“ORTHO CONNECT does just that, bringing improved functionality to laboratory information systems that are often relatively rigid and outdated. It’s the perfect complement to our ORTHO VISION platform of analyzers.”

AGA spends a lot of time on Capitol Hill advocating to help gastroenterologists in practice better care for their patients and receive fair reimbursement. Therefore, we were pleased that the budget deal passed by Congress and signed by the president in February included several policy victories that AGA has been working diligently on for many years.

IPAB repeal

AGA, and all of organized medicine, have long opposed the Independent Payment Advisory Board (IPAB) that was created as part of the Affordable Care Act. IPAB is an unelected, unaccountable board whose sole purpose is to cut Medicare spending from providers should Medicare reach a certain threshold of spending. Since hospitals are exempt from their purview, physicians would be particularly vulnerable to cuts. However, repealing IPAB has had bipartisan support over the years, and we applaud Congress for listening to us and the medical community and taking action.

Misvalued codes

AGA and the physician community were also successful in removing a provision that would have extended the misvalued codes initiative for the next two years to reallocate savings from potentially overvalued codes. AGA, the Alliance of Specialty Medicine and the AMA opposed the original provision expanding the misvalued codes initiative and have argued that virtually all codes under the fee schedule, including gastroenterology, have been reevaluated and have already faced significant cuts. In the final agreement, Congress eliminated recapturing savings from the misvalued codes initiative and instead lowered overall updates for physician reimbursement under Medicare by .25 percent for 1 year. Although AGA would prefer this reduction not be included, it is much better than the misvalued codes provision, which disproportionately impacts specialties, like gastroenterology.

Geographic Practice Cost Index

The budget agreement extends the work for the Geographic Practice Cost Index (GPCI) floor for two additional years, which avoids a decrease in Medicare reimbursement for physicians that practice in rural areas. The work GPCI is a variable that Medicare uses to adjust the work component of physician payment based on where they live. A work GPCI floor of 1.0 protects physicians in low-cost, often rural areas, from being paid less for the work they do.

Meaningful use standards

The package addresses electronic health record (EHR) standards and eases requirements for physicians. The language removes the mandate that meaningful use standards become more stringent over time, which is a major financial burden for physician practices. The language also gives physicians more time to submit and receive a hardship exemption from the current EHR standards that would apply to meaningful use and the Quality Payment Program’s advancing care information performance category.

Biosimilars coverage under Medicare Part D

The agreement also levels the playing field between biologics and biosimilars by adding biosimilars to the Medicare Coverage Gap Discount Program. Additionally, by providing the 50 percent discount equally, beneficiary out-of-pocket costs will be reduced and the Medicare program will save money as a result of covering the less expensive medication.

AGA and the medical community have fought long and hard for these provisions and are happy to see them finally being implemented. We thank all of our members who have worked along with us to ensure that the voice of gastroenterology continues to be heard on Capitol Hill.

AGA spends a lot of time on Capitol Hill advocating to help gastroenterologists in practice better care for their patients and receive fair reimbursement. Therefore, we were pleased that the budget deal passed by Congress and signed by the president in February included several policy victories that AGA has been working diligently on for many years.

IPAB repeal

AGA, and all of organized medicine, have long opposed the Independent Payment Advisory Board (IPAB) that was created as part of the Affordable Care Act. IPAB is an unelected, unaccountable board whose sole purpose is to cut Medicare spending from providers should Medicare reach a certain threshold of spending. Since hospitals are exempt from their purview, physicians would be particularly vulnerable to cuts. However, repealing IPAB has had bipartisan support over the years, and we applaud Congress for listening to us and the medical community and taking action.

Misvalued codes

AGA and the physician community were also successful in removing a provision that would have extended the misvalued codes initiative for the next two years to reallocate savings from potentially overvalued codes. AGA, the Alliance of Specialty Medicine and the AMA opposed the original provision expanding the misvalued codes initiative and have argued that virtually all codes under the fee schedule, including gastroenterology, have been reevaluated and have already faced significant cuts. In the final agreement, Congress eliminated recapturing savings from the misvalued codes initiative and instead lowered overall updates for physician reimbursement under Medicare by .25 percent for 1 year. Although AGA would prefer this reduction not be included, it is much better than the misvalued codes provision, which disproportionately impacts specialties, like gastroenterology.

Geographic Practice Cost Index

The budget agreement extends the work for the Geographic Practice Cost Index (GPCI) floor for two additional years, which avoids a decrease in Medicare reimbursement for physicians that practice in rural areas. The work GPCI is a variable that Medicare uses to adjust the work component of physician payment based on where they live. A work GPCI floor of 1.0 protects physicians in low-cost, often rural areas, from being paid less for the work they do.

Meaningful use standards

The package addresses electronic health record (EHR) standards and eases requirements for physicians. The language removes the mandate that meaningful use standards become more stringent over time, which is a major financial burden for physician practices. The language also gives physicians more time to submit and receive a hardship exemption from the current EHR standards that would apply to meaningful use and the Quality Payment Program’s advancing care information performance category.

Biosimilars coverage under Medicare Part D

The agreement also levels the playing field between biologics and biosimilars by adding biosimilars to the Medicare Coverage Gap Discount Program. Additionally, by providing the 50 percent discount equally, beneficiary out-of-pocket costs will be reduced and the Medicare program will save money as a result of covering the less expensive medication.

AGA and the medical community have fought long and hard for these provisions and are happy to see them finally being implemented. We thank all of our members who have worked along with us to ensure that the voice of gastroenterology continues to be heard on Capitol Hill.

AGA spends a lot of time on Capitol Hill advocating to help gastroenterologists in practice better care for their patients and receive fair reimbursement. Therefore, we were pleased that the budget deal passed by Congress and signed by the president in February included several policy victories that AGA has been working diligently on for many years.

IPAB repeal

AGA, and all of organized medicine, have long opposed the Independent Payment Advisory Board (IPAB) that was created as part of the Affordable Care Act. IPAB is an unelected, unaccountable board whose sole purpose is to cut Medicare spending from providers should Medicare reach a certain threshold of spending. Since hospitals are exempt from their purview, physicians would be particularly vulnerable to cuts. However, repealing IPAB has had bipartisan support over the years, and we applaud Congress for listening to us and the medical community and taking action.

Misvalued codes

AGA and the physician community were also successful in removing a provision that would have extended the misvalued codes initiative for the next two years to reallocate savings from potentially overvalued codes. AGA, the Alliance of Specialty Medicine and the AMA opposed the original provision expanding the misvalued codes initiative and have argued that virtually all codes under the fee schedule, including gastroenterology, have been reevaluated and have already faced significant cuts. In the final agreement, Congress eliminated recapturing savings from the misvalued codes initiative and instead lowered overall updates for physician reimbursement under Medicare by .25 percent for 1 year. Although AGA would prefer this reduction not be included, it is much better than the misvalued codes provision, which disproportionately impacts specialties, like gastroenterology.

Geographic Practice Cost Index

The budget agreement extends the work for the Geographic Practice Cost Index (GPCI) floor for two additional years, which avoids a decrease in Medicare reimbursement for physicians that practice in rural areas. The work GPCI is a variable that Medicare uses to adjust the work component of physician payment based on where they live. A work GPCI floor of 1.0 protects physicians in low-cost, often rural areas, from being paid less for the work they do.

Meaningful use standards

The package addresses electronic health record (EHR) standards and eases requirements for physicians. The language removes the mandate that meaningful use standards become more stringent over time, which is a major financial burden for physician practices. The language also gives physicians more time to submit and receive a hardship exemption from the current EHR standards that would apply to meaningful use and the Quality Payment Program’s advancing care information performance category.

Biosimilars coverage under Medicare Part D

The agreement also levels the playing field between biologics and biosimilars by adding biosimilars to the Medicare Coverage Gap Discount Program. Additionally, by providing the 50 percent discount equally, beneficiary out-of-pocket costs will be reduced and the Medicare program will save money as a result of covering the less expensive medication.

AGA and the medical community have fought long and hard for these provisions and are happy to see them finally being implemented. We thank all of our members who have worked along with us to ensure that the voice of gastroenterology continues to be heard on Capitol Hill.

In utero exposure to some antiepileptic drugs was linked to decreased educational achievement at the age of 7 years, in results of a matched-case control study.

Compared with controls, children exposed in the womb to sodium valproate alone, or to multiple antiepileptics (AEDs), had lower scores on U.K standardized tests routinely administered to 7-year-olds, according to results published in the Journal of Neurology, Neurosurgery & Psychiatry.

The results provide evidence showing that in utero exposure to some AEDs may lead to developmental issues in children, according to lead author Arron S. Lacey, Wales Epilepsy Research Network, Swansea University Medical School, Swansea, England, and coauthors.

“Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” Dr. Lacey concluded in a discussion of their study results.

SOURCE: Lacey AS et al. J Neurol Neurosurg Psychiatry. 2018 Mar 25. doi: 10.1136/jnnp-201-317515.

In utero exposure to some antiepileptic drugs was linked to decreased educational achievement at the age of 7 years, in results of a matched-case control study.

Compared with controls, children exposed in the womb to sodium valproate alone, or to multiple antiepileptics (AEDs), had lower scores on U.K standardized tests routinely administered to 7-year-olds, according to results published in the Journal of Neurology, Neurosurgery & Psychiatry.

The results provide evidence showing that in utero exposure to some AEDs may lead to developmental issues in children, according to lead author Arron S. Lacey, Wales Epilepsy Research Network, Swansea University Medical School, Swansea, England, and coauthors.

“Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” Dr. Lacey concluded in a discussion of their study results.

SOURCE: Lacey AS et al. J Neurol Neurosurg Psychiatry. 2018 Mar 25. doi: 10.1136/jnnp-201-317515.

In utero exposure to some antiepileptic drugs was linked to decreased educational achievement at the age of 7 years, in results of a matched-case control study.

Compared with controls, children exposed in the womb to sodium valproate alone, or to multiple antiepileptics (AEDs), had lower scores on U.K standardized tests routinely administered to 7-year-olds, according to results published in the Journal of Neurology, Neurosurgery & Psychiatry.

The results provide evidence showing that in utero exposure to some AEDs may lead to developmental issues in children, according to lead author Arron S. Lacey, Wales Epilepsy Research Network, Swansea University Medical School, Swansea, England, and coauthors.

“Women with epilepsy should be informed of this risk, and alternative treatment regimens should be discussed before their pregnancy with a physician that specializes in epilepsy,” Dr. Lacey concluded in a discussion of their study results.

SOURCE: Lacey AS et al. J Neurol Neurosurg Psychiatry. 2018 Mar 25. doi: 10.1136/jnnp-201-317515.

Obesity and severe obesity rose significantly in adults but not in children from 2007 to 2016, according to data from the National Health and Nutrition Examination Survey.

The age-standardized prevalence of obesity – defined as a body mass index of 30 or more – among adults aged 20 years and over increased from 33.7% for the 2-year period of 2007-2008 to 39.6% in 2015-2016, while the prevalence of severe obesity – defined as a body mass index of 40 kg/m2 or more – went from 5.7% to 7.7% over that same period, Craig M. Hales, MD, and his associates at the Centers for Disease Control and Prevention in Hyattsville, Md., and Atlanta said in a research letter published in JAMA.

The prevalence of obesity in children aged 2-19 years – defined as BMI at or above the sex-specific 95th percentile – increased, but not significantly, from 16.8% in 2007-2008 to 18.5% in 2015-2016, with most of that increase coming in the last 2 years. Severe obesity – BMI at or above 120% of the sex-specific 95th percentile – rose from 4.9% to 5.6% over those 10 years, but the last 2-year period saw the rate drop from 6% in 2013-2014, the investigators reported.

For the most recent reporting period, boys were more likely than girls to be obese (19.1% vs. 17.8%) and severely obese (6.3% vs. 4.9%), and both obesity and severe obesity were more common with increasing age. Obesity prevalence went from 13.9% in those aged 2-5 years to 20.6% in 12- to 19-year-olds, and severe obesity was 1.8% in the youngest group and 7.7% in the oldest, with the middle-age group (6-11 years) in the middle in both categories, they said

Among the adults, obesity was more common in women than men (41.1% vs. 37.9%) for 2015-2016, as was severe obesity (9.7% vs. 5.6%). Obesity and severe obesity were both highest in those aged 40-59 years, but obesity prevalence was lowest in the younger group (20-39 years) and severe obesity was least common in the older group (60 years and older), Dr. Hales and his associates said.

The analysis involved 16,875 children and 27,449 adults over the 10-year period. The investigators did not report any conflicts of interest.

rfranki@frontlinemedcom.com

SOURCE: Hales CM et al. JAMA 2018 Mar 23. doi: 10.1001/jama.2018.3060.

Obesity and severe obesity rose significantly in adults but not in children from 2007 to 2016, according to data from the National Health and Nutrition Examination Survey.

The age-standardized prevalence of obesity – defined as a body mass index of 30 or more – among adults aged 20 years and over increased from 33.7% for the 2-year period of 2007-2008 to 39.6% in 2015-2016, while the prevalence of severe obesity – defined as a body mass index of 40 kg/m2 or more – went from 5.7% to 7.7% over that same period, Craig M. Hales, MD, and his associates at the Centers for Disease Control and Prevention in Hyattsville, Md., and Atlanta said in a research letter published in JAMA.

The prevalence of obesity in children aged 2-19 years – defined as BMI at or above the sex-specific 95th percentile – increased, but not significantly, from 16.8% in 2007-2008 to 18.5% in 2015-2016, with most of that increase coming in the last 2 years. Severe obesity – BMI at or above 120% of the sex-specific 95th percentile – rose from 4.9% to 5.6% over those 10 years, but the last 2-year period saw the rate drop from 6% in 2013-2014, the investigators reported.

For the most recent reporting period, boys were more likely than girls to be obese (19.1% vs. 17.8%) and severely obese (6.3% vs. 4.9%), and both obesity and severe obesity were more common with increasing age. Obesity prevalence went from 13.9% in those aged 2-5 years to 20.6% in 12- to 19-year-olds, and severe obesity was 1.8% in the youngest group and 7.7% in the oldest, with the middle-age group (6-11 years) in the middle in both categories, they said

Among the adults, obesity was more common in women than men (41.1% vs. 37.9%) for 2015-2016, as was severe obesity (9.7% vs. 5.6%). Obesity and severe obesity were both highest in those aged 40-59 years, but obesity prevalence was lowest in the younger group (20-39 years) and severe obesity was least common in the older group (60 years and older), Dr. Hales and his associates said.

The analysis involved 16,875 children and 27,449 adults over the 10-year period. The investigators did not report any conflicts of interest.

rfranki@frontlinemedcom.com

SOURCE: Hales CM et al. JAMA 2018 Mar 23. doi: 10.1001/jama.2018.3060.

Obesity and severe obesity rose significantly in adults but not in children from 2007 to 2016, according to data from the National Health and Nutrition Examination Survey.

The age-standardized prevalence of obesity – defined as a body mass index of 30 or more – among adults aged 20 years and over increased from 33.7% for the 2-year period of 2007-2008 to 39.6% in 2015-2016, while the prevalence of severe obesity – defined as a body mass index of 40 kg/m2 or more – went from 5.7% to 7.7% over that same period, Craig M. Hales, MD, and his associates at the Centers for Disease Control and Prevention in Hyattsville, Md., and Atlanta said in a research letter published in JAMA.

The prevalence of obesity in children aged 2-19 years – defined as BMI at or above the sex-specific 95th percentile – increased, but not significantly, from 16.8% in 2007-2008 to 18.5% in 2015-2016, with most of that increase coming in the last 2 years. Severe obesity – BMI at or above 120% of the sex-specific 95th percentile – rose from 4.9% to 5.6% over those 10 years, but the last 2-year period saw the rate drop from 6% in 2013-2014, the investigators reported.

For the most recent reporting period, boys were more likely than girls to be obese (19.1% vs. 17.8%) and severely obese (6.3% vs. 4.9%), and both obesity and severe obesity were more common with increasing age. Obesity prevalence went from 13.9% in those aged 2-5 years to 20.6% in 12- to 19-year-olds, and severe obesity was 1.8% in the youngest group and 7.7% in the oldest, with the middle-age group (6-11 years) in the middle in both categories, they said

Among the adults, obesity was more common in women than men (41.1% vs. 37.9%) for 2015-2016, as was severe obesity (9.7% vs. 5.6%). Obesity and severe obesity were both highest in those aged 40-59 years, but obesity prevalence was lowest in the younger group (20-39 years) and severe obesity was least common in the older group (60 years and older), Dr. Hales and his associates said.

The analysis involved 16,875 children and 27,449 adults over the 10-year period. The investigators did not report any conflicts of interest.

rfranki@frontlinemedcom.com

SOURCE: Hales CM et al. JAMA 2018 Mar 23. doi: 10.1001/jama.2018.3060.

PHILADELPHIA – Tenofovir alafenamide, the newest kid on the block for treatment of chronic hepatitis B, not only has less bone and renal effects than tenofovir disoproxil, but now also appears to improve those parameters in patients switched over from the older tenofovir formulation, according to Paul Kwo, MD.

“Renal function, as well as hip and spine bone mineral density measurements, all improve after you flip,” said Dr. Kwo, director of hepatology at Stanford (Calif.) University.

Andrew D. Bowser/Frontline Medical News

Dr. Kwo described some of the latest data on the newer tenofovir formulation in a hepatitis B update he gave at the conference, jointly provided by Rutgers and Global Academy for Medical Education.

Tenofovir alafenamide, a nucleoside analogue reverse transcriptase inhibitor, was approved in November 2016 for treatment of adults with chronic hepatitis B virus (HBV) infection and compensated liver disease.

It has similar efficacy to tenofovir disoproxil, with fewer bone and renal effects, according to results of two large international phase 3 trials.

Some of the latest data, presented in October 2017 at The Liver Meeting in Washington, show that switching patients from tenofovir disoproxil to tenofovir alafenamide improved creatinine clearance and increased rates of alanine aminotransferase normalization, with sustained rates of virologic control, over 48 weeks of treatment.

Similar results were seen for bone mineral density. “It goes up over time, and you approach bone mineral density levels that are similar to [levels in] those who are on tenofovir alafenamide long term,” Dr. Kwo said, commenting on results of the study.

PHILADELPHIA – Tenofovir alafenamide, the newest kid on the block for treatment of chronic hepatitis B, not only has less bone and renal effects than tenofovir disoproxil, but now also appears to improve those parameters in patients switched over from the older tenofovir formulation, according to Paul Kwo, MD.

“Renal function, as well as hip and spine bone mineral density measurements, all improve after you flip,” said Dr. Kwo, director of hepatology at Stanford (Calif.) University.

Andrew D. Bowser/Frontline Medical News

Dr. Kwo described some of the latest data on the newer tenofovir formulation in a hepatitis B update he gave at the conference, jointly provided by Rutgers and Global Academy for Medical Education.

Tenofovir alafenamide, a nucleoside analogue reverse transcriptase inhibitor, was approved in November 2016 for treatment of adults with chronic hepatitis B virus (HBV) infection and compensated liver disease.

It has similar efficacy to tenofovir disoproxil, with fewer bone and renal effects, according to results of two large international phase 3 trials.

Some of the latest data, presented in October 2017 at The Liver Meeting in Washington, show that switching patients from tenofovir disoproxil to tenofovir alafenamide improved creatinine clearance and increased rates of alanine aminotransferase normalization, with sustained rates of virologic control, over 48 weeks of treatment.

Similar results were seen for bone mineral density. “It goes up over time, and you approach bone mineral density levels that are similar to [levels in] those who are on tenofovir alafenamide long term,” Dr. Kwo said, commenting on results of the study.

PHILADELPHIA – Tenofovir alafenamide, the newest kid on the block for treatment of chronic hepatitis B, not only has less bone and renal effects than tenofovir disoproxil, but now also appears to improve those parameters in patients switched over from the older tenofovir formulation, according to Paul Kwo, MD.

“Renal function, as well as hip and spine bone mineral density measurements, all improve after you flip,” said Dr. Kwo, director of hepatology at Stanford (Calif.) University.

Andrew D. Bowser/Frontline Medical News

Dr. Kwo described some of the latest data on the newer tenofovir formulation in a hepatitis B update he gave at the conference, jointly provided by Rutgers and Global Academy for Medical Education.

Tenofovir alafenamide, a nucleoside analogue reverse transcriptase inhibitor, was approved in November 2016 for treatment of adults with chronic hepatitis B virus (HBV) infection and compensated liver disease.

It has similar efficacy to tenofovir disoproxil, with fewer bone and renal effects, according to results of two large international phase 3 trials.

Some of the latest data, presented in October 2017 at The Liver Meeting in Washington, show that switching patients from tenofovir disoproxil to tenofovir alafenamide improved creatinine clearance and increased rates of alanine aminotransferase normalization, with sustained rates of virologic control, over 48 weeks of treatment.

Similar results were seen for bone mineral density. “It goes up over time, and you approach bone mineral density levels that are similar to [levels in] those who are on tenofovir alafenamide long term,” Dr. Kwo said, commenting on results of the study.