WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Adjuvant treatments appear to have no significant detrimental long-term effects on sperm count in men being treated for clinical stage I testicular cancer, results of a recent investigation suggest.

Sperm number and concentration were largely stable over time in patients who received a round of chemotherapy or radiation to lymph nodes following orchiectomy, according to results of the 182-patient study.

Investigators said they still offer sperm banking before orchiectomy, since some patients will have low sperm counts prior to orchiectomy that persist after the procedure.
Moreover, the type of testicular cancer and the potential need for other postorchiectomy treatments are often “unknown factors” that underscore the importance of sperm banking, said the researchers, led by Kristina Weibring, MD, of Karolinska University Hospital, Stockholm.

“Assisted reproductive measures may be necessary for these patients regardless of any treatment given,” the researchers noted. The report is in Annals of Oncology.

The lack of effect on sperm counts in this study stands in contrast to previous studies, which clearly show the detrimental effects of multiple chemotherapy cycles on sperm recovery, the investigators said.

Their study comprised 182 patients 18-50 years of age with clinical stage I testicular cancer who underwent unilateral orchiectomy. Depending on tumor characteristics, the patients then received one cycle of adjuvant carboplatin, one cycle of a bleomycin, etoposide, and cisplatin (BEP) regimen, surveillance, or adjuvant radiotherapy to the infradiaphragmal para-aortic and ipsilateral iliac lymph nodes. Sperm samples were obtained at 6, 12, 24, 36, and 60 months after the completion of treatment.

While there was a transient drop in the radiation-treated patients at the 6-month evaluation, mean total sperm number otherwise increased over time in all groups, according to the investigators’ report.

Similarly, mean sperm concentration significantly increased from baseline to 12 months post treatment in the surveillance, BEP, and carboplatin groups, with a nonsignificant decrease in the radiotherapy group, they said in the report.

There were generally no significant differences in sperm count or concentration for the treatments, compared with surveillance, beyond a significant decrease in mean sperm count for radiation versus surveillance, they added.

There were likewise no significant changes in sperm measures for seminoma and nonseminoma patients at any point over the 5 years of evaluation, reported data show.

“With the results of this study, we can now inform our patients that adjuvant chemotherapy does not seem to affect the testicular function,” Dr. Weibring and her colleagues concluded.

The authors reported that they had no conflicts of interest related to the study, which was supported by the Swedish Cancer Society, among other sources.

SOURCE: Weibring K et al. Ann Oncol. 2019 Feb 25. doi: 10.1093/annonc/mdz017/5348526.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

Diet plays an important role in patient response to anti-programmed death-1 (PD-1) cancer immunotherapy, preliminary findings from a gut microbiome study involving 146 melanoma patients suggest.

Specifically, a high-fiber diet was associated with a more diverse gut microbiome and with improved response to anti-PD-1 therapy, whereas a diet high in sugar and processed meat was associated with fewer of the gut bacteria known to be associated with improved response, Christine Spencer, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research (AACR) annual meeting in Atlanta.

“We found that patients who reported eating high-fiber diets were about five times as likely to respond to anti-PD-1 checkpoint blockade immunotherapy (odds ratio vs. low-fiber diet, 5.3),” said Dr. Spencer, a research scientist at the Parker Institute for Cancer Immunotherapy.

Notably, more than 40% of patients reported taking probiotics, and those, surprisingly, were also associated with reduced gut microbiome diversity, she said.

For this study, Dr. Spencer and her colleagues at the University of Texas MD Anderson Cancer Center, Houston, analyzed prospectively collected fecal samples from 146 melanoma patients, and collected baseline diet information via the National Cancer Institute dietary screener questionnaire, as well as information about probiotic and antibiotic use, in a subset of 113 who were initiating therapy at MD Anderson. Those patients were then followed to assess therapy response.

“Our early data suggest that different foods and supplements may impact response to cancer immunotherapy in patients, and we think this is likely mediated by the gut microbiome,” she said.

Since only 20%-30% of cancer patients respond to immunotherapy, the findings hint at potential approaches for improving gut microbiome diversity, and thus response to anti-PD-1 cancer immunotherapy.

“Eat your high-fiber foods: fruits, vegetables, and whole grains – lots of different kinds and lots of them,” she said. “High-fiber diets have been linked to health benefits in several other contexts, and this study, although preliminary, shows fiber is linked to more favorable gut microbiome in patients, and better response to cancer immunotherapy.”

Conversations about the use of probiotic supplements also are important, she said.

“A lot of people have the perception that probiotics will provide health benefits, but that might not be the case in cancer patients. We’re not saying all of them are bad, but the message is that these factors have never before been studied in patients on immunotherapy, and our data suggest for the first time that they could matter,” she said, noting that future directions include validation of the findings in larger cohorts.

SOURCE: Spencer C et al. AACR 2019, Abstract preview.

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³