Gynecology

CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.

In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.

The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.

The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.

The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.

The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.

“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.

Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.

A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.

“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.

Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.

She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.

Pembrolizumab

The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.

Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.

The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.

Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.

The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.

Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.

An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.

Pembrolizumab is approved as second-line therapy in advanced melanoma.

The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.

In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.

The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.

The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.

The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.

The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.

“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.

Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.

A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.

“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.

Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.

She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.

Pembrolizumab

The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.

Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.

The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.

Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.

The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.

Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.

An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.

Pembrolizumab is approved as second-line therapy in advanced melanoma.

The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Two monoclonal antibodies were clinically active in heavily pretreated advanced ovarian cancer in a pair of phase Ib studies presented at the annual meeting of the American Society of Clinical Oncology.

In the JAVELIN trial, the objective response rate with avelumab was 10.7% after a median follow-up of 5 months in patients who were not preselected for PD-L1 (programmed death ligand 1) positivity at enrollment.

The objective response rate in the KEYNOTE-028 trial was 11.5% with the PD-1 inhibitor pembrolizumab (Keytruda) after a median follow-up of 11 months in PD-L1–positive patients.

The investigational agent avelumab inhibits PD-1 and PD-L1 interactions, but preclinical models have also suggested that antibody-dependent cellular cytotoxicity, which can directly result in lysing of tumor cells, is an additional mechanism of action, lead investigator Dr. Mary “Nora” L. Disis of the Fred Hutchinson Cancer Research Center, Seattle, and the Seattle Cancer Care Alliance said.

The expansion phase of the phase Ib JAVELIN trial has enrolled more than 840 patients with solid tumors in 11 indications and evaluated avelumab 10 mg/kg IV every 2 weeks until progression in 75 unselected patients with refractory or recurrent ovarian cancer. Most had received at least three previous lines of therapy (68%), and 70.7% had serous histology.

The objective response rate of 10.7% was based on eight partial responses by RECIST (Response Evaluation Criteria in Solid Tumors). In addition, 44% of patients have stable disease, resulting in a disease control rate of 54.7%. The median time to response was 9 weeks, and the median duration of response was 21 weeks.

“The majority of responses are durable and ongoing at the time of this report,” Dr. Disis said.

Tumor shrinkage by at least 30% was observed in 11 patients (14.7%), including both patients enrolled with clear cell histology. Two additional patients have a partial response by immune-related response criteria, boosting the objective response rate to about 15%, she said.

A subgroup analysis showed intriguing trends for higher response rates in patients with lower vs. higher tumor burden (15% vs. 5.7%), with at least one prior line of treatment vs. two lines or at least three lines (21.4% vs. 10% vs. 7.8%, respectively), and with platinum-sensitive vs. platinum-resistant disease (20% vs. 9.1%), Dr. Disis said.

“These data, of course, because of the short follow-up rate are fairly immature, but we’ll continue to explore these trends as the data do mature,” she said.

Treatment-related adverse events of any grade were reported in 69.3% of patients, most commonly fatigue, chills, nausea, and diarrhea. Six patients (8%) had a grade 3 treatment-related adverse event, with no grade 4 or 5 adverse events or deaths related to avelumab reported, Dr. Disis said. Nine patients (12%) discontinued treatment because of an adverse event.

She noted that this is the largest reported dataset of patients with refractory or recurrent ovarian cancer treated with anti–PD-L1 therapy and that phase III clinical development is planned.

Pembrolizumab

The KEYSTONE-028 trial was conducted in 26 women with PD-L1–positive ovarian cancer, of whom 81% had received at least four previous lines of therapy, Dr. Andrea Varga of Institut Gustave Roussy, Villejuif, France, said. The histology was adenocarcinoma in 46.2%, high-grade serous carcinoma in 34.6%, and other in 19.3%.

Of the 96 patients screened for the trial, 51% had PD-L1–positive tumors.

The 11.5% response rate for pembrolizumab 10 mg/kg every 2 weeks was based on one complete response and two partial responses. Stable disease was reported in six patients, for a disease control rate of 34.6%, Dr. Varga said. “Keep in mind, we are talking about a very heavily pretreated cohort of patients,” she added.

Overall, 23% of patients had at least a 30% decrease in tumor size. At the time of the analysis, the complete response and two partial responses were ongoing.

The median time to response was relatively early at 8 weeks, and the median duration of response has not been reached, indicating the durable nature of the responses, she said.

Adverse events of any grade were reported in 69.2% of patients, typically arthralgia, diarrhea, and nausea that was tolerable and easily managed. One patient had a grade 3-4 treatment-related increase in transaminase levels, and one patient had grade 3 pancreatitis. There were no treatment-related deaths or discontinuations because of an adverse event.

An analysis of the relationship between response and PD-L1 expression as well as other potential predictive biomarkers is ongoing, Dr. Varga said.

Pembrolizumab is approved as second-line therapy in advanced melanoma.

The JAVELIN trial was sponsored by Merck KGaA. Dr. Disis reported owning stock in Epiphany Biosciences and VentiRx; receiving honoraria from Celgene and Emergent BioSolutions; consulting or advising for Celgene, EMD Serono, Emergent BioSolutions, and VentiRx; receiving research funding from Seattle Genetics and VentiRx; and holding patents with the University of Washington. KEYNOTE-028 was supported by Merck Sharp & Dohme, with editorial assistance provided by Merck and the APO Group. Dr. Varga reported no relevant financial conflicts.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Disappointing topline overall survival results from TRINOVA-1 reported late last year dashed enthusiasm for trebananib in recurrent ovarian cancer, but a subgroup analysis suggests the anti-angiopoietin therapy may yet have a use.

In patients with ascites at baseline, adding trebananib to paclitaxel provided a nearly 30% survival advantage, increasing median overall survival from 12.3 months to 14.5 months (hazard ratio, 0.72; P = .011), Dr. Bradley Monk reported at the annual meeting of the American Society of Clinical Oncology.

There was no overall survival benefit in the full intent-to-treat population. Median overall survival was 18.3 months for single-agent paclitaxel and 19.3 months for the combination (HR, 0.95; P = .52).

Presence of ascites at baseline was a prespecified subgroup, stressed Dr. Monk, director of gynecologic oncology at St. Joseph’s Hospital, Phoenix, who noted that 32% of women fell into this subgroup (295/919 patients).

Women with and without ascites at baseline had the same age, primary tumor type, number of prior lines of therapy, and prior antiangiogenic therapy, although more patients with ascites had a platinum-free interval of less than 6 months (58% vs. 49%).

“So they were a poor prognosis group not only because of the ascites, but they had more platinum-resistant disease,” he said.

The TRINOVA-1 trial previously demonstrated a significant increase in the primary endpoint of median progression-free survival (PFS) from 5.4 months to 7.2 months when adding weekly trebananib to weekly paclitaxel (HR, 0.66; P < .001).

At baseline, about 40% of patients had received one or two prior lines of prior therapy and roughly a fourth received three prior lines. Patients received an average of 2.2 lines of additional anticancer therapy after progression on study.

An exploratory analysis of PFS after subsequent therapy revealed a median PFS of 12.5 months in the trebananib group vs. 10.9 months in the paclitaxel group (HR, 0.85; P = .024), Dr. Monk said.

Discussant Dr. Don Dizon, with Massachusetts General Hospital in Boston, said the results provide a strong signal of benefit in women with recurrent ovarian cancer and ascites, but can’t be considered definitive without further study.

Both men observed that treatment with trebananib plus paclitaxel was associated with an increase in adverse events. Trebananib was associated with 32% more localized edema of any grade (59% vs. 27%), but most of these events were grade 1 or 2, Dr. Monk said. The paclitaxel and trebananib groups had similar grade 3 (56% vs. 60%) and grade 4 events (12% vs. 12%) and patient-reported Functional Assessment of Cancer Therapy-Ovarian (FACT-O) scores at week 25.

Amgen funded the study. Dr. Monk reported having no conflicts of interest. Dr. Dizon reported employment and an advisory or consulting role with UpToDate and institutional research funding from Aeterna Zentaris and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.

Elizabeth Mechcatie/ Frontline Medical News

But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.

No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.

Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.

Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.

Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.

In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.

Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.

In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.

In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.

In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.

In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.

In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.

One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.

The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.

Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.

Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.

In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.

During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.

Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.

Elizabeth Mechcatie/ Frontline Medical News

But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.

No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.

Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.

Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.

Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.

In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.

Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.

In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.

In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.

In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.

In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.

In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.

One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.

The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.

Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.

Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.

In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.

During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.

Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.

emechcatie@frontlinemedcom.com

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel has supported the approval of flibanserin, an oral, centrally-acting, non-hormonal drug taken once a day for treating hypoactive sexual desire disorder in premenopausal women.

Elizabeth Mechcatie/ Frontline Medical News

But the panel also recommended some conditions, including a risk management plan to address serious adverse effects associated with the drug, a requirement for physician certification, and postmarketing studies to further evaluate and monitor the drug’s safety and efficacy. At a joint meeting of two FDA advisory panels on June 4 members of the Bone, Reproductive and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 18 to 6 that the overall benefit-risk profile of flibanserin supported approval for treating hypoactive sexual desire disorder (HSDD) in premenopausal women, provided that certain risk management options beyond labeling were implemented.

No panelist voted for the option of approval with labeling alone to manage the risks of the drug. The main safety issues raised by the FDA were the risks of hypotension and syncope – effects associated with the drug alone and exacerbated by alcohol and by co-administration with CYPA34 inhibitors.

Those in favor of approval said that the drug had only a modest beneficial effect in a controlled, limited population, but cited the unmet need for a treatment for HSDD. They strongly supported certification of prescribers to assure the drug is used to treat the appropriate patients and that patients are fully counseled about the potential risks.

Several panelists said that alcohol should be contraindicated in women taking the drug and that an alcohol interaction study should be conducted in women only. The manufacturer, Sprout Pharmaceuticals, conducted such a study but enrolled 23 men and only two women.

Flibanserin is a “post-synaptic 5-HT1A agonist 5-HT2A antagonist,” a non-hormonal treatment with sedating effects; the recommended dose is 100 mg taken every day at bedtime. It is mainly metabolized by CYP3A4.

In three phase III 24-week North American studies, women treated with flibanserin experienced significant improvements in the number of satisfying sexual events (SSEs) per month and sexual desire from baseline. The three studies enrolled premenopausal women whose mean age was 36 years. Most women were white, ten percent were black, and 8% were Hispanic. They met the DSM-IV criteria for HSDD for at least 6 months and were in a stable, monogamous relationship with a sexually functional partner for at least 1 year (mean was 11 years). Flibanserin was given to 1,227 study participants, while 1,238 received placebo.

Oral contraceptives, weak CYP3A4 inhibitors, were allowed in the three studies, but other CYP3A4 inhibitors, including fluticasone and grapefruit, were among the exclusion criteria. Perimenopausal or postmenopasual women were excluded.

In all three studies, the change from baseline in the number of satisfying sexual events (SSEs) was a primary endpoint. In the most recent trial, the mean change in SSEs from baseline was 1.5 SSEs per month among those on placebo, versus 2.5 among those on the drug.

In the two earlier studies, the mean increases were 1.6 and 1.9 SSEs among those on flibanserin, versus 0.8 and 1.1 respectively, among those on placebo.

In the first two studies, the primary endpoint that evaluated the treatment effect on sexual desire was “eDiary Desire,” a measure of the most intense level of desire during the previous 24 hours.

In the most recent study, the mean change from baseline to week 24 in the desire domain of the Female Sexual Function Index (FSFI-Desire) over 28 days was a co-primary endpoint (it was a secondary endpoint in the first two studies). In the first two studies flibanserin did not have a significant effect over placebo on the second primary endpoint, sexual desire, as measured by the eDiary Desire measurement, but the effect on a secondary endpoint, measured by FSFI-Desire, was statistically significant.

In the third pivotal study there were significant improvements associated with treatment over placebo in the FSFI-Desire endpoint.

One panelist voting in favor of approval, Dr. Walid Gellad, co-director of the Center for Pharmaceutical Policy and Prescribing at the University of Pittsburgh, said that if this were the seventh drug for the indication, “this would be a very different discussion.” But it is clear than many women suffer with HSDD, and there are many women who can benefit from flibanserin, although “the benefits are modest...maybe less than modest,” he added.

The risk of syncope, while rare and not associated with any deaths in the study, is a serious safety issue because it occurs unexpectedly and can be accentuated by other factors, he added.

Since the studies were conducted in a select patient population, a Risk Evaluation and Mitigation Strategy (REMS) was needed, he said, with prescriber certification to make sure it is prescribed to appropriate patients, who are those as close as possible to the patients enrolled in the study.

Since 2009, when Boehringer Ingelheim submitted the drug for approval, the FDA has declined twice to approve flibanserin. Reasons for the first decision not to approve included inadequate evidence that it was effective and the need for more information on its effects when used with other drugs and alcohol.

In 2013, it was resubmitted for approval by the new manufacturer, Sprout Pharmaceuticals, with another phase III study and other data, but it was not approved by the FDA for reasons that included numerically small treatment differences compared with placebo that did not outweigh safety concerns, according to the agency. The company appealed this decision, which was denied, and then conducted an additional study and filed for approval again.

During the open public hearing, numerous representatives of health organizations and women with HSDD cited the critical need for an FDA-approved option for women with the disorder, who currently have a multitude of unapproved, unproven, and questionable products marketed for this use.

Speakers opposing approval cited the small magnitude in improvements (at best, 8 more SSEs a year), which were not outweighed by the risks, and other issues, including the inclusion of only two women in the alcohol interaction study, the likelihood of off-label use in postmenopausal women, and the possibility that the drug could result in a significant number of syncope cases.

The FDA usually follows the recommendations of its advisory panels. Panelists were cleared of potential conflicts of interest related to the topic of the meeting. The FDA is expected to make a decision by August 2015.

emechcatie@frontlinemedcom.com

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – Adding bevacizumab to standard carboplatin and paclitaxel chemotherapy reduced the risk of progression by 41%, compared with chemotherapy alone for patients with advanced or recurrent endometrial cancer in the MITO END-2 study.

Median investigator-assessed progression-free survival was 8.7 months for chemotherapy alone and 13 months for bevacizumab plus chemotherapy (hazard ratio, 0.59; P = .036).

A subgroup analysis of the primary end point showed a significant benefit favoring the bevacizumab (Avastin) arm for patients who were older than 65 years, had an EGOG performance status of 1-2, had recurrent disease, and serous or clear cell histology.

Patrice Wendling/Frontline Medical News

“MITO END-2 is the first randomized trial suggesting efficacy of bevacizumab in advanced or recurrent endometrial cancer. These results merit, in our opinion, further exploration in a randomized phase III trial,” study author Dr. Domenica Lorusso said at the annual meeting of the American Society of Clinical Oncology.

Discussant Dr. Rebecca Kristeleit of University College London said, “I think most promising is that benefits appear greatest in the groups with the greatest need – those older patients, patients with poor prognosis, poor histological subtypes, and recurrence.”

MITO END-2 evenly randomized 108 women with stage III-IV or recurrent type 1 or type 2 endometrial cancer treated with 0-1 previous lines of chemotherapy to receive standard carboplatin and paclitaxel (Taxol) chemotherapy (AUC5) for 6-8 cycles with or without bevacizumab 15 mg/kg. Bevacizumab maintenance was continued until progression or unacceptable toxicity. In all, 5% of patients had prior chemotherapy, about 25% had serous or clear cell histology, and 65% had recurrent disease.

Among 92 evaluable patients, the objective response rate was 54.3% vs. 71.7% (P = .065) and 6-month disease control rate 69% vs. 83% (P = .09), both favoring the experimental arm, Dr. Lorusso of Fondazione IRCCS National Cancer Institute, Milan, said.

Overall survival data are immature with only 34% of required events, but show a similar trend, she said. Median OS was 18 months in patients receiving chemotherapy and 23.5 months in those receiving bevacizumab plus chemotherapy (HR, 0.65; P = .24).

Patrice Wendling/Frontline Medical News

No new safety signals appeared, but particular attention should be paid to cardiovascular toxicity when using bevacizumab in this population, which is typically older and has several comorbidities that are risk factors for cardiovascular disorders, Dr. Lorusso said. In the bevacizumab arm, one myocardial infarction, three arterial thromboses, and three venous thromboses occurred.

Dr. Kristeleit said there has been limited development of new treatments for endometrial cancer and that this must be a time for “catching up.” Advanced endometrial cancer is among the most common gynecologic cancers in the Western world and yet there are no approved molecular targeted agents, no validated predictive biomarkers, and there is a limited understanding of histopathologic selection, despite prognoses known to vary with the different subtypes.

“There’s a lot we need to do to focus our efforts in development of novel treatments for this group of patients,” she said.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

CHICAGO – The aromatase inhibitor anastrozole reduces the risk of disease recurrence better than tamoxifen for postmenopausal ductal carcinoma in situ (DCIS), particularly in younger women, preliminary results of a phase III study show.

At 10 years, 93.5% of women treated with anastrozole (Arimidex) were breast cancer free, compared with 89.2% of women treated with tamoxifen (Nolvadex) (hazard ratio, 0.73; P value = .03).

Patrice Wendling/Frontline Medical News

This benefit was driven by a significant effect for anastrozole in younger women aged less than 60 years (HR, 0.52; P = .003), but not in those aged 60 years and older (HR, 0.95; P = 0.77). The interaction between treatment and age was statistically significant (P = .04), Dr. Richard Margolese reported in a late-breaking abstract at the annual meeting of the American Society of Clinical Oncology.

“We now have another option for adjuvant therapy with DCIS. Women can take tamoxifen or anastrozole and, if they’re in the right group, it might be preferable to take anastrozole,” Dr. Margolese, professor of surgical oncology at Jewish General Hospital, McGill University, Montreal, said.

Aromatase inhibitors have been shown in invasive cancer to be superior to tamoxifen with regard to improved disease-free survival (DFS) and reduced contralateral breast cancer.

To determine whether they could offer better suppression with fewer side effects in DCIS, investigators for the NRG Oncology/NSABP B-35 study randomly assigned 3,104 postmenopausal women with DCIS treated by lumpectomy to tamoxifen 20 mg/day or anastrozole 1 mg/day, each for 5 years plus breast radiation. Patients could have estrogen receptor– or progesterone receptor–positive disease. Most were white (87.4%), and 53% were at least 60 years old. Median follow-up was 9 years.

At 10 years, DFS rates were similar between the anastrozole and tamoxifen groups (82.7% vs. 77.9%; P = .21).

When broken down by age, however, once again the benefit with anastrozole was significant in younger women (HR, 0.69, P = .02), but not in older women (HR, 1.03; P = .79), Dr. Margolese said.

Overall survival rates at 10 years were similar at 92.1% in the tamoxifen group and 92.5% in the anastrozole group (P =.48).

The number of uterine cancers, one of the more worrisome side effects of tamoxifen, was reduced from 17 with tamoxifen to 8 with anastrozole, but the confidence intervals were too wide to be meaningful (relative risk, 0.47; 95% CI, 0.18-1.15), he said.

As expected, osteoporotic fractures were higher with anastrozole at 69 vs. 50 with tamoxifen, but the difference also was not significant (RR, 1.38; 95% CI, 0.95-2.03).

With respect to thromboembolic events, grade 2 deep vein thrombosis was reported in 4 patients treated with tamoxifen and 1 treated with anastrozole. In the tamoxifen group, 20 patients had grade 3 pulmonary embolism, and 17 had grade 4 life-threatening PE, compared with 8 and 3 patients, respectively, in the anastrozole group. There was one thromboembolic death, with anastrozole, Dr. Margolese said.

Grade 0-1 hot flashes were more common with anastrozole than tamoxifen (965 events vs. 881 events), while the reverse was true for grade 2 hot flashes (570 events vs. 654 events). No grade 3 or 4 events occurred.

Joint and muscle pains are widely known to be a problem peculiar to aromatase inhibitors, but a self-report system showed roughly equal rates of these events in the two groups, Dr. Margolese said. Most tamoxifen and anastrozole patients reported low-grade 0-1 arthralgia events (1,177 vs. 1,031), with fewer grade 2 (302 vs. 427) or grade 3 (55 vs. 77) events, and only 1 grade 4 event with tamoxifen. Myalgia followed a similar pattern: grade 0-1 events (1,367 vs. 1,317), grade 2 (150 vs. 187), grade 3 (18 vs. 30), with 1 grade 4 event with anastrozole.

“Anastrozole is quite a suitable drug for treatment of DCIS,” Dr. Margolese said. “The safety factors and contraindications show it to be less of a problem than tamoxifen, especially in the possibly life-threatening side of the contraindications, and it is at least as effective, and in some groups more effective than tamoxifen.”

Finally, anastrozole reduced the number of contralateral invasive breast cancers from 36 with tamoxifen to 20. This translated into a significant 55% risk reduction (HR, 0.55; P = .03), which compares favorably with a roughly 50% reduction for tamoxifen in prior breast cancer prevention studies and raises the question of anastrozole as a prevention therapy, he said.

During a press briefing on the study, concerns were raised about the side effects associated with aromatase inhibitors. Dr. Margolese responded that the choice of therapy is a personal judgment to be made with a woman’s physician. For some women, the trauma of a cancer diagnosis drives the decision to take adjuvant therapy, while for others potential side effects weigh more heavily.

Susan London/Frontline Medical News

ASCO expert Dr. Don Dizon agreed and said the results of B-35 answer a very important clinical question and will allow physicians who treat women with DCIS to counsel them on an individual level about their treatment options.

The study was funded by the National Institutes of Health. Dr. Margolese reported no relevant conflicts of interest. Dr. Dizon reported employment and a consultant or advisory board role with UpToDate and research funding to his institution from AstraZeneca and GlaxoSmithKline.

pwendling@frontlinemedcom.com

On Twitter @pwendl

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

When Dr. Harald zur Hausen received the 2008 Nobel Prize in Physiology or Medicine for his discovery of the link between human papillomavirus (HPV) infections and genital cancers, he completed a 40-year odyssey to prove that viruses caused human cancer. Initially, zur Hausen, working in the University of Pennsylvania laboratory of the noted virologists Drs. Werner and Gertrude Henle, discovered that the Epstein-Barr virus was involved in the development of Burkitt lymphoma.¹ On return to his native Germany, he sought a link between HPV and genital tumors.²

First he isolated HPV 6 and HPV 11 directly from genital warts.³ Then zur Hausen utilized the nucleic acid sequences from HPV6 and the technique of low stringency hybridization to discover HPV 16 and HPV 18 in cervical cancer specimens.^4,5 Oncogenic HPV DNA contains 2 genes that produce the oncoproteins E6 and E7. E6 increases the degradation of p53 and E7 inactivates the retino-blastoma protein.⁶ The double-hit inactivation of 2 tumor suppressor genes, p53 and retinoblastoma protein, increases the mitotic activity of the infected cells, eventually leading to cancer.

zur Hausen tried to persuade companies to develop anti-HPV vaccines but was rebuffed for years. Today, building on his research, we have HPV vaccines that are 2-valent (against HPV types 16 and 18), 4-valent (against HPV types 6, 11, 16, and 18), and 9-valent (against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58). zur Hausen richly deserved the Nobel Prize for his life-saving discoveries.

Cervical, vulvar, and vaginal cancers
HPV types 16 and 18 cause about 70% of cervical cancers. HPV types 31, 33, 45, 52, and 58 cause about 20% of cervical cancers.⁷ The 2-, 4-, and 9-valent HPV vaccines have been demonstrated to prevent premalignant cervical disease, including cervical intraepithelial neoplasia (CIN) 2 and CIN 3 and adenocarcinoma in situ.^8–11 The development of a 9-valent HPV vaccine is an important advance because it provides more complete immunization against cancer causing viruses.

Approximately 70% of vaginal cancers are caused by HPV infections.¹² Among squamous cell vulvar cancers, HPV is detected in approximately 70% of cancers with warty or basaloid histology and 12% of cancers with keratinizing histology.¹³ In vulvar cancer, HPV 16, 33, and 18 are the most common types detected, representing 73%, 7%, and 5% of cases, respectively. The HPV 4- and 9-valent vaccines have been reported to reduce precancerous lesions of the vagina and vulva.^9,11 In most trials, vaccinations that occur before exposure to HPV through sexual encounters appear to provide greater protection than vaccinations that occur after HPV infection.

Anal cancer
Approximately 90% of anal cancers are caused by HPV infection, and HPV types 16 and 18 are detected in 81% and 4% of anal cancers, respectively.¹⁴ Among men who have sex with men, the HPV 4-valent vaccine reduced the rate of anal intraepithelial neoplasia, a precursor to anal cancer, by 50%.¹⁵ Women receiving the HPV 2-valent vaccine had an 84% reduction in the detection of anal cancer involving HPV types 16 and 18.¹⁶

Penile cancer
Approximately 48% of penile cancers harbor oncogenic HPV types.17 Among penile cancers the prevalence of HPV varies from 22% in verrucous cancer to 66% in basaloid and warty cancer. The most prevalent HPV types were 16, 6, and 18, which were observed in 31%, 7%, and 7% of the cancers, respectively.17 Penile cancer is not common and there are no studies directly demonstrating that HPV vaccination prevents penile cancer.

Oropharyngeal cancer
The rate of oropharyngeal cancer caused by HPV is rising rapidly and increasing more rapidly among men than among women.¹⁸ Remarkably, HPV-induced oropharyngeal cancer is projected to become more common than cervical cancer in 2020.¹⁸

In one report, 72% of oropharyngeal cancers harbored HPV 16, and antibodies against the HPV 16 oncoproteins E6 and E7 were detected in the blood of 64% of the cancer cases.¹⁹ In a case control study, having 6 or more lifetime oral-sex partners was associated with a 3.4-fold (95% confidence interval, 1.5 to 6.5) increased risk of developing oropharyngeal cancer.¹⁹

According to a population survey, 10% of men and 3.6% of women harbor HPV viruses in their oropharynx.²⁰ In this study approximately 50% of the HPV viruses detected were high-risk types, with the following rank-order prevalence from highest to lowest: 16, 66, 51, 39, 56, 52, 59, 18, 53, 45, 35, 33, and 31.²⁰ Theoretically, the 9-valent vaccine, with protection against HPV types 16, 18, 31, 33, 45, and 52, may be an optimal choice to prevent HPV-induced oropharyngeal cancer because of its broad coverage.

No study has yet proven that HPV vaccination reduces the risk of developing oropharyngeal cancer, but one study demonstrated that vaccination of girls against HPV types 16 and 18 reduced oral carriage of HPV 16 and HPV 18 by 93%.²¹ Vaccinating boys against HPV has been reported to be cost effective because it could reduce the high health care expenditures associated with treating oropharyngeal cancer.²²

Will you be an immunization champion?
Although HPV vaccination reduces the disease burden of cervical, vulvar, vaginal, and anal neoplasia, the CDC reported that, as of 2013, only 38% of girls and 14% of boys in the United States had received 3 doses of HPV vaccine.²³ The realization that oropharyngeal cancer caused by HPV is rapidly increasing may provide another catalyst to redouble our efforts to increase the vaccination rates for both boys and girls.

zur Hausen and many other experts have passionately advocated for vaccinating all boys and girls in order to maximize the beneficial effects of HPV vaccination.24 Every clinician can become an immunization champion by advocating that all boys and girls be vaccinated against HPV.

Share your thoughts on this article! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name and the city and state in which you practice.

The FBI has launched an investigation into the use of power morcellators for hysterectomy, and is seeking information on what Johnson & Johnson knew about the use of the devices and the risk of spreading uterine sarcoma, according to a report in the Wall Street Journal.

According to the publication, FBI agents have “interviewed a retired pathologist who alerted [Johnson & Johnson] about potential problems with morcellators in 2006, a doctor who went public after her own cancer was worsened by the tool in 2013, and a California woman who has collected names of close to 400 patients and families of patients who may have been harmed by the tool.”

The Food and Drug Administration warned in November 2014 that power morcellators should not be used in the “vast majority” of women after 2 days of advisory committee hearings last July. Johnson & Johnson halted sales of its devices in July as well.

Read more at wsj.com (subscription required).

dfulton@frontlinemedcom.com

On Twitter @denisefulton

The FBI has launched an investigation into the use of power morcellators for hysterectomy, and is seeking information on what Johnson & Johnson knew about the use of the devices and the risk of spreading uterine sarcoma, according to a report in the Wall Street Journal.

According to the publication, FBI agents have “interviewed a retired pathologist who alerted [Johnson & Johnson] about potential problems with morcellators in 2006, a doctor who went public after her own cancer was worsened by the tool in 2013, and a California woman who has collected names of close to 400 patients and families of patients who may have been harmed by the tool.”

The Food and Drug Administration warned in November 2014 that power morcellators should not be used in the “vast majority” of women after 2 days of advisory committee hearings last July. Johnson & Johnson halted sales of its devices in July as well.

Read more at wsj.com (subscription required).

dfulton@frontlinemedcom.com

On Twitter @denisefulton

The FBI has launched an investigation into the use of power morcellators for hysterectomy, and is seeking information on what Johnson & Johnson knew about the use of the devices and the risk of spreading uterine sarcoma, according to a report in the Wall Street Journal.

According to the publication, FBI agents have “interviewed a retired pathologist who alerted [Johnson & Johnson] about potential problems with morcellators in 2006, a doctor who went public after her own cancer was worsened by the tool in 2013, and a California woman who has collected names of close to 400 patients and families of patients who may have been harmed by the tool.”

The Food and Drug Administration warned in November 2014 that power morcellators should not be used in the “vast majority” of women after 2 days of advisory committee hearings last July. Johnson & Johnson halted sales of its devices in July as well.

Read more at wsj.com (subscription required).

dfulton@frontlinemedcom.com

On Twitter @denisefulton

To identify patients at increased risk for certain types of cancer, ob.gyns. should perform and regularly update hereditary cancer risk assessments, according to a new recommendation from the American College of Obstetricians and Gynecologists.

Patients at increased risk for hereditary cancer syndromes should be referred to a cancer genetics specialist for further assessment and counseling, according to the opinion from ACOG’s Committee on Genetics (Obstet. Gynecol. 2015;125:1538-43).

Alexander Raths/Fotolia.com

Personal and family histories provide key information to determine the appropriateness of genetic counseling, which is distinct from genetic testing. Discussed in the counseling visit, the decision for genetic testing is based on family history, pedigree analysis, and, in some cases, pathology reports and confirmation of cancer deaths.

Patient intake forms are used in many office settings to gather relevant information. Online versions of intake forms, such as the Surgeon General’s “My Family Health Portrait,” can facilitate documentation of comprehensive histories. The American Society of Clinical Oncology also has identified some key elements of an adequate family history for assessing cancer risk, including first- and second-degree relatives, maternal and paternal sides, European Jewish ancestry, age of onset and type of cancer, and results of predisposition tests in any relative.

There are several indicators for the presence of hereditary cancer syndromes, including cancer diagnosed at an unusually young age, the presence of several different types of cancer, several close relatives with the same type of cancer, unusual presentation (such as breast cancer in a man), certain birth defects (such as skin growths or skeletal abnormalities associated with inherited cancer syndromes), and Ashkenazi Jewish ancestry.

The ACOG committee opinion identifies common hereditary cancer syndromes involved in gynecologic cancers, including hereditary breast and ovarian cancer syndrome and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes.

Mutations in DNA repair genes BRCA1 and BRCA2 cause hereditary breast and ovarian cancer syndrome and account for 5%-15% of all breast and ovarian cancers in the United States. The carrier frequency in the general population is 1 in 500, but it is much higher (1 in 40) in the Ashkenazi Jewish population. Women with hereditary breast and ovarian cancer syndrome have a 65%-74% lifetime risk of breast cancer and 39%-46% (BRCA1) or 12%-20% (BRCA2) risk of ovarian cancer.

Also caused by DNA repair defects, Lynch syndrome, or hereditary nonpolyposis colorectal cancer, has a prevalence of 1 in 600 to 1 in 3,000. Individuals with Lynch syndrome have increased risk of colon (52%-82%), endometrial (25%-60%), and ovarian (4%-24%) cancers. Malignancies associated with Lynch syndrome include uterine, gastric, small bowel, hepatobiliary, breast, brain, and sebaceous skin cancers.

The presence of Li-Fraumeni syndrome increases the risk of osteosarcoma, breast cancer, colon cancer, adrenocortical carcinoma, leukemia and lymphoma, and brain cancer. Caused by mutations in the tumor suppressor gene TP53, individuals with the syndrome have a 90% risk of cancer by age 60 years. Patients diagnosed with a Li-Fraumeni syndrome–associated malignancy should be referred to a cancer genetics specialist for counseling, according to the committee opinion.

Individuals with the relatively rare (1 in 200,000) Cowden syndrome usually have pathognomonic skin lesions, including papillomatous papules on the face and mucous membranes, by age 30 years. The presence of Cowden syndrome increases the lifetime risk of breast cancer to 25%-50% and endometrial cancer to 5%-10%. Clinicians should consult frequently updated guidelines to determine which patients should be referred for genetic evaluation.

Mutations in serine/threonine kinase 11 cause Peutz-Jehgers syndrome. Two of the following three criteria characterize the syndrome: two or more hamartomatous polyps in the GI tract; mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia, or fingers; and a family history of Peutz-Jeghers syndrome. Women with Peutz-Jeghers syndrome have a 50% increased lifetime risk of breast cancer and increased risk of ovarian, uterine, and cervical cancer.

To identify patients at increased risk for certain types of cancer, ob.gyns. should perform and regularly update hereditary cancer risk assessments, according to a new recommendation from the American College of Obstetricians and Gynecologists.

Patients at increased risk for hereditary cancer syndromes should be referred to a cancer genetics specialist for further assessment and counseling, according to the opinion from ACOG’s Committee on Genetics (Obstet. Gynecol. 2015;125:1538-43).

Alexander Raths/Fotolia.com

Personal and family histories provide key information to determine the appropriateness of genetic counseling, which is distinct from genetic testing. Discussed in the counseling visit, the decision for genetic testing is based on family history, pedigree analysis, and, in some cases, pathology reports and confirmation of cancer deaths.

Patient intake forms are used in many office settings to gather relevant information. Online versions of intake forms, such as the Surgeon General’s “My Family Health Portrait,” can facilitate documentation of comprehensive histories. The American Society of Clinical Oncology also has identified some key elements of an adequate family history for assessing cancer risk, including first- and second-degree relatives, maternal and paternal sides, European Jewish ancestry, age of onset and type of cancer, and results of predisposition tests in any relative.

There are several indicators for the presence of hereditary cancer syndromes, including cancer diagnosed at an unusually young age, the presence of several different types of cancer, several close relatives with the same type of cancer, unusual presentation (such as breast cancer in a man), certain birth defects (such as skin growths or skeletal abnormalities associated with inherited cancer syndromes), and Ashkenazi Jewish ancestry.

The ACOG committee opinion identifies common hereditary cancer syndromes involved in gynecologic cancers, including hereditary breast and ovarian cancer syndrome and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes.

Mutations in DNA repair genes BRCA1 and BRCA2 cause hereditary breast and ovarian cancer syndrome and account for 5%-15% of all breast and ovarian cancers in the United States. The carrier frequency in the general population is 1 in 500, but it is much higher (1 in 40) in the Ashkenazi Jewish population. Women with hereditary breast and ovarian cancer syndrome have a 65%-74% lifetime risk of breast cancer and 39%-46% (BRCA1) or 12%-20% (BRCA2) risk of ovarian cancer.

Also caused by DNA repair defects, Lynch syndrome, or hereditary nonpolyposis colorectal cancer, has a prevalence of 1 in 600 to 1 in 3,000. Individuals with Lynch syndrome have increased risk of colon (52%-82%), endometrial (25%-60%), and ovarian (4%-24%) cancers. Malignancies associated with Lynch syndrome include uterine, gastric, small bowel, hepatobiliary, breast, brain, and sebaceous skin cancers.

The presence of Li-Fraumeni syndrome increases the risk of osteosarcoma, breast cancer, colon cancer, adrenocortical carcinoma, leukemia and lymphoma, and brain cancer. Caused by mutations in the tumor suppressor gene TP53, individuals with the syndrome have a 90% risk of cancer by age 60 years. Patients diagnosed with a Li-Fraumeni syndrome–associated malignancy should be referred to a cancer genetics specialist for counseling, according to the committee opinion.

Individuals with the relatively rare (1 in 200,000) Cowden syndrome usually have pathognomonic skin lesions, including papillomatous papules on the face and mucous membranes, by age 30 years. The presence of Cowden syndrome increases the lifetime risk of breast cancer to 25%-50% and endometrial cancer to 5%-10%. Clinicians should consult frequently updated guidelines to determine which patients should be referred for genetic evaluation.

Mutations in serine/threonine kinase 11 cause Peutz-Jehgers syndrome. Two of the following three criteria characterize the syndrome: two or more hamartomatous polyps in the GI tract; mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia, or fingers; and a family history of Peutz-Jeghers syndrome. Women with Peutz-Jeghers syndrome have a 50% increased lifetime risk of breast cancer and increased risk of ovarian, uterine, and cervical cancer.

To identify patients at increased risk for certain types of cancer, ob.gyns. should perform and regularly update hereditary cancer risk assessments, according to a new recommendation from the American College of Obstetricians and Gynecologists.

Patients at increased risk for hereditary cancer syndromes should be referred to a cancer genetics specialist for further assessment and counseling, according to the opinion from ACOG’s Committee on Genetics (Obstet. Gynecol. 2015;125:1538-43).

Alexander Raths/Fotolia.com

Personal and family histories provide key information to determine the appropriateness of genetic counseling, which is distinct from genetic testing. Discussed in the counseling visit, the decision for genetic testing is based on family history, pedigree analysis, and, in some cases, pathology reports and confirmation of cancer deaths.

Patient intake forms are used in many office settings to gather relevant information. Online versions of intake forms, such as the Surgeon General’s “My Family Health Portrait,” can facilitate documentation of comprehensive histories. The American Society of Clinical Oncology also has identified some key elements of an adequate family history for assessing cancer risk, including first- and second-degree relatives, maternal and paternal sides, European Jewish ancestry, age of onset and type of cancer, and results of predisposition tests in any relative.

There are several indicators for the presence of hereditary cancer syndromes, including cancer diagnosed at an unusually young age, the presence of several different types of cancer, several close relatives with the same type of cancer, unusual presentation (such as breast cancer in a man), certain birth defects (such as skin growths or skeletal abnormalities associated with inherited cancer syndromes), and Ashkenazi Jewish ancestry.

The ACOG committee opinion identifies common hereditary cancer syndromes involved in gynecologic cancers, including hereditary breast and ovarian cancer syndrome and Lynch, Li-Fraumeni, Cowden, and Peutz-Jeghers syndromes.

Mutations in DNA repair genes BRCA1 and BRCA2 cause hereditary breast and ovarian cancer syndrome and account for 5%-15% of all breast and ovarian cancers in the United States. The carrier frequency in the general population is 1 in 500, but it is much higher (1 in 40) in the Ashkenazi Jewish population. Women with hereditary breast and ovarian cancer syndrome have a 65%-74% lifetime risk of breast cancer and 39%-46% (BRCA1) or 12%-20% (BRCA2) risk of ovarian cancer.

Also caused by DNA repair defects, Lynch syndrome, or hereditary nonpolyposis colorectal cancer, has a prevalence of 1 in 600 to 1 in 3,000. Individuals with Lynch syndrome have increased risk of colon (52%-82%), endometrial (25%-60%), and ovarian (4%-24%) cancers. Malignancies associated with Lynch syndrome include uterine, gastric, small bowel, hepatobiliary, breast, brain, and sebaceous skin cancers.

The presence of Li-Fraumeni syndrome increases the risk of osteosarcoma, breast cancer, colon cancer, adrenocortical carcinoma, leukemia and lymphoma, and brain cancer. Caused by mutations in the tumor suppressor gene TP53, individuals with the syndrome have a 90% risk of cancer by age 60 years. Patients diagnosed with a Li-Fraumeni syndrome–associated malignancy should be referred to a cancer genetics specialist for counseling, according to the committee opinion.

Individuals with the relatively rare (1 in 200,000) Cowden syndrome usually have pathognomonic skin lesions, including papillomatous papules on the face and mucous membranes, by age 30 years. The presence of Cowden syndrome increases the lifetime risk of breast cancer to 25%-50% and endometrial cancer to 5%-10%. Clinicians should consult frequently updated guidelines to determine which patients should be referred for genetic evaluation.

Mutations in serine/threonine kinase 11 cause Peutz-Jehgers syndrome. Two of the following three criteria characterize the syndrome: two or more hamartomatous polyps in the GI tract; mucocutaneous hyperpigmentation of the mouth, lips, nose, eyes, genitalia, or fingers; and a family history of Peutz-Jeghers syndrome. Women with Peutz-Jeghers syndrome have a 50% increased lifetime risk of breast cancer and increased risk of ovarian, uterine, and cervical cancer.