Genitourinary Cancer

Two subgroups of men with node-positive prostate cancer are more likely to benefit from adjuvant radiotherapy after surgery than others, investigators report online in the Journal of Clinical Oncology.

A retrospective observational study of 1,107 patients receiving adjuvant hormonal therapy with or without radiotherapy, found that men with one or two positive lymph nodes and intermediate- to high-grade, non–specimen-confined disease, and men with three or four positive nodes regardless of other tumor characteristics, saw significantly improved cancer-specific mortality at 8 years associated with radiotherapy (hazard ratio, 0.30; P = .002 for the former and HR, 0.21; P = .02, for the latter). Adjuvant radiotherapy did not improve survival in patients with extremely favorable (two or fewer positive lymph nodes, specimen-confined, and/or low-grade tumor) or extremely unfavorable (greater than four positive nodes) prostate cancer.

Investigators, led by Dr. Firas Abdollah of the Mayo Clinic, Rochester, Minn., looked at the records of patients treated between 1988 and 2010 at the Mayo Clinic and San Raffaele Hospital in Milan, Italy, with radical prostatectomy and anatomically extended pelvic lymph node dissection before being treated with adjuvant hormonal therapy, and adjuvant radiotherapy at the discretion of the physician (35% of the cohort received radiotherapy).

“The beneficial impact of adjuvant radiotherapy on survival in patients with prostate cancer with lymph node invasion can depend on individualized tumor characteristics,” Dr. Abdollah and his colleagues wrote (J. Clin. Onc. 2014 Sept. 22;[doi:10.1200/JCO.2014.58.1058]).

Those not expected to benefit could be spared unnecessary treatment and adverse effects associated with radiotherapy, they said. Previous studies have suggested that two positive lymph nodes might serve as a cutoff for indicating radiotherapy, the researchers noted, while this study added the additional subgroup of patients with three or four positive nodes. Dr. Abdollah and colleagues noted as limitations of their study its nonrandomized, retrospective design, and the fact that the decision to initiate radiotherapy was left to the clinical judgment of the treating physician, allowing for the possibility of selection bias. None of the researchers declared conflicts of interest.

Two subgroups of men with node-positive prostate cancer are more likely to benefit from adjuvant radiotherapy after surgery than others, investigators report online in the Journal of Clinical Oncology.

A retrospective observational study of 1,107 patients receiving adjuvant hormonal therapy with or without radiotherapy, found that men with one or two positive lymph nodes and intermediate- to high-grade, non–specimen-confined disease, and men with three or four positive nodes regardless of other tumor characteristics, saw significantly improved cancer-specific mortality at 8 years associated with radiotherapy (hazard ratio, 0.30; P = .002 for the former and HR, 0.21; P = .02, for the latter). Adjuvant radiotherapy did not improve survival in patients with extremely favorable (two or fewer positive lymph nodes, specimen-confined, and/or low-grade tumor) or extremely unfavorable (greater than four positive nodes) prostate cancer.

Investigators, led by Dr. Firas Abdollah of the Mayo Clinic, Rochester, Minn., looked at the records of patients treated between 1988 and 2010 at the Mayo Clinic and San Raffaele Hospital in Milan, Italy, with radical prostatectomy and anatomically extended pelvic lymph node dissection before being treated with adjuvant hormonal therapy, and adjuvant radiotherapy at the discretion of the physician (35% of the cohort received radiotherapy).

“The beneficial impact of adjuvant radiotherapy on survival in patients with prostate cancer with lymph node invasion can depend on individualized tumor characteristics,” Dr. Abdollah and his colleagues wrote (J. Clin. Onc. 2014 Sept. 22;[doi:10.1200/JCO.2014.58.1058]).

Those not expected to benefit could be spared unnecessary treatment and adverse effects associated with radiotherapy, they said. Previous studies have suggested that two positive lymph nodes might serve as a cutoff for indicating radiotherapy, the researchers noted, while this study added the additional subgroup of patients with three or four positive nodes. Dr. Abdollah and colleagues noted as limitations of their study its nonrandomized, retrospective design, and the fact that the decision to initiate radiotherapy was left to the clinical judgment of the treating physician, allowing for the possibility of selection bias. None of the researchers declared conflicts of interest.

Two subgroups of men with node-positive prostate cancer are more likely to benefit from adjuvant radiotherapy after surgery than others, investigators report online in the Journal of Clinical Oncology.

A retrospective observational study of 1,107 patients receiving adjuvant hormonal therapy with or without radiotherapy, found that men with one or two positive lymph nodes and intermediate- to high-grade, non–specimen-confined disease, and men with three or four positive nodes regardless of other tumor characteristics, saw significantly improved cancer-specific mortality at 8 years associated with radiotherapy (hazard ratio, 0.30; P = .002 for the former and HR, 0.21; P = .02, for the latter). Adjuvant radiotherapy did not improve survival in patients with extremely favorable (two or fewer positive lymph nodes, specimen-confined, and/or low-grade tumor) or extremely unfavorable (greater than four positive nodes) prostate cancer.

Investigators, led by Dr. Firas Abdollah of the Mayo Clinic, Rochester, Minn., looked at the records of patients treated between 1988 and 2010 at the Mayo Clinic and San Raffaele Hospital in Milan, Italy, with radical prostatectomy and anatomically extended pelvic lymph node dissection before being treated with adjuvant hormonal therapy, and adjuvant radiotherapy at the discretion of the physician (35% of the cohort received radiotherapy).

“The beneficial impact of adjuvant radiotherapy on survival in patients with prostate cancer with lymph node invasion can depend on individualized tumor characteristics,” Dr. Abdollah and his colleagues wrote (J. Clin. Onc. 2014 Sept. 22;[doi:10.1200/JCO.2014.58.1058]).

Those not expected to benefit could be spared unnecessary treatment and adverse effects associated with radiotherapy, they said. Previous studies have suggested that two positive lymph nodes might serve as a cutoff for indicating radiotherapy, the researchers noted, while this study added the additional subgroup of patients with three or four positive nodes. Dr. Abdollah and colleagues noted as limitations of their study its nonrandomized, retrospective design, and the fact that the decision to initiate radiotherapy was left to the clinical judgment of the treating physician, allowing for the possibility of selection bias. None of the researchers declared conflicts of interest.

Enzalutamide, an androgen receptor blocker, has been approved by the Food and Drug Administration to treat men with metastatic castration-resistant prostate cancer who have not received chemotherapy, manufacturer Medivation announced Sept. 10.

The drug, which is marketed under the brand name Xtandi, received FDA approval in August 2012 as a second-line treatment for metastatic castration-resistant prostate cancer (MCRPC) in men previously receiving docetaxel.

Approval was based on the results of the PREVAIL phase III trial. Interim results of the trial were presented earlier this year at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO).

A same-day announcement by ASCO noted that the "pre-specified interim analysis for OS [overall survival] demonstrated a statistically significant improvement in patients who received enzalutamide," with a median overall survival of 32.4 months vs. 30.2 months in the placebo arm. "The OS improvement was supported by a statistically significant prolongation of [radiographic progression-free survival] in patients who received" the once-daily dose of 160 mg of enzalutamide, compared with placebo.

Additionally, the median time to initiation of cytotoxic chemotherapy was 28 months in the enzalutamide arm, compared with 10.8 months in the placebo arm.

The most common side effects in 10% or more of patients receiving enzalutamide from this trial and the randomized trial used for its initial approval were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight loss, headache, hypertension, and dizziness/vertigo.

According to its prescribing information, enzalutamide is being recommended at the 160-mg dose, taken orally with or without food.

gtwachtman@frontlinemedcom.com

Enzalutamide, an androgen receptor blocker, has been approved by the Food and Drug Administration to treat men with metastatic castration-resistant prostate cancer who have not received chemotherapy, manufacturer Medivation announced Sept. 10.

The drug, which is marketed under the brand name Xtandi, received FDA approval in August 2012 as a second-line treatment for metastatic castration-resistant prostate cancer (MCRPC) in men previously receiving docetaxel.

Approval was based on the results of the PREVAIL phase III trial. Interim results of the trial were presented earlier this year at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO).

A same-day announcement by ASCO noted that the "pre-specified interim analysis for OS [overall survival] demonstrated a statistically significant improvement in patients who received enzalutamide," with a median overall survival of 32.4 months vs. 30.2 months in the placebo arm. "The OS improvement was supported by a statistically significant prolongation of [radiographic progression-free survival] in patients who received" the once-daily dose of 160 mg of enzalutamide, compared with placebo.

Additionally, the median time to initiation of cytotoxic chemotherapy was 28 months in the enzalutamide arm, compared with 10.8 months in the placebo arm.

The most common side effects in 10% or more of patients receiving enzalutamide from this trial and the randomized trial used for its initial approval were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight loss, headache, hypertension, and dizziness/vertigo.

According to its prescribing information, enzalutamide is being recommended at the 160-mg dose, taken orally with or without food.

gtwachtman@frontlinemedcom.com

Enzalutamide, an androgen receptor blocker, has been approved by the Food and Drug Administration to treat men with metastatic castration-resistant prostate cancer who have not received chemotherapy, manufacturer Medivation announced Sept. 10.

The drug, which is marketed under the brand name Xtandi, received FDA approval in August 2012 as a second-line treatment for metastatic castration-resistant prostate cancer (MCRPC) in men previously receiving docetaxel.

Approval was based on the results of the PREVAIL phase III trial. Interim results of the trial were presented earlier this year at the Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology (ASCO).

A same-day announcement by ASCO noted that the "pre-specified interim analysis for OS [overall survival] demonstrated a statistically significant improvement in patients who received enzalutamide," with a median overall survival of 32.4 months vs. 30.2 months in the placebo arm. "The OS improvement was supported by a statistically significant prolongation of [radiographic progression-free survival] in patients who received" the once-daily dose of 160 mg of enzalutamide, compared with placebo.

Additionally, the median time to initiation of cytotoxic chemotherapy was 28 months in the enzalutamide arm, compared with 10.8 months in the placebo arm.

The most common side effects in 10% or more of patients receiving enzalutamide from this trial and the randomized trial used for its initial approval were asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight loss, headache, hypertension, and dizziness/vertigo.

According to its prescribing information, enzalutamide is being recommended at the 160-mg dose, taken orally with or without food.

gtwachtman@frontlinemedcom.com

Pharmaceutical or surgical androgen deprivation should be continued indefinitely in men with metastatic castration-resistant prostate cancer, and abiraterone acetate/prednisone, enzalutamide, or radium-223 should also be offered, according to updated guidelines published online Sept. 8 in the Journal of Clinical Oncology.

The question posed to the panel of experts convened by the American Society of Clinical Oncology and Cancer Care Ontario (CCO) was simple: Which systemic therapies improve outcomes in men with metastatic castration-resistant prostate cancer? The effort builds on previous recommendations from both groups (BMC Cancer 2006;6:112 and Clin. Oncol. [R. Coll. Radiol.] 2013; 25:406-30).

"For men with androgen-sensitive metastatic disease, continuous androgen-deprivation therapy is the current standard of care," wrote the panel of authors led by Dr. Ethan Basch of University of North Carolina, Chapel Hill. "Ultimately, many of these men will develop castration-resistant prostate cancer (CRPC), warranting additional lines of therapy added to androgen-deprivation therapy."

The panel conducted a systematic review of medical literature published through June 2014 to search for trials that could inform recommendations. Studies were included if they were randomized, controlled trials or summaries based on such trials; if they included men with metastatic CRPC; if they compared systemic therapy, alone or in combination with other agents, versus placebo or other drug regimens; and if they were published English-language reports.

The researchers excluded articles if they involved only androgen-deprivation therapy, bone targeted agents, or radionuclides. Trials were required to have at least 50 patients per study arm, and in mixed study populations at least 90% of men were required to have metastases.

Based on analysis of 26 randomized, controlled trials, the panel determined that when added to androgen deprivation, three treatments demonstrated strong evidence of survival as well as QOL benefit, with a favorable benefit-risk profile: abiraterone acetate, enzalutamide, and radium-223 (for patients with predominantly bone metastases). "The toxicity profile of radium-223 is favorable when historically compared with other radiopharmaceuticals used in this population," the panel wrote.

"It is not known whether combining radium-223 with other treatments improves clinical outcomes. Radium-223 should be considered for patients with bone disease, whereas abiraterone or enzalutamide should be considered for those with bone and/or soft tissue disease. Use of any of these agents in combination should be restricted to the context of prospective clinical trials," they said (J. Clin. Oncol. 2014 Sept. 8 [doi:10.1200/jco.2013.54.8404]).

The panel also found that docetaxel with prednisone remains an acceptable therapy to offer patients based on strong evidence of improved survival, pain, and overall QOL, "but it has a relatively higher risk of toxicity when compared historically with abiraterone, enzalutamide, or radium-223. Potential harms of this therapy should be discussed with patients at the time of decision making in relation to the apparently lower risk of harms associated with other options and to the patient’s individual circumstances. If administered, docetaxel should be given every 3 weeks, which has been shown to be superior to a once-per-week schedule."

For men who are asymptomatic or mildly asymptomatic, sipuleucel-T "remains an option" as risks of harm are "relatively low," though impact on QOL has not been formally studied.

For men who have previously received docetaxel, cabazitaxel with prednisone offers a statistically significant overall survival benefit, "although it does not seem to substantially improve pain; impact on QOL is not known, but it carries a substantial toxicity profile," the panel wrote. A high toxicity risk is associated with the use of mitoxanthrone after docetaxel. No survival benefit has been observed with this agent, but it "may be commercially available where others are not and is generally less costly."

Clinical trials of several products have been conducted in men with CRPC without evidence of overall benefit in clinically meaningful patient outcomes, including atrasentan, bevacizumab, calcitriol, GVAX, orteronel, satraplatin, sunitinib, and zibotentan. "Products have been tested alone or in addition to docetaxel," the panel wrote. "Of these, bevacizumab and sunitinib have been approved by regulatory authorities for other indications."

The panel emphasized that patients "should be fully informed about the extent of potential benefit as well as harm and cost of treatment before making decisions. ASCO and CCO consider it essential to good clinical practice to [ensure] that this information and the goals of care are understood. Many patients misunderstand the goals of care in the setting of metastatic disease to be curative rather than palliative. This may lead to decisions to accept excess toxicity or cost based on incorrect assumptions about potential benefit. Palliative care should be offered to all patients, particularly to those exhibiting symptoms or QOL decrements," the panel said.

Members of the panel reported consultancy or advisory roles and funding from numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Pharmaceutical or surgical androgen deprivation should be continued indefinitely in men with metastatic castration-resistant prostate cancer, and abiraterone acetate/prednisone, enzalutamide, or radium-223 should also be offered, according to updated guidelines published online Sept. 8 in the Journal of Clinical Oncology.

The question posed to the panel of experts convened by the American Society of Clinical Oncology and Cancer Care Ontario (CCO) was simple: Which systemic therapies improve outcomes in men with metastatic castration-resistant prostate cancer? The effort builds on previous recommendations from both groups (BMC Cancer 2006;6:112 and Clin. Oncol. [R. Coll. Radiol.] 2013; 25:406-30).

"For men with androgen-sensitive metastatic disease, continuous androgen-deprivation therapy is the current standard of care," wrote the panel of authors led by Dr. Ethan Basch of University of North Carolina, Chapel Hill. "Ultimately, many of these men will develop castration-resistant prostate cancer (CRPC), warranting additional lines of therapy added to androgen-deprivation therapy."

The panel conducted a systematic review of medical literature published through June 2014 to search for trials that could inform recommendations. Studies were included if they were randomized, controlled trials or summaries based on such trials; if they included men with metastatic CRPC; if they compared systemic therapy, alone or in combination with other agents, versus placebo or other drug regimens; and if they were published English-language reports.

The researchers excluded articles if they involved only androgen-deprivation therapy, bone targeted agents, or radionuclides. Trials were required to have at least 50 patients per study arm, and in mixed study populations at least 90% of men were required to have metastases.

Based on analysis of 26 randomized, controlled trials, the panel determined that when added to androgen deprivation, three treatments demonstrated strong evidence of survival as well as QOL benefit, with a favorable benefit-risk profile: abiraterone acetate, enzalutamide, and radium-223 (for patients with predominantly bone metastases). "The toxicity profile of radium-223 is favorable when historically compared with other radiopharmaceuticals used in this population," the panel wrote.

"It is not known whether combining radium-223 with other treatments improves clinical outcomes. Radium-223 should be considered for patients with bone disease, whereas abiraterone or enzalutamide should be considered for those with bone and/or soft tissue disease. Use of any of these agents in combination should be restricted to the context of prospective clinical trials," they said (J. Clin. Oncol. 2014 Sept. 8 [doi:10.1200/jco.2013.54.8404]).

The panel also found that docetaxel with prednisone remains an acceptable therapy to offer patients based on strong evidence of improved survival, pain, and overall QOL, "but it has a relatively higher risk of toxicity when compared historically with abiraterone, enzalutamide, or radium-223. Potential harms of this therapy should be discussed with patients at the time of decision making in relation to the apparently lower risk of harms associated with other options and to the patient’s individual circumstances. If administered, docetaxel should be given every 3 weeks, which has been shown to be superior to a once-per-week schedule."

For men who are asymptomatic or mildly asymptomatic, sipuleucel-T "remains an option" as risks of harm are "relatively low," though impact on QOL has not been formally studied.

For men who have previously received docetaxel, cabazitaxel with prednisone offers a statistically significant overall survival benefit, "although it does not seem to substantially improve pain; impact on QOL is not known, but it carries a substantial toxicity profile," the panel wrote. A high toxicity risk is associated with the use of mitoxanthrone after docetaxel. No survival benefit has been observed with this agent, but it "may be commercially available where others are not and is generally less costly."

Clinical trials of several products have been conducted in men with CRPC without evidence of overall benefit in clinically meaningful patient outcomes, including atrasentan, bevacizumab, calcitriol, GVAX, orteronel, satraplatin, sunitinib, and zibotentan. "Products have been tested alone or in addition to docetaxel," the panel wrote. "Of these, bevacizumab and sunitinib have been approved by regulatory authorities for other indications."

The panel emphasized that patients "should be fully informed about the extent of potential benefit as well as harm and cost of treatment before making decisions. ASCO and CCO consider it essential to good clinical practice to [ensure] that this information and the goals of care are understood. Many patients misunderstand the goals of care in the setting of metastatic disease to be curative rather than palliative. This may lead to decisions to accept excess toxicity or cost based on incorrect assumptions about potential benefit. Palliative care should be offered to all patients, particularly to those exhibiting symptoms or QOL decrements," the panel said.

Members of the panel reported consultancy or advisory roles and funding from numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Pharmaceutical or surgical androgen deprivation should be continued indefinitely in men with metastatic castration-resistant prostate cancer, and abiraterone acetate/prednisone, enzalutamide, or radium-223 should also be offered, according to updated guidelines published online Sept. 8 in the Journal of Clinical Oncology.

The question posed to the panel of experts convened by the American Society of Clinical Oncology and Cancer Care Ontario (CCO) was simple: Which systemic therapies improve outcomes in men with metastatic castration-resistant prostate cancer? The effort builds on previous recommendations from both groups (BMC Cancer 2006;6:112 and Clin. Oncol. [R. Coll. Radiol.] 2013; 25:406-30).

"For men with androgen-sensitive metastatic disease, continuous androgen-deprivation therapy is the current standard of care," wrote the panel of authors led by Dr. Ethan Basch of University of North Carolina, Chapel Hill. "Ultimately, many of these men will develop castration-resistant prostate cancer (CRPC), warranting additional lines of therapy added to androgen-deprivation therapy."

The panel conducted a systematic review of medical literature published through June 2014 to search for trials that could inform recommendations. Studies were included if they were randomized, controlled trials or summaries based on such trials; if they included men with metastatic CRPC; if they compared systemic therapy, alone or in combination with other agents, versus placebo or other drug regimens; and if they were published English-language reports.

The researchers excluded articles if they involved only androgen-deprivation therapy, bone targeted agents, or radionuclides. Trials were required to have at least 50 patients per study arm, and in mixed study populations at least 90% of men were required to have metastases.

Based on analysis of 26 randomized, controlled trials, the panel determined that when added to androgen deprivation, three treatments demonstrated strong evidence of survival as well as QOL benefit, with a favorable benefit-risk profile: abiraterone acetate, enzalutamide, and radium-223 (for patients with predominantly bone metastases). "The toxicity profile of radium-223 is favorable when historically compared with other radiopharmaceuticals used in this population," the panel wrote.

"It is not known whether combining radium-223 with other treatments improves clinical outcomes. Radium-223 should be considered for patients with bone disease, whereas abiraterone or enzalutamide should be considered for those with bone and/or soft tissue disease. Use of any of these agents in combination should be restricted to the context of prospective clinical trials," they said (J. Clin. Oncol. 2014 Sept. 8 [doi:10.1200/jco.2013.54.8404]).

The panel also found that docetaxel with prednisone remains an acceptable therapy to offer patients based on strong evidence of improved survival, pain, and overall QOL, "but it has a relatively higher risk of toxicity when compared historically with abiraterone, enzalutamide, or radium-223. Potential harms of this therapy should be discussed with patients at the time of decision making in relation to the apparently lower risk of harms associated with other options and to the patient’s individual circumstances. If administered, docetaxel should be given every 3 weeks, which has been shown to be superior to a once-per-week schedule."

For men who are asymptomatic or mildly asymptomatic, sipuleucel-T "remains an option" as risks of harm are "relatively low," though impact on QOL has not been formally studied.

For men who have previously received docetaxel, cabazitaxel with prednisone offers a statistically significant overall survival benefit, "although it does not seem to substantially improve pain; impact on QOL is not known, but it carries a substantial toxicity profile," the panel wrote. A high toxicity risk is associated with the use of mitoxanthrone after docetaxel. No survival benefit has been observed with this agent, but it "may be commercially available where others are not and is generally less costly."

Clinical trials of several products have been conducted in men with CRPC without evidence of overall benefit in clinically meaningful patient outcomes, including atrasentan, bevacizumab, calcitriol, GVAX, orteronel, satraplatin, sunitinib, and zibotentan. "Products have been tested alone or in addition to docetaxel," the panel wrote. "Of these, bevacizumab and sunitinib have been approved by regulatory authorities for other indications."

The panel emphasized that patients "should be fully informed about the extent of potential benefit as well as harm and cost of treatment before making decisions. ASCO and CCO consider it essential to good clinical practice to [ensure] that this information and the goals of care are understood. Many patients misunderstand the goals of care in the setting of metastatic disease to be curative rather than palliative. This may lead to decisions to accept excess toxicity or cost based on incorrect assumptions about potential benefit. Palliative care should be offered to all patients, particularly to those exhibiting symptoms or QOL decrements," the panel said.

Members of the panel reported consultancy or advisory roles and funding from numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Detection of AR-V7 in the peripheral blood appears to be a marker of resistance to both enzalutamide and abiraterone treatment in men who have metastatic castration-resistant prostate cancer, according to a report published online Sept. 3 in the New England Journal of Medicine.

In a blinded prospective study involving 62 patients, researchers explored whether the presence of AR-V7 (androgen-receptor splice variant 7 messenger RNA) in circulating tumor cells would predict resistance to enzalutamide and abiraterone, two new agents that act on different molecular pathways to inhibit androgen-receptor signaling. If their findings are confirmed in larger studies, "it is possible that AR-V7 could be used as a biomarker to predict resistance ... and to facilitate treatment selection," reported Dr. Emmanuel S. Antonarakis of Johns Hopkins University, Baltimore, and his associates.

However, it is important to note that these results do not demonstrate a causal role for AR-V7 in mediating resistance to enzalutamide or abiraterone. It is possible that AR-V7 is simply a marker of more advanced disease or a higher disease burden, the investigators added.

The two drugs "represent important advances in the management of castration-resistant prostate cancer." But a substantial proportion of patients don’t benefit from them, "and a clearer understanding of the mechanisms underlying resistance to these drugs would facilitate selection of alternative therapies for such patients," Dr. Antonarakis and his associates said.

In this study, men with metastatic castration-resistant prostate cancer who were about to begin standard treatment with enzalutamide (31 patients) or abiraterone (31 patients) provided peripheral blood samples for analysis of circulating tumor cells at baseline.

After a median follow-up of approximately 5 months, the prostate-specific antigen (PSA) response in the enzalutamide group was 0% among men who were AR-V7 positive, compared with 53% among men who were AR-V7 negative. In the abiraterone group, the PSA response was 0% among men who were AR-V7 positive, compared with 68% among men who were AR-V7 negative. Not one of the AR-V7-positive patients showed any appreciable clinical benefit from these drugs, the investigators reported (New Engl. J. Med. 2014 Sept. 3 [doi: 10.1056/NEJMoa1315815]).

In addition, progression-free survival was shorter among AR-V7-positive men than among men who had no detectable AR-V7, whether that endpoint was measured by PSA level, radiography, or clinical signs and symptoms.

This study was supported by the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, and the National Institutes of Health. Dr. Antonarakis reported receiving personal fees from Sanofi, Dendreon, and Janssen Biotech, and his associates reported ties to numerous industry sources.

Detection of AR-V7 in the peripheral blood appears to be a marker of resistance to both enzalutamide and abiraterone treatment in men who have metastatic castration-resistant prostate cancer, according to a report published online Sept. 3 in the New England Journal of Medicine.

In a blinded prospective study involving 62 patients, researchers explored whether the presence of AR-V7 (androgen-receptor splice variant 7 messenger RNA) in circulating tumor cells would predict resistance to enzalutamide and abiraterone, two new agents that act on different molecular pathways to inhibit androgen-receptor signaling. If their findings are confirmed in larger studies, "it is possible that AR-V7 could be used as a biomarker to predict resistance ... and to facilitate treatment selection," reported Dr. Emmanuel S. Antonarakis of Johns Hopkins University, Baltimore, and his associates.

However, it is important to note that these results do not demonstrate a causal role for AR-V7 in mediating resistance to enzalutamide or abiraterone. It is possible that AR-V7 is simply a marker of more advanced disease or a higher disease burden, the investigators added.

The two drugs "represent important advances in the management of castration-resistant prostate cancer." But a substantial proportion of patients don’t benefit from them, "and a clearer understanding of the mechanisms underlying resistance to these drugs would facilitate selection of alternative therapies for such patients," Dr. Antonarakis and his associates said.

In this study, men with metastatic castration-resistant prostate cancer who were about to begin standard treatment with enzalutamide (31 patients) or abiraterone (31 patients) provided peripheral blood samples for analysis of circulating tumor cells at baseline.

After a median follow-up of approximately 5 months, the prostate-specific antigen (PSA) response in the enzalutamide group was 0% among men who were AR-V7 positive, compared with 53% among men who were AR-V7 negative. In the abiraterone group, the PSA response was 0% among men who were AR-V7 positive, compared with 68% among men who were AR-V7 negative. Not one of the AR-V7-positive patients showed any appreciable clinical benefit from these drugs, the investigators reported (New Engl. J. Med. 2014 Sept. 3 [doi: 10.1056/NEJMoa1315815]).

In addition, progression-free survival was shorter among AR-V7-positive men than among men who had no detectable AR-V7, whether that endpoint was measured by PSA level, radiography, or clinical signs and symptoms.

This study was supported by the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, and the National Institutes of Health. Dr. Antonarakis reported receiving personal fees from Sanofi, Dendreon, and Janssen Biotech, and his associates reported ties to numerous industry sources.

Detection of AR-V7 in the peripheral blood appears to be a marker of resistance to both enzalutamide and abiraterone treatment in men who have metastatic castration-resistant prostate cancer, according to a report published online Sept. 3 in the New England Journal of Medicine.

In a blinded prospective study involving 62 patients, researchers explored whether the presence of AR-V7 (androgen-receptor splice variant 7 messenger RNA) in circulating tumor cells would predict resistance to enzalutamide and abiraterone, two new agents that act on different molecular pathways to inhibit androgen-receptor signaling. If their findings are confirmed in larger studies, "it is possible that AR-V7 could be used as a biomarker to predict resistance ... and to facilitate treatment selection," reported Dr. Emmanuel S. Antonarakis of Johns Hopkins University, Baltimore, and his associates.

However, it is important to note that these results do not demonstrate a causal role for AR-V7 in mediating resistance to enzalutamide or abiraterone. It is possible that AR-V7 is simply a marker of more advanced disease or a higher disease burden, the investigators added.

The two drugs "represent important advances in the management of castration-resistant prostate cancer." But a substantial proportion of patients don’t benefit from them, "and a clearer understanding of the mechanisms underlying resistance to these drugs would facilitate selection of alternative therapies for such patients," Dr. Antonarakis and his associates said.

In this study, men with metastatic castration-resistant prostate cancer who were about to begin standard treatment with enzalutamide (31 patients) or abiraterone (31 patients) provided peripheral blood samples for analysis of circulating tumor cells at baseline.

After a median follow-up of approximately 5 months, the prostate-specific antigen (PSA) response in the enzalutamide group was 0% among men who were AR-V7 positive, compared with 53% among men who were AR-V7 negative. In the abiraterone group, the PSA response was 0% among men who were AR-V7 positive, compared with 68% among men who were AR-V7 negative. Not one of the AR-V7-positive patients showed any appreciable clinical benefit from these drugs, the investigators reported (New Engl. J. Med. 2014 Sept. 3 [doi: 10.1056/NEJMoa1315815]).

In addition, progression-free survival was shorter among AR-V7-positive men than among men who had no detectable AR-V7, whether that endpoint was measured by PSA level, radiography, or clinical signs and symptoms.

This study was supported by the Prostate Cancer Foundation, the Department of Defense Prostate Cancer Research Program, and the National Institutes of Health. Dr. Antonarakis reported receiving personal fees from Sanofi, Dendreon, and Janssen Biotech, and his associates reported ties to numerous industry sources.

ORLANDO – Prostate-specific antigen density, total number of biopsies, and later year of diagnosis were significantly associated with disease progression in men under active surveillance for low-risk prostate cancer.

Of 808 study subjects, 554 met strict criteria for active surveillance based on the following criteria: stage less than cT3, prostate-specific antigen (PSA) level less than 10 ng/mL, Gleason score of 6 or less, less than a third of biopsies positive, and less than 50% single-core positive; 254 patients did not meet these strict criteria.

At 5 years after diagnosis, prostate cancer–specific survival was 100%, overall survival was 98%, metastasis-free survival was greater than 99%, and treatment-free survival was 60% Dr. Christopher J. Welty reported at the annual meeting of the American Urological Association.

On multivariate analysis, factors associated with disease progression were PSA density (hazard ratio, 2.06 for 0.1-0.15, and 2.83 for values exceeding 0.15), total number of biopsies (hazard ratio, 0.76), and later year of diagnosis (hazard ratio, 1.16), said Dr. Welty of the University of California, San Francisco. PSA density is based on PSA value per unit volume of prostate.

Study subjects were enrolled in active surveillance at UCSF between 1990 and 2012 and had a mean age of 62 years. Active surveillance consisted of quarterly PSA testing with risk-adapted use of serial prostate biopsy and reimaging. Participants underwent a median of three repeat biopsies during a median of 57 months.

"Of the clinical parameters tested, the likelihood of biopsy progression during active surveillance was most strongly associated with PSA density at diagnosis; the association was modified by prostate size," he said. A stronger association was seen in men with smaller prostates (less than 30 cc), and as expected, patients with larger prostates tended to have lower PSA density than the general cohort, which is a limitation of the study.

This study was supported in part by the U.S. Department of Defense Prostate Cancer Research Program. Dr. Welty reported having no disclosures.

ORLANDO – Prostate-specific antigen density, total number of biopsies, and later year of diagnosis were significantly associated with disease progression in men under active surveillance for low-risk prostate cancer.

Of 808 study subjects, 554 met strict criteria for active surveillance based on the following criteria: stage less than cT3, prostate-specific antigen (PSA) level less than 10 ng/mL, Gleason score of 6 or less, less than a third of biopsies positive, and less than 50% single-core positive; 254 patients did not meet these strict criteria.

At 5 years after diagnosis, prostate cancer–specific survival was 100%, overall survival was 98%, metastasis-free survival was greater than 99%, and treatment-free survival was 60% Dr. Christopher J. Welty reported at the annual meeting of the American Urological Association.

On multivariate analysis, factors associated with disease progression were PSA density (hazard ratio, 2.06 for 0.1-0.15, and 2.83 for values exceeding 0.15), total number of biopsies (hazard ratio, 0.76), and later year of diagnosis (hazard ratio, 1.16), said Dr. Welty of the University of California, San Francisco. PSA density is based on PSA value per unit volume of prostate.

Study subjects were enrolled in active surveillance at UCSF between 1990 and 2012 and had a mean age of 62 years. Active surveillance consisted of quarterly PSA testing with risk-adapted use of serial prostate biopsy and reimaging. Participants underwent a median of three repeat biopsies during a median of 57 months.

"Of the clinical parameters tested, the likelihood of biopsy progression during active surveillance was most strongly associated with PSA density at diagnosis; the association was modified by prostate size," he said. A stronger association was seen in men with smaller prostates (less than 30 cc), and as expected, patients with larger prostates tended to have lower PSA density than the general cohort, which is a limitation of the study.

This study was supported in part by the U.S. Department of Defense Prostate Cancer Research Program. Dr. Welty reported having no disclosures.

ORLANDO – Prostate-specific antigen density, total number of biopsies, and later year of diagnosis were significantly associated with disease progression in men under active surveillance for low-risk prostate cancer.

Of 808 study subjects, 554 met strict criteria for active surveillance based on the following criteria: stage less than cT3, prostate-specific antigen (PSA) level less than 10 ng/mL, Gleason score of 6 or less, less than a third of biopsies positive, and less than 50% single-core positive; 254 patients did not meet these strict criteria.

At 5 years after diagnosis, prostate cancer–specific survival was 100%, overall survival was 98%, metastasis-free survival was greater than 99%, and treatment-free survival was 60% Dr. Christopher J. Welty reported at the annual meeting of the American Urological Association.

On multivariate analysis, factors associated with disease progression were PSA density (hazard ratio, 2.06 for 0.1-0.15, and 2.83 for values exceeding 0.15), total number of biopsies (hazard ratio, 0.76), and later year of diagnosis (hazard ratio, 1.16), said Dr. Welty of the University of California, San Francisco. PSA density is based on PSA value per unit volume of prostate.

Study subjects were enrolled in active surveillance at UCSF between 1990 and 2012 and had a mean age of 62 years. Active surveillance consisted of quarterly PSA testing with risk-adapted use of serial prostate biopsy and reimaging. Participants underwent a median of three repeat biopsies during a median of 57 months.

"Of the clinical parameters tested, the likelihood of biopsy progression during active surveillance was most strongly associated with PSA density at diagnosis; the association was modified by prostate size," he said. A stronger association was seen in men with smaller prostates (less than 30 cc), and as expected, patients with larger prostates tended to have lower PSA density than the general cohort, which is a limitation of the study.

This study was supported in part by the U.S. Department of Defense Prostate Cancer Research Program. Dr. Welty reported having no disclosures.

Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.

The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).

Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.

The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.

lnikolaides@frontlinemedcom.com

On Twitter @nikolaideslaura

Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.

The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).

Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.

The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.

lnikolaides@frontlinemedcom.com

On Twitter @nikolaideslaura

Updates on non- and muscle-invasive bladder cancer, neoadjuvant and adjuvant therapy, organ preservation therapy, treatment of advanced and metastatic disease, and treatment of relapse are included in recently published, revised clinical practice guidelines for bladder cancer.

The European Society for Medical Oncology (ESMO) guidelines focus on transitional cell carcinoma and were published online Aug. 5 in Annals of Oncology (Ann. Oncol. 2014 [doi: 10.1093/annonc/mdu223]).

Dr. Joaquim Bellmunt, director of the bladder cancer center at Dana-Farber Cancer Institute, Boston, and his associates on the ESMO guidelines working group noted that the most common presenting symptom is painless hematuria, seen in more than 80% of patients. Approximately 70% of patients with bladder cancer are over age 65, they added.

The complete ESMO guidelines for diagnosis, treatment, and follow-up of bladder cancer are available at the ESMO website or at the Annals of Oncology website.

lnikolaides@frontlinemedcom.com

On Twitter @nikolaideslaura

Compared with open radical cystectomy, robot-assisted laparoscopic radical cystectomy did not reduce the number or severity of complications among patients with bladder cancer enrolled in a single-center randomized clinical trial, according to a letter to the editor in the New England Journal of Medicine.

Retrospective studies have suggested that the robot-assisted laparoscopic approach reduces the complication rate and shortens the length of hospitalization in patients with bladder cancer, many of whom are older, are smokers, and have coexisting conditions. This trial was designed to compare that approach against open radical cystectomy, with both procedures using extracorporeal urinary diversion, in 118 patients who had stage Ta-3N0-3M0 bladder cancer, said Dr. Bernard H. Bochner and his associates at Memorial Sloan Kettering Cancer Center, New York.

Courtesy Wikimedia Commons/Nimur/Creative Commons

The primary outcome – the rate of complications of grade 2-5 within 90 days of surgery—was 62% (37 of 60 patients) with robot-assisted laparoscopic surgery, which was not significantly different from the 66% rate (38 of 58 patients) with open surgery. Similarly, the rates of high-grade complications were not significantly different (22% vs 21%), and the mean length of hospitalization was identical (8 days) in both groups. The amount of intraoperative blood loss was smaller with the robot-assisted surgery (mean difference, 159 cc), but the duration of surgery was shorter with open surgery (mean difference, 127 minutes).

"Because the trial was performed by experienced surgeons at a single, high-volume referral center, the results may not be generalizable to all clinical settings. Nonetheless, these results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation," Dr. Bochner and his associates said (N. Engl. J. Med. 2014;371:389-90).

This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer. Dr. Bochner and his associates reported no financial conflicts of interest.

Compared with open radical cystectomy, robot-assisted laparoscopic radical cystectomy did not reduce the number or severity of complications among patients with bladder cancer enrolled in a single-center randomized clinical trial, according to a letter to the editor in the New England Journal of Medicine.

Retrospective studies have suggested that the robot-assisted laparoscopic approach reduces the complication rate and shortens the length of hospitalization in patients with bladder cancer, many of whom are older, are smokers, and have coexisting conditions. This trial was designed to compare that approach against open radical cystectomy, with both procedures using extracorporeal urinary diversion, in 118 patients who had stage Ta-3N0-3M0 bladder cancer, said Dr. Bernard H. Bochner and his associates at Memorial Sloan Kettering Cancer Center, New York.

Courtesy Wikimedia Commons/Nimur/Creative Commons

The primary outcome – the rate of complications of grade 2-5 within 90 days of surgery—was 62% (37 of 60 patients) with robot-assisted laparoscopic surgery, which was not significantly different from the 66% rate (38 of 58 patients) with open surgery. Similarly, the rates of high-grade complications were not significantly different (22% vs 21%), and the mean length of hospitalization was identical (8 days) in both groups. The amount of intraoperative blood loss was smaller with the robot-assisted surgery (mean difference, 159 cc), but the duration of surgery was shorter with open surgery (mean difference, 127 minutes).

"Because the trial was performed by experienced surgeons at a single, high-volume referral center, the results may not be generalizable to all clinical settings. Nonetheless, these results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation," Dr. Bochner and his associates said (N. Engl. J. Med. 2014;371:389-90).

This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer. Dr. Bochner and his associates reported no financial conflicts of interest.

Compared with open radical cystectomy, robot-assisted laparoscopic radical cystectomy did not reduce the number or severity of complications among patients with bladder cancer enrolled in a single-center randomized clinical trial, according to a letter to the editor in the New England Journal of Medicine.

Retrospective studies have suggested that the robot-assisted laparoscopic approach reduces the complication rate and shortens the length of hospitalization in patients with bladder cancer, many of whom are older, are smokers, and have coexisting conditions. This trial was designed to compare that approach against open radical cystectomy, with both procedures using extracorporeal urinary diversion, in 118 patients who had stage Ta-3N0-3M0 bladder cancer, said Dr. Bernard H. Bochner and his associates at Memorial Sloan Kettering Cancer Center, New York.

Courtesy Wikimedia Commons/Nimur/Creative Commons

The primary outcome – the rate of complications of grade 2-5 within 90 days of surgery—was 62% (37 of 60 patients) with robot-assisted laparoscopic surgery, which was not significantly different from the 66% rate (38 of 58 patients) with open surgery. Similarly, the rates of high-grade complications were not significantly different (22% vs 21%), and the mean length of hospitalization was identical (8 days) in both groups. The amount of intraoperative blood loss was smaller with the robot-assisted surgery (mean difference, 159 cc), but the duration of surgery was shorter with open surgery (mean difference, 127 minutes).

"Because the trial was performed by experienced surgeons at a single, high-volume referral center, the results may not be generalizable to all clinical settings. Nonetheless, these results highlight the need for randomized trials to inform the benefits and risks of new surgical technologies before widespread implementation," Dr. Bochner and his associates said (N. Engl. J. Med. 2014;371:389-90).

This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers at Memorial Sloan Kettering Cancer Center, Pin Down Bladder Cancer, and the Michael A. and Zena Wiener Research and Therapeutics Program in Bladder Cancer. Dr. Bochner and his associates reported no financial conflicts of interest.

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

emechcatie@frontlinemedcom.com

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

emechcatie@frontlinemedcom.com

GAITHERSBURG, MD. – A Food and Drug Administration advisory panel agreed that a device that thermally ablates the prostate gland using high-intensity focused ultrasound should not be approved for treating men with localized prostate cancer now, because of issues that included no proof of efficacy and a high rate of adverse events for a noninvasive treatment.

At a meeting on July 30, the FDA’s Gastroenterology and Urology Devices Panel voted 8-0, with one abstention, that the benefits of the high-intensity focused ultrasound (HIFU) therapy did not outweigh the risks for the proposed indication, the primary treatment of prostate cancer in subjects with low-risk, localized prostate cancer. Available in Europe for 15 years, the Ablatherm integrated imaging device is manufactured by EDAP TMS, a French company. The components of the computer-controlled device include a treatment module, a control console, and an endorectal probe that is inserted rectally, heating the target tissue to therapeutic levels, while the patient is under general or spinal anesthesia. The company describes HIFU therapy as a "minimally invasive treatment during which the Ablatherm device precisely focuses ablative energy on the prostate gland while avoiding damage to sensitive adjacent anatomy."

But in separate questions, the panel unanimously voted that there was not reasonable assurance that the device was effective for the proposed indication. The vote on the safety issue alone was mixed, with panelists voting 5-3, with one abstention, that there was not reasonable assurance that the device was safe for the indication.

The company had problems completing enrollment in the U.S. pivotal trial, which compared HIFU treatment to cryotherapy, and provided several other analyses, including comparisons of the results with data from a registry and other clinical trials. The FDA reviewers raised multiple issues with the data, and panelists agreed, citing issues with safety and efficacy, including the efficacy endpoint used in the pivotal trial.

"I don’t think the potential benefits outweigh the risk," said Dr. Eric Klein, chairman of the Glickman Urological and Kidney Institute, at the Cleveland Clinic. His negative vote on the efficacy question, he noted, "relates mostly to the fact that patients with low-risk prostate cancer are at low risk for progression andbeing harmed by their disease and there are other management strategies that have lower risk than this proposed therapy."

Dr. Patrick Walsh, professor of urology, Johns Hopkins University, Baltimore, said that "at the present time, I do not believe there’s any evidence that efficacy, which has not been proven, outweighs what I look at as significant side effects." Describing a noninvasive treatment that has a 41% rate of serious adverse events as safe was "excessive," he added. (In the pivotal study, the rate of severe adverse events was 41%.)

Another panelist, Dr. Marc Garnick, professor of medicine, Harvard Medical School, Boston, said that he appreciated the technologic advance that HIFU represents and acknowledged the difficulties involved in studying the treatment in the low-risk population. However, as a practicing physician who counsels many patients with early-stage, low-risk cancer trying to make a decision about primary therapy versus active surveillance, he said it "would be very, very difficult for me to make a recommendation for HIFU therapy if one takes a look at the metastasis-free survival and the cancer-specific survival in patients with low-risk features that basically don’t get any therapy and compared that to some of the vagaries of the safety considerations that they would be subjected to with HIFU."

The U.S. pivotal study was a nonrandomized, multicenter prospective study comparing HIFU to cryotherapy in patients with low-risk, localized prostate cancer (a prostate-specific antigen level of 10 ng/mL or less, clinical stage T1 to T2a cancer, and a Gleason score of 6 or less). But the study was not completed because of problems enrolling patents, and only 135 patients were enrolled in the HIFU arm and 5 in the cryotherapy arm, instead of 205 patients in each arm, as planned.

Among the 135 HIFU-treated patients, the primary endpoint, biochemical relapse-free survival (based on the Phoenix criteria for biochemical recurrence, the nadir PSA level plus 2.0 ng/mL) at 2 years was 90.5%, and the cumulative positive biopsy rate was 28%.

Other analyses provided by the manufacturer included a comparison of long-term follow-up data on a subgroup of 227 patients from a European registry of patients treated with Ablatherm HIFU, who met the criteria of those on the pivotal study, with outcomes among 148 patients with low-risk prostate cancer in the radical prostatectomy arm of the U.S. Veterans Affairs PIVOT (Prostate Cancer Intervention Versus Observation Trial). PIVOT investigators compared radical prostatectomy with observation among men with clinically localized prostate cancer; the trial was conducted between 1996 and 2002. Metastases were reported in 3 of the 227 HIFU-treated patients (1.3%) and in 6 of 148 (4.1%) of those in PIVOT. The cumulative risk at 8 years was similar in both groups, 1.1 % among those treated with HIFU and 1.4% among the low-risk PIVOT patients.

In the pivotal study, almost all of the patients (97%) treated with HIFU had an adverse event; 82% had a moderate or severe adverse event. Adverse events included erectile dysfunction in 67%, urinary retention in 49%, urinary incontinence in 39%, urinary stricture in 35%, urethral injury in 15%, and bowel dysfunction in 21%. Most of these adverse events resolved in most patients over time, but at 24 months, 44% of the treated patients still had erectile dysfunction.

The FDA reviewers said that it was unclear whether HIFU therapy provides a benefit for patients with low-risk prostate cancer, and said that they were concerned about the 28% positive biopsy rate in the pivotal trial. Based on the evidence provided, "we can conclude that a single whole-gland HIFU treatment session does not get rid of all the cancer within the prostate gland in a significant percentage of patients," said one of the FDA reviewers, Dr. Jonathan Jarow of the FDA’s office of hematology and oncology products in the FDA’s Center for Drug Evaluation and Research. The FDA has never approved a treatment for prostate cancer based on PSA results, he pointed out.

Panelists generally agreed that the biochemical survival rate at 2 years using the Phoenix criteria could not be used to show the treatment was effective for a nonradiation treatment in patients with low-risk prostate cancer, pointing out that the criteria had not been validated with this technology. Several panelists said that the device might be effective but that it was not possible to determine that with the available data.

In a statement issued by EDAP after the meeting concluded, Marc Oczachowski, the company’s chief executive officer, said that the company "will continue to work diligently with the FDA as it carefully completes its final review" of the Ablatherm HIFU application.

The device has been used to treat about 40,000 patients with low-risk disease worldwide, according to EDAP.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts.

emechcatie@frontlinemedcom.com