Genitourinary Cancer

Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.

However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.

Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.

"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.

Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."

Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.

This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.

The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.

Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.

The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.

The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.

Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.

At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.

Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).

This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.

Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.

"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.

At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.

There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.

These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.

It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.

This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.

Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.

However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.

Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.

"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.

Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."

Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.

This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.

The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.

Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.

The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.

The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.

Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.

At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.

Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).

This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.

Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.

"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.

At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.

There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.

These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.

It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.

This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.

Both a printed and a web-based interactive "decision aid" for prostate cancer screening improved men’s understanding of the risks and benefits of screening, compared with usual care, according to a report published online July 29 in JAMA Internal Medicine.

However, neither form of decision aid altered the rate of prostate cancer screening 1 year later, said Kathryn L. Taylor, Ph.D., of the Lombardi Comprehensive Cancer Center, Georgetown University, Washington, and her associates.

Decision aids are tools for informing patients about a medical condition – in this case, prostate cancer – and reviewing the possible benefits, harms, and scientific uncertainties regarding screening options. These aids are particularly useful when there are trade-offs between risks and benefits; the efficacy and outcomes of screening are unclear; and/or overdiagnosis and overtreatment are genuine concerns – all of which apply to prostate cancer screening.

"Most men overestimate the benefits of prostate cancer screening and are unaware of its limitations," the investigators said.

Decision aids are not intended to either encourage or discourage screening. Instead, they "present the benefits and limitations of screening to help men make choices consistent with their preferences."

Dr. Taylor and her colleagues performed a randomized clinical trial to compare the usefulness of two decision aids against usual care in the long-term (1-year) choice to participate in or refrain from prostate cancer screening. The study subjects were 1,879 outpatients aged 45-70 years, who were recruited from any one of three Washington, D.C., health systems.

This study population was one of the largest and most representative to date to participate in a randomized trial of this issue. African Americans accounted for 40% of the subjects, and about 24% were from lower socioeconomic backgrounds, the investigators noted.

The two decision aids had identical content and were presented at an eighth-grade reading level. Both included general information about the prostate gland, as well as descriptions of screening tests and possible results. They covered treatment options and possible adverse effects, and they reviewed the risk factors for prostate cancer.

Both decision aids encouraged the men to discuss screening with a physician. They also included a values clarification tool and references for further information.

The web-based interactive decision aid had, in addition to these, a narrator who read most of the text aloud, pop-up definitions of medical terms, video testimonials, and animation.

The study subjects were randomly assigned to receive the print decision aid (628 men), the web-based decision aid (625 men), or usual care (626 men). They were assessed at baseline, 1 month after study assignment, and 13 months after study assignment for their knowledge of prostate cancer and prostate cancer testing; the controversy over screening; risk factors; and the benefits and limitations of treatment.

Subjects also reported the conflict they experienced over the decision to participate in or abstain from prostate cancer screening, as well as their satisfaction regarding their most recent decision to either participate in or abstain from screening.

At the 13-month assessment, the subjects also reported whether they had undergone a PSA test, a digital rectal exam, or both during the 1-year follow-up period.

Both decision aids were more effective than usual care in increasing the subjects’ knowledge and reducing their decisional conflict, with effect sizes indicating clinically significant differences, Dr. Taylor and her associates reported (JAMA Intern. Med. 2013 July 29 [doi: 10.1001/jamainternmed.2013.9523]).

This is the first study to find reduced decisional conflict for a year following a decision-aid intervention, and suggests that these tools help men to remain certain about their screening choice.

Even though 90% of the men said that they had access to the Internet and 67% said they used it daily, the web-based decision aid was not significantly more effective than the print decision aid at imparting knowledge or reducing decisional conflict. "In fact, participants in the print arm [of the study] reported significantly greater satisfaction than those in the web arm at the 1-month assessment," the researchers said.

"These results call into question the widespread assumption that interactive, web-based delivery necessarily leads to better outcomes," they added.

At the end of follow-up, 58.3% of the study subjects reported that they had been screened for prostate cancer since their baseline assessment. This rate was "virtually unchanged" from the 59.3% rate of screening they reported before the study commenced.

There also were no significant differences in rates of screening among men given the print decision aid, those given the web-based decision aid, and those given usual care.

These findings suggest that the decision aids offer neutrality and don’t influence the choice of whether or not to undergo screening, "which allows patients and providers to individualize the decision," Dr. Taylor and her associates said.

It remains critical to assist men in making informed decisions regarding screening for prostate cancer, because of the conflicting recommendations for screening and the mixed messages about its effectiveness, they added.

This study was supported by the National Cancer Institute, the Department of Defense, and the Lombardi Comprehensive Cancer Center. No financial conflicts of interest were reported.

Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.

Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).

The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.

The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.

These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).

All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.

The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).

A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.

These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.

Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.

In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.

The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.

This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.

The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.

The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.

A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.

The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.

Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).

The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.

The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.

These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).

All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.

The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).

A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.

These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.

Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.

In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.

The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.

This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.

The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.

The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.

A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.

The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Radium-223 prolonged overall survival by nearly 4 months in men with castration-resistant prostate cancer that had metastasized to bone and reduced the risk of death by 30% in an international phase III clinical trial reported online July 17 in the New England Journal of Medicine.

Compared with placebo, the treatment also improved quality of life and significantly prolonged the time to the first symptomatic skeletal event, the time to an increase in PSA level, and the time to an increase in total alkaline phosphatase level. Further, radium-223 provided these benefits while consistently inducing a lower rate of adverse events than did placebo, said Dr. Christopher Parker of Royal Marsden Hospital, Sutton (U.K.), and his associates in the ALSYMPCA (Alpharadin in Symptomatic Prostate Cancer Patients) randomized trial (NCT00699751).

The industry-sponsored trial was terminated early when an interim analysis by an independent monitoring committee showed a clear benefit of the treatment over placebo. Dr. Parker and his colleagues reported the results of their updated analysis involving 63% of the patients who received all 6 monthly injections of radium-223 and 47% who received all 6 monthly injections of placebo during the 3-year treatment period.

The study subjects were 921 men at 136 study centers in 19 countries who had progressive castration-resistant prostate cancer with two or more symptomatic bone metastases and no visceral metastases. All of them required regular analgesic medication or other treatment to address cancer-related bone pain.

These patients were stratified according to whether or not they had been treated with docetaxel or a bisphosphonate and according to their baseline alkaline phosphatase level, then randomly assigned to receive 6 monthly intravenous injections of either radium-223 (614 subjects) or matching placebo (307 subjects).

All of the study subjects concurrently received the best standard of care available at each of their treatment centers, which could include local external-beam radiation therapy, glucocorticoids, antiandrogens, ketoconazole, or estrogens. Thus, the study findings should be generalizable to routine clinical practice, Dr. Parker and his associates noted.

The primary endpoint, median overall survival, was 14.9 months in the radium-223 group, which was significantly longer than the 11.3-month median overall survival in the placebo group, the researchers said (N. Engl. J. Med. 2013 July 17 [doi:10.1056/NEJMoa1213755]).

A total of 528 patients in the intention-to-treat population died; 54% of the radium-223 group and 64% of the placebo group died. The risk of death from any cause was 30% lower among men who received radium-223 than among those who received placebo.

These differences in overall survival were consistent across all subgroups of patients, regardless of alkaline phosphatase level at baseline, current use of bisphosphonates, previous treatment with docetaxel, any use of opioids, and the extent of the underlying cancer.

Compared with placebo, radium-223 significantly prolonged the interval to the first symptomatic skeletal event (15.6 months vs. 9.8 months). It also prolonged the time until total alkaline phosphatase level and PSA level showed an increase.

In addition, a significantly higher proportion of patients who received the active treatment (25%) than placebo (16%) reported a meaningful improvement in quality of life, as measured by the FACT-P score.

The overall incidence of adverse events, that of serious adverse events, that of grade 3 or 4 adverse events, and that of hematologic adverse events all were lower with radium-223 than with placebo. The number of patients who discontinued the study drug also was lower with radium-223 than with placebo.

This favorable safety profile is attributed to the highly targeted action of radium-223, which "minimizes myelosuppression and has limited effects on normal tissue," Dr. Parker and his associates said.

The ALSYMPCA trial included an important subgroup of patients: those who declined or weren’t eligible for docetaxel therapy. Many patients with castration-resistant prostate cancer and bone metastases do not receive docetaxel because of their frail condition, the presence of coexisting conditions that preclude use of the drug, or their refusal of chemotherapy. Thus this study addressed "an important unmet need in a population that is not served by current therapies," they added.

The researchers noted that prostate cancer therapy has evolved since this trial was initiated, and new data have been accumulated regarding cabazitaxel, abiraterone, and enzalutamide. Future studies should assess whether radium-223 might be suitable for sequential or concurrent use with these agents.

A phase I-II trial is now under way evaluating the combination of radium-223 with docetaxel, they said.

The ALSYMPCA trial was funded, designed, and conducted by Algeta and Bayer HealthCare Pharmaceuticals in collaboration with the study investigators. Dr. Parker reported ties to Amgen, Astellas, Bayer, Janssen, Bristol-Myers Squibb, BN ImmunoTherapeutics, Takeda, and Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Androgen deprivation therapy was strongly associated with an increased risk of acute kidney injury among men with nonmetastatic prostate cancer, according to a report in the July 17 issue of JAMA.

This elevation in risk varied slightly among different types of androgen deprivation agents, and was strongest with therapies that combine gonadotropin-releasing hormone agonists with oral antiandrogens. That suggests "a possible additive effect ... on both receptor antagonism and reduction of testosterone excretion," said Francesco Lapi, Pharm.D., Ph.D., of the Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, and his associates (JAMA 2013;310:289-96).

The researchers discovered the risk elevation in what they described as the first population-based study to investigate the association between androgen deprivation therapy and acute kidney injury. They performed the study because even though the treatment traditionally has been reserved for advanced disease, it is now used increasingly in patients with earlier stages of prostate cancer.

In addition, the investigators were prompted to examine a possible link because of the high mortality (approximately 50%) associated with acute kidney injury.

"Although only one case report of flutamide-related acute kidney injury has been published to date, androgen deprivation therapy and its hypogonadal effect have well-known consequences consistent with our findings," they noted.

Dr. Lapi and his colleagues used two large databases in the United Kingdom, the Clinical Practice Research Datalink and the Hospital Episodes Statistics database, to identify 10,250 men newly diagnosed as having prostate cancer in 1998-2008 who were 40 years of age or older at diagnosis and were followed for a mean of 4 years. This yielded more than 42,000 person-years of follow-up.

A total of 232 cases of acute kidney injury occurred, for an overall incidence of 5.5/1,000 person-years, said Dr. Lapi and his associates.

These cases were matched for age, year of diagnosis, and duration of follow-up with 2,721 control subjects who did not develop acute kidney injury.

Compared with control subjects, men who were using androgen deprivation therapy had a significantly increased risk of acute kidney injury, with an odds ratio of 2.48. That association did not change when the data were adjusted to account for possible confounders, such as comorbidities known to impair kidney function, medications known to have renal toxicity, the severity of the underlying prostate cancer, and the intensity of other cancer treatments.

The investigators then analyzed the data according to type of androgen deprivation therapy, dividing the regimens into six mutually exclusive categories: gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin); oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide); combined androgen blockade (GnRH agonists plus oral antiandrogens); bilateral orchiectomy; estrogens; and combinations of those.

The odds ratios were highest for combined androgen blockade and also were significantly elevated for other combination therapies. Only the odd ratios for oral antiandrogens alone and for orchiectomy alone failed to reach statistical significance, although both were above 1.0, the investigators said.

The duration of androgen deprivation therapy was examined in a further analysis of the data. The risk of acute kidney injury was highest early in the course of treatment and decreased slightly, but it remained significantly elevated with longer duration of use.

Finally, in a sensitivity analysis that excluded the 54 cases and 842 controls who had abnormal creatinine levels at baseline, the results were consistent with those of the primary analysis.

The mechanism by which androgen deprivation therapy exerts an adverse effect on the kidney is not known, but the treatment is known to raise the risks of the metabolic syndrome and cardiovascular disease. "A similar rationale can be postulated for the risk of acute kidney injury," Dr. Lapi and his associates said.

The dyslipidemia and hyperglycemia of the metabolic syndrome may promote tubular atrophy and interstitial fibrosis, and may impair glomerular function by expanding and thickening the membranes of the interstitial tubules. Both dyslipidemia and hyperglycemia also raise the risk of thrombosis and induce oxidative stress, which can impact renal function.

In addition, testosterone is thought to protect the kidneys by inducing vasodilation in the renal vessels and enhancing nitric oxide production. So, antagonizing testosterone could promote damage to the glomerulus. And the hypogonadism induced by androgen deprivation can also lead to estrogen deficiency, reducing estrogen’s protective effect against ischemic renal injury, the investigators said.

The study was supported by Prostate Cancer Canada, the Canadian Institutes of Health Research, and Fonds de recherche en Sant

Androgen deprivation therapy was strongly associated with an increased risk of acute kidney injury among men with nonmetastatic prostate cancer, according to a report in the July 17 issue of JAMA.

This elevation in risk varied slightly among different types of androgen deprivation agents, and was strongest with therapies that combine gonadotropin-releasing hormone agonists with oral antiandrogens. That suggests "a possible additive effect ... on both receptor antagonism and reduction of testosterone excretion," said Francesco Lapi, Pharm.D., Ph.D., of the Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, and his associates (JAMA 2013;310:289-96).

The researchers discovered the risk elevation in what they described as the first population-based study to investigate the association between androgen deprivation therapy and acute kidney injury. They performed the study because even though the treatment traditionally has been reserved for advanced disease, it is now used increasingly in patients with earlier stages of prostate cancer.

In addition, the investigators were prompted to examine a possible link because of the high mortality (approximately 50%) associated with acute kidney injury.

"Although only one case report of flutamide-related acute kidney injury has been published to date, androgen deprivation therapy and its hypogonadal effect have well-known consequences consistent with our findings," they noted.

Dr. Lapi and his colleagues used two large databases in the United Kingdom, the Clinical Practice Research Datalink and the Hospital Episodes Statistics database, to identify 10,250 men newly diagnosed as having prostate cancer in 1998-2008 who were 40 years of age or older at diagnosis and were followed for a mean of 4 years. This yielded more than 42,000 person-years of follow-up.

A total of 232 cases of acute kidney injury occurred, for an overall incidence of 5.5/1,000 person-years, said Dr. Lapi and his associates.

These cases were matched for age, year of diagnosis, and duration of follow-up with 2,721 control subjects who did not develop acute kidney injury.

Compared with control subjects, men who were using androgen deprivation therapy had a significantly increased risk of acute kidney injury, with an odds ratio of 2.48. That association did not change when the data were adjusted to account for possible confounders, such as comorbidities known to impair kidney function, medications known to have renal toxicity, the severity of the underlying prostate cancer, and the intensity of other cancer treatments.

The investigators then analyzed the data according to type of androgen deprivation therapy, dividing the regimens into six mutually exclusive categories: gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin); oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide); combined androgen blockade (GnRH agonists plus oral antiandrogens); bilateral orchiectomy; estrogens; and combinations of those.

The odds ratios were highest for combined androgen blockade and also were significantly elevated for other combination therapies. Only the odd ratios for oral antiandrogens alone and for orchiectomy alone failed to reach statistical significance, although both were above 1.0, the investigators said.

The duration of androgen deprivation therapy was examined in a further analysis of the data. The risk of acute kidney injury was highest early in the course of treatment and decreased slightly, but it remained significantly elevated with longer duration of use.

Finally, in a sensitivity analysis that excluded the 54 cases and 842 controls who had abnormal creatinine levels at baseline, the results were consistent with those of the primary analysis.

The mechanism by which androgen deprivation therapy exerts an adverse effect on the kidney is not known, but the treatment is known to raise the risks of the metabolic syndrome and cardiovascular disease. "A similar rationale can be postulated for the risk of acute kidney injury," Dr. Lapi and his associates said.

The dyslipidemia and hyperglycemia of the metabolic syndrome may promote tubular atrophy and interstitial fibrosis, and may impair glomerular function by expanding and thickening the membranes of the interstitial tubules. Both dyslipidemia and hyperglycemia also raise the risk of thrombosis and induce oxidative stress, which can impact renal function.

In addition, testosterone is thought to protect the kidneys by inducing vasodilation in the renal vessels and enhancing nitric oxide production. So, antagonizing testosterone could promote damage to the glomerulus. And the hypogonadism induced by androgen deprivation can also lead to estrogen deficiency, reducing estrogen’s protective effect against ischemic renal injury, the investigators said.

The study was supported by Prostate Cancer Canada, the Canadian Institutes of Health Research, and Fonds de recherche en Sant

Androgen deprivation therapy was strongly associated with an increased risk of acute kidney injury among men with nonmetastatic prostate cancer, according to a report in the July 17 issue of JAMA.

This elevation in risk varied slightly among different types of androgen deprivation agents, and was strongest with therapies that combine gonadotropin-releasing hormone agonists with oral antiandrogens. That suggests "a possible additive effect ... on both receptor antagonism and reduction of testosterone excretion," said Francesco Lapi, Pharm.D., Ph.D., of the Centre for Clinical Epidemiology, Jewish General Hospital, Montreal, and his associates (JAMA 2013;310:289-96).

The researchers discovered the risk elevation in what they described as the first population-based study to investigate the association between androgen deprivation therapy and acute kidney injury. They performed the study because even though the treatment traditionally has been reserved for advanced disease, it is now used increasingly in patients with earlier stages of prostate cancer.

In addition, the investigators were prompted to examine a possible link because of the high mortality (approximately 50%) associated with acute kidney injury.

"Although only one case report of flutamide-related acute kidney injury has been published to date, androgen deprivation therapy and its hypogonadal effect have well-known consequences consistent with our findings," they noted.

Dr. Lapi and his colleagues used two large databases in the United Kingdom, the Clinical Practice Research Datalink and the Hospital Episodes Statistics database, to identify 10,250 men newly diagnosed as having prostate cancer in 1998-2008 who were 40 years of age or older at diagnosis and were followed for a mean of 4 years. This yielded more than 42,000 person-years of follow-up.

A total of 232 cases of acute kidney injury occurred, for an overall incidence of 5.5/1,000 person-years, said Dr. Lapi and his associates.

These cases were matched for age, year of diagnosis, and duration of follow-up with 2,721 control subjects who did not develop acute kidney injury.

Compared with control subjects, men who were using androgen deprivation therapy had a significantly increased risk of acute kidney injury, with an odds ratio of 2.48. That association did not change when the data were adjusted to account for possible confounders, such as comorbidities known to impair kidney function, medications known to have renal toxicity, the severity of the underlying prostate cancer, and the intensity of other cancer treatments.

The investigators then analyzed the data according to type of androgen deprivation therapy, dividing the regimens into six mutually exclusive categories: gonadotropin-releasing hormone (GnRH) agonists (leuprolide, goserelin, triptorelin); oral antiandrogens (cyproterone acetate, flutamide, bicalutamide, nilutamide); combined androgen blockade (GnRH agonists plus oral antiandrogens); bilateral orchiectomy; estrogens; and combinations of those.

The odds ratios were highest for combined androgen blockade and also were significantly elevated for other combination therapies. Only the odd ratios for oral antiandrogens alone and for orchiectomy alone failed to reach statistical significance, although both were above 1.0, the investigators said.

The duration of androgen deprivation therapy was examined in a further analysis of the data. The risk of acute kidney injury was highest early in the course of treatment and decreased slightly, but it remained significantly elevated with longer duration of use.

Finally, in a sensitivity analysis that excluded the 54 cases and 842 controls who had abnormal creatinine levels at baseline, the results were consistent with those of the primary analysis.

The mechanism by which androgen deprivation therapy exerts an adverse effect on the kidney is not known, but the treatment is known to raise the risks of the metabolic syndrome and cardiovascular disease. "A similar rationale can be postulated for the risk of acute kidney injury," Dr. Lapi and his associates said.

The dyslipidemia and hyperglycemia of the metabolic syndrome may promote tubular atrophy and interstitial fibrosis, and may impair glomerular function by expanding and thickening the membranes of the interstitial tubules. Both dyslipidemia and hyperglycemia also raise the risk of thrombosis and induce oxidative stress, which can impact renal function.

In addition, testosterone is thought to protect the kidneys by inducing vasodilation in the renal vessels and enhancing nitric oxide production. So, antagonizing testosterone could promote damage to the glomerulus. And the hypogonadism induced by androgen deprivation can also lead to estrogen deficiency, reducing estrogen’s protective effect against ischemic renal injury, the investigators said.

The study was supported by Prostate Cancer Canada, the Canadian Institutes of Health Research, and Fonds de recherche en Sant

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

CHICAGO – Prostate cancer outcomes were predicted by a test that measures the expression of cell cycle progression genes, according to results from a retrospective analysis of prostate tissue samples from five patient cohorts.

The Prolaris test gives each tissue sample a cell cycle progression (CCP) score based on measures of 31 CCP genes, normalized to 15 "housekeeper" genes. A unit change in the test is defined as a doubling in CCP genes. For each unit increase in the test’s score, there was a two- to threefold increase in the risk of disease progression, Dr. Jack M. Cuzick reported at the annual meeting of the American Society of Clinical Oncology.

The CCP signature of Myriad Genetics’ Prolaris test was a highly significant predictor of outcome, said Dr. Cuzick of the Wolfson Institute of Preventive Medicine, London. In all five studies, the hazard ratio per unit change in the CCP score was similar, ranging from 1.89 to 2.92. The findings indicate that the effect size for the CCP score is robust in multiple patient cohorts and diverse clinical settings.

The test provides information for differentiating aggressive and indolent disease beyond that available from clinicopathologic variables, he said. As the natural history of prostate cancer can be variable and difficult to predict, the Prolaris test could help to match treatment more appropriately to each individual’s risk of progression.

In the study that examined the test’s predictive value, five patient groups were evaluated. Formalin-fixed tissue samples were obtained from two English patient cohorts that were conservatively managed (n = 337 and 349), two U.S. patient cohorts that underwent radical prostatectomy (366 men treated at Scott & White Hospital, Temple, Tex.; and 413 men treated at the University of California, San Francisco), and one U.S. cohort that underwent external beam radiation therapy (141 men treated at the Durham, N.C., VA Medical Center).

The cohort of conservatively managed English patients was from the late 1990s and had more than 15 years of follow up. In the 337-patient cohort diagnosed via transurethral resection of the prostate (TURP) and conservatively managed, there were 57 deaths from prostate cancer. In the 349-patient cohort diagnosed via needle biopsy and conservatively managed, there were 90 deaths from prostate cancer.

For each unit increase in the CCP score, the hazard ratio for the cohort diagnosed via TURP was 2.9 and the hazard ratio for those diagnosed via needle biopsy was 2. The CCP score was the dominant variable for predicting death from prostate cancer in univariate analysis (P = 6.1 x 10^–22 after diagnosis via TURP, and P = 8.6 x 10^–10 after diagnosis via needle biopsy). In both studies, the CCP score remained highly significant in multivariate analysis and was a stronger predictor of disease-specific mortality than other prognostic variables, he said.

In the U.S. prostatectomy cohorts, there were 132 biochemical recurrences (BCRs) in the first cohort and 83 BCRs in the second cohort. With each unit increase in the CCP score, there was a doubling of risk for recurrence. After prostatectomy, the CCP score predicted BCR in univariate analysis (Scott & White: P = 5.6 x 10^–9; University of California: P = 2.23 x 10^–6) and provided additional prognostic information in multivariate analysis (Scott & White: P = 3.3 x 10^–6; University of California: P = 9.5 x10^–5).

After radiation therapy, the CCP score predicted BCR in univariate (P = .0017) and multivariate (P = .034) analysis. In the 141-patient cohort that was diagnosed by needle biopsy and underwent external beam radiation, there were 19 prostate cancer deaths and more than a doubling of risk with each unit increase in CCP score.

CCP scores only modestly correlated with the Gleason score and prostate-specific antigen (PSA) value. The test adds value beyond those measures, Dr. Cuzick said.

CCP scores predict patient outcome in multiple clinical settings, provide independent information beyond clinicopathological variables, and help to further differentiate aggressive from indolent prostate cancer. With low-grade Gleason 6 cancers, the results can aid in telling who is at low risk and who needs aggressive therapy, he concluded.

The study was funded by Myriad Genetics, the maker of the Prolaris test. Dr. Cuzick received honoraria and research support from Myriad.

Enzalutamide is an androgen receptor-signaling inhibitor that is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment; exhibits increased affinity for the androgen receptor; and induces tumor reduction, rather than slowing growth, in preclinical models. The recently reported AFFIRM study showed that enzalutamide treatment after chemotherapy significantly prolonged overall survival (OS), radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and time to skeletal-related events (SREs) in men with castration-resistant prostate cancer. This trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

*Click on the links to the left for PDFs of the full article and related Commentary.  

Enzalutamide is an androgen receptor-signaling inhibitor that is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment; exhibits increased affinity for the androgen receptor; and induces tumor reduction, rather than slowing growth, in preclinical models. The recently reported AFFIRM study showed that enzalutamide treatment after chemotherapy significantly prolonged overall survival (OS), radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and time to skeletal-related events (SREs) in men with castration-resistant prostate cancer. This trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

*Click on the links to the left for PDFs of the full article and related Commentary.  

Enzalutamide is an androgen receptor-signaling inhibitor that is reported to differ from conventional antiandrogen agents in that it inhibits androgen receptor nuclear translocation, DNA binding, and coactivator recruitment; exhibits increased affinity for the androgen receptor; and induces tumor reduction, rather than slowing growth, in preclinical models. The recently reported AFFIRM study showed that enzalutamide treatment after chemotherapy significantly prolonged overall survival (OS), radiographic progression-free survival (PFS), time to prostate-specific antigen (PSA) progression, and time to skeletal-related events (SREs) in men with castration-resistant prostate cancer. This trial formed the basis for the recent approval of enzalutamide for the treatment of patients with metastatic castrationresistant prostate cancer who have previously received docetaxel.

*Click on the links to the left for PDFs of the full article and related Commentary.  

The use of the most advanced technologies for treating prostate cancer, such as intensity-modulated radiotherapy and robotic prostatectomy, is common and increasing among the very men least likely to benefit from treatment, according to a report published June 26 in JAMA.

In a retrospective cohort study involving nearly 56,000 men newly diagnosed with prostate cancer during a recent 5-year period, advanced treatment technologies steadily supplanted more conservative approaches in older men who had low-risk disease, a high risk of dying from some other cause, or both, said Dr. Bruce L. Jacobs of the University of Michigan, Ann Arbor, and his associates (JAMA 2013;309:2587-95).

Paradoxically, this increase occurred against a backdrop of "increasing awareness about the indolent nature of some prostate cancers and of growing dialogue about limiting treatment in these patients," the researchers noted.

"Our findings suggest that, even during this period of enhanced stewardship, incentives favoring the diffusion of these technologies outweighed those related to implementing a more conservative management strategy," they said.

Dr. Jacobs and his colleagues examined this issue using data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database after noting the rapid growth in the use of advanced treatment technologies, as well as the aggressive direct-to-consumer marketing and other "incentives" propelling that growth. They identified men aged 66 years and older whose prostate cancer was diagnosed during a 5-year period and who were followed for 1-6 years afterward.

The study population comprised 23,633 men who underwent intensity-modulated radiotherapy (IMRT) and 5,881 who had robotic prostatectomy, who were compared with 3,926 men who underwent traditional external-beam radiation therapy, 6,123 who had open radical prostatectomy, and 16,384 who opted for watchful waiting (observation).

The investigators estimated the study subjects’ probability of dying within 10 years based on age, race, comorbidity, socioeconomic class, type of residence (urban or rural), and the region of the country in which they lived.

As expected, the use of the advanced technologies increased over time in the entire study population. But it also increased among the men who "stood to gain the least in terms of survival."

During the 5-year study period, the use of both IMRT and robotic prostatectomy increased from 32% to 44% of men who had low-risk disease based on the clinical stage of their tumor, Gleason score, and prostate-specific antigen (PSA) level. The use of both also increased from 36% to 57% of men who were at high risk of dying from another cause. And it rose from 25% to 34% of men who had both low-risk disease and a high risk of noncancer mortality.

At the same time, the use of more conservative approaches declined to a similar degree in these low-risk patients.

In a further analysis of the data, the use of advanced treatment technologies in men who were the most unlikely to die of prostate cancer increased from 13% at the start of the 5-year period to 24% at the end, a relative increase of 85%, Dr. Jacobs and his associates said.

These trends are particularly concerning because both IMRT and robotic prostatectomy are considerably more expensive than the less aggressive approaches they are displacing, the researchers added.

Some clinicians and patients may believe that the more advanced technologies yield better outcomes, but "comparative studies have shown that the advantages of these newer treatments are marginal at best," Dr. Jacobs and his colleagues said.

"More diligence is needed to reduce the potentially unnecessary treatment of men with a low risk of dying from prostate cancer," they said.

The study was supported by the American Cancer Society, the National Institutes of Health, Blue Cross Blue Shield of Michigan, and the National Cancer Institute. Dr. Jacobs reported no financial conflicts of interest, and two of his associates reported ties to ArborMetrix and HistoSonics.

The use of the most advanced technologies for treating prostate cancer, such as intensity-modulated radiotherapy and robotic prostatectomy, is common and increasing among the very men least likely to benefit from treatment, according to a report published June 26 in JAMA.

In a retrospective cohort study involving nearly 56,000 men newly diagnosed with prostate cancer during a recent 5-year period, advanced treatment technologies steadily supplanted more conservative approaches in older men who had low-risk disease, a high risk of dying from some other cause, or both, said Dr. Bruce L. Jacobs of the University of Michigan, Ann Arbor, and his associates (JAMA 2013;309:2587-95).

Paradoxically, this increase occurred against a backdrop of "increasing awareness about the indolent nature of some prostate cancers and of growing dialogue about limiting treatment in these patients," the researchers noted.

"Our findings suggest that, even during this period of enhanced stewardship, incentives favoring the diffusion of these technologies outweighed those related to implementing a more conservative management strategy," they said.

Dr. Jacobs and his colleagues examined this issue using data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database after noting the rapid growth in the use of advanced treatment technologies, as well as the aggressive direct-to-consumer marketing and other "incentives" propelling that growth. They identified men aged 66 years and older whose prostate cancer was diagnosed during a 5-year period and who were followed for 1-6 years afterward.

The study population comprised 23,633 men who underwent intensity-modulated radiotherapy (IMRT) and 5,881 who had robotic prostatectomy, who were compared with 3,926 men who underwent traditional external-beam radiation therapy, 6,123 who had open radical prostatectomy, and 16,384 who opted for watchful waiting (observation).

The investigators estimated the study subjects’ probability of dying within 10 years based on age, race, comorbidity, socioeconomic class, type of residence (urban or rural), and the region of the country in which they lived.

As expected, the use of the advanced technologies increased over time in the entire study population. But it also increased among the men who "stood to gain the least in terms of survival."

During the 5-year study period, the use of both IMRT and robotic prostatectomy increased from 32% to 44% of men who had low-risk disease based on the clinical stage of their tumor, Gleason score, and prostate-specific antigen (PSA) level. The use of both also increased from 36% to 57% of men who were at high risk of dying from another cause. And it rose from 25% to 34% of men who had both low-risk disease and a high risk of noncancer mortality.

At the same time, the use of more conservative approaches declined to a similar degree in these low-risk patients.

In a further analysis of the data, the use of advanced treatment technologies in men who were the most unlikely to die of prostate cancer increased from 13% at the start of the 5-year period to 24% at the end, a relative increase of 85%, Dr. Jacobs and his associates said.

These trends are particularly concerning because both IMRT and robotic prostatectomy are considerably more expensive than the less aggressive approaches they are displacing, the researchers added.

Some clinicians and patients may believe that the more advanced technologies yield better outcomes, but "comparative studies have shown that the advantages of these newer treatments are marginal at best," Dr. Jacobs and his colleagues said.

"More diligence is needed to reduce the potentially unnecessary treatment of men with a low risk of dying from prostate cancer," they said.

The study was supported by the American Cancer Society, the National Institutes of Health, Blue Cross Blue Shield of Michigan, and the National Cancer Institute. Dr. Jacobs reported no financial conflicts of interest, and two of his associates reported ties to ArborMetrix and HistoSonics.

The use of the most advanced technologies for treating prostate cancer, such as intensity-modulated radiotherapy and robotic prostatectomy, is common and increasing among the very men least likely to benefit from treatment, according to a report published June 26 in JAMA.

In a retrospective cohort study involving nearly 56,000 men newly diagnosed with prostate cancer during a recent 5-year period, advanced treatment technologies steadily supplanted more conservative approaches in older men who had low-risk disease, a high risk of dying from some other cause, or both, said Dr. Bruce L. Jacobs of the University of Michigan, Ann Arbor, and his associates (JAMA 2013;309:2587-95).

Paradoxically, this increase occurred against a backdrop of "increasing awareness about the indolent nature of some prostate cancers and of growing dialogue about limiting treatment in these patients," the researchers noted.

"Our findings suggest that, even during this period of enhanced stewardship, incentives favoring the diffusion of these technologies outweighed those related to implementing a more conservative management strategy," they said.

Dr. Jacobs and his colleagues examined this issue using data from the Surveillance, Epidemiology, and End Results (SEER) Medicare database after noting the rapid growth in the use of advanced treatment technologies, as well as the aggressive direct-to-consumer marketing and other "incentives" propelling that growth. They identified men aged 66 years and older whose prostate cancer was diagnosed during a 5-year period and who were followed for 1-6 years afterward.

The study population comprised 23,633 men who underwent intensity-modulated radiotherapy (IMRT) and 5,881 who had robotic prostatectomy, who were compared with 3,926 men who underwent traditional external-beam radiation therapy, 6,123 who had open radical prostatectomy, and 16,384 who opted for watchful waiting (observation).

The investigators estimated the study subjects’ probability of dying within 10 years based on age, race, comorbidity, socioeconomic class, type of residence (urban or rural), and the region of the country in which they lived.

As expected, the use of the advanced technologies increased over time in the entire study population. But it also increased among the men who "stood to gain the least in terms of survival."

During the 5-year study period, the use of both IMRT and robotic prostatectomy increased from 32% to 44% of men who had low-risk disease based on the clinical stage of their tumor, Gleason score, and prostate-specific antigen (PSA) level. The use of both also increased from 36% to 57% of men who were at high risk of dying from another cause. And it rose from 25% to 34% of men who had both low-risk disease and a high risk of noncancer mortality.

At the same time, the use of more conservative approaches declined to a similar degree in these low-risk patients.

In a further analysis of the data, the use of advanced treatment technologies in men who were the most unlikely to die of prostate cancer increased from 13% at the start of the 5-year period to 24% at the end, a relative increase of 85%, Dr. Jacobs and his associates said.

These trends are particularly concerning because both IMRT and robotic prostatectomy are considerably more expensive than the less aggressive approaches they are displacing, the researchers added.

Some clinicians and patients may believe that the more advanced technologies yield better outcomes, but "comparative studies have shown that the advantages of these newer treatments are marginal at best," Dr. Jacobs and his colleagues said.

"More diligence is needed to reduce the potentially unnecessary treatment of men with a low risk of dying from prostate cancer," they said.

The study was supported by the American Cancer Society, the National Institutes of Health, Blue Cross Blue Shield of Michigan, and the National Cancer Institute. Dr. Jacobs reported no financial conflicts of interest, and two of his associates reported ties to ArborMetrix and HistoSonics.

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – Dose-dense chemotherapy reduced the risk of progression or death by 34% compared with standard therapy in young patients who had poor-risk germ cell tumors with unfavorable tumor marker decline in the phase III GETUG 13 trial.

Neurotoxicity was increased, but manageable. There was no excess of second cancers, as observed in other trials. And the overall survival rate after 3 years now exceeds 75% in these patients with poor-prognosis disease.

"The dose-dense regimen should become the new standard treatment for these patients with poor-risk disease and slow tumor marker decline," Dr. Karim Fizazi, with the Institut Gustave Roussy, Villejuif, France, said at the meeting.

For patients with poor-prognosis germ cell tumors, the standard treatment – involving four cycles of bleomycin, etoposide and cisplatin (BEP) chemotherapy – was established in 1987. Over the last decade, the prognostic role of tumor marker decline has been demonstrated, but all of the phase III trials in the last 25 years have reported negative results and 48% of patients achieve a cure at 5 years, he said.

Patrice Wendling/IMNG Medical Media

The GETUG (Genitourinary Tumor Group) 13 investigators hypothesized that personalized treatment, including individualized cumulative doses of bleomycin, should be used only for patients with early unfavorable tumor marker decline; that paclitaxel, ifosfamide, and increased oxaliplatin dose intensity would have an incremental and small benefit in the first-line setting; and that toxic deaths from neutropenic fever and secondary leukemia could be prevented through the use of granulocyte colony-stimulating factor (G-CSF) and capping etoposide at 2 g/m².

In all, 263 patients with various poor-risk germ cell tumors were enrolled, and 254 underwent tumor marker analysis on day 21 after the first cycle of BEP. Of these, 51 patients with favorable tumor decline continued on BEP for a total of four courses, and 203 patients with unfavorable tumor decline were randomized to continue on BEP for a total of four courses (n = 105) or to receive a dose-dense regimen (n = 98) consisting of paclitaxel-BEP plus oxaliplatin 130 mg/m² on day 10 for two cycles, followed by two cycles of cisplatin 100 mg on day 1; ifosfamide 2 mg/m² on days 10, 12, and 14; and continuous-infusion bleomycin 25 U/d on days 10-14. The trial was amended so all patients received G-CSF support. Oxaliplatin was deleted from cycles 3-4 of the dose-dense regimen after excess neurotoxicity was observed in the first 10 patients, Dr. Fizazi said.

Tumor marker decline was calculated using a logarithmic formula (J. Clin. Oncol. 2004;22:3868-76).

At 3 years, the primary endpoint of progression-free survival was 59% in the dose-dense group and 48% in the unfavorable tumor decline group randomized to BEP (hazard ratio, 0.66; P = .05), Dr. Fizazi said. At last follow-up, 63 patients in the dose-dense group were alive and continuously free of progression, compared with 46 in the BEP unfavorable group.

Progression-free survival favored the dose-dense regimen in all subgroups tested, with patients with mediastinal primary or extrapulmonary visceral metastases tending to benefit more, he said.

There was a nonsignificant trend for overall survival in patients receiving the dose-dense regimen, with 3-year rates of 73% in the dose-dense group and 65% in the unfavorable BEP arm (HR 0.78; P = .34).

Toxicities in the dose-dense and BEP groups were comparable for neutropenic fever (17% in both), toxic deaths (1% in both), and second cancers (1% vs. 4%). Patients in the dose-dense arm experienced more neurotoxicities that were grade 2 or higher (23% vs. 4%), and they were significantly less likely to undergo salvage high-dose chemotherapy and transplant (6% vs. 16%; P = .01), Dr. Fizazi said.

The prognostic value of tumor marker decline was again demonstrated in outcome comparisons, he said. At 3 years, the favorable BEP group, as compared with the unfavorable BEP group, had significantly better rates of progression-free survival (70% vs. 48%; HR, 0.66; P = .01) and overall survival (84% vs. 65%; HR, 0.65; P = .02).

The study was sponsored by the University of Texas M.D. Anderson Cancer Center, Houston, and by Unicancer in Europe, with support from Institut National du Cancer, Ligue Nationale contre le Cancer, Sanofi-Aventis, Chugai, Baxter, and Faulding Pharmaceuticals. Dr. Fizazi and Dr. Bokemeyer reported no relevant disclosures.

pwendling@frontlinemedcom.com

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

CHICAGO – The salvage chemotherapy regimen of paclitaxel, ifosfamide, and cisplatin was active in the first-line treatment of intermediate- and poor-risk germ cell tumors in a small multicenter phase II study.

Overall, 28 of 41 evaluable patients achieved a complete response (68%), including 57% of intermediate risk (8/14) and 74% of poor-risk (20/27) patients.

"TIP demonstrated promising efficacy and met its prespecified endpoint as worthy of further study," Dr. Darren Feldman said at the annual meeting of the American Society of Clinical Oncology.

Paclitaxel (Taxol), ifosfamide (Ifex) and cisplatin (Platinol), or TIP, has become a standard regimen for germ cell tumor patients requiring salvage chemotherapy, demonstrating an approximately 70% complete response rate and 63% progression-free survival after a median of 6 years in relapsed patients.

As a result of the findings, a multicenter, randomized phase II trial has been initiated comparing TIP with standard BEP (bleomycin, etoposide, and cisplatin) as first-line therapy in intermediate- and poor-risk patients, said Dr. Feldman, with Memorial Sloan-Kettering Cancer Center in New York.

The current trial enrolled 44 men with germ cell tumors that were International Germ Cell Cancer Collaborative Group (IGCCCG) poor-risk (66%) or modified intermediate-risk, defined by serum lactate dehydrogenase (LDH) three times the upper limit of normal, if LDH was the only intermediate-risk criterion.

Histology was non-seminoma in 86% and the testis was the primary tumor site in 68%. Median patient age was 27 years.

Four cycles of TIP every 21 days was given, as planned, in 89% of patients. The regimen contained paclitaxel 120 mg/m² daily on days 1-2; ifosfamide 1,200 mg/m² mixed 1:1 with Mesna 1,200 mg/m², both daily on days 1-5; and cisplatin 20 mg/m² daily on days 1-5. Peg-filgrastim 6 mg was given subcutaneously as neutropenic fever prophylaxis on day 6 or 7.

An additional one to two cycles of adjuvant TIP could be administered if viable germ cell tumor was found at postchemotherapy surgery. Paclitaxel was initially dosed at 240 mg/m² over 5 days, but the dosing was changed to 2 days because of allergic infusion reactions.

In all, 27 of the 41 patients achieved a complete response to chemotherapy, defined by marker and radiographic normalization or marker normalization with full resection of all tumor masses and pathology revealing teratoma or necrosis, Dr. Feldman said.

One patient achieved a complete response to chemotherapy plus surgery, defined by marker normalization plus full resection with viable germ cell tumor in the specimen, but negative margins.

Partial responses, lasting 4 weeks with negative markers, were observed in 36% of intermediate-risk (5/14) and 4% of poor-risk patients (1/27). Favorable responses (CR plus PR) were seen in 93% and 78%, and incomplete responses in 7% and 22%.

After a median follow-up of 3.1 years, the estimated progression-free survival was 79% overall, 87% among intermediate-risk patients and 76% among poor-risk patients, Dr. Feldman said.

"These results compare favorably to historic results and, in fact, look similar to what would be expected in IGCCCG good- or intermediate-risk patients," he added.

At the time of the analysis, 80% of patients remained progression free and only two had died, resulting in an estimated 3-year overall survival rate of 95%.

TIP had an acceptable safety profile, with no treatment-related deaths and grade 3/4 events limited to hematologic or electrolyte abnormalities, Dr. Feldman said.

Dr. Feldman reported having no financial disclosures. A coauthor reported a consultant/advisory role with Bristol-Myers Squibb.

pwendling@frontlinemedcom.com

CHICAGO – Dr. Nicholas Vogelzang, investigator on the ALSYMPCA trial, discusses new data on Radium 223 (Xofigo) and new research on castration-resistant metastatic prostate cancer at the ASCO Annual Meeting 2013.

CHICAGO – Dr. Nicholas Vogelzang, investigator on the ALSYMPCA trial, discusses new data on Radium 223 (Xofigo) and new research on castration-resistant metastatic prostate cancer at the ASCO Annual Meeting 2013.

CHICAGO – Dr. Nicholas Vogelzang, investigator on the ALSYMPCA trial, discusses new data on Radium 223 (Xofigo) and new research on castration-resistant metastatic prostate cancer at the ASCO Annual Meeting 2013.

A new practice guideline released at the American Urological Association annual meeting presents the clinical framework to help weigh the risks and benefits of providing adjuvant and salvage radiation therapy after prostatectomy.

"There is now a document that guides us in offering the best clinical practices for anyone who undergoes radical prostatectomy regarding their follow-up care with radiotherapy," said Dr. Richard K. Valicenti of the department of radiation oncology at the University of California, Davis.

One practice standard in the guideline advises physicians to offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy, because studies have shown that this therapy can result in reductions in prostate-specific antigen (PSA) recurrence, local recurrence, and clinical progression. The adverse findings that would warrant this therapy include seminal vesicle invasion, positive surgical margins, or extraprostatic extension.

"The data are overwhelmingly consistent that it [radiotherapy] will improve on tumor control rates, as well as progression-free survival," Dr. Valicenti said, adding that these patients should also experience improved quality of life.

In addition to the above practice standard, the guideline, issued jointly by the American Society for Radiation Oncology (ASTRO) and the American Urological Association (AUA), made the following recommendations:

• Inform patients with localized prostate cancer considering radical prostatectomy about the possibility that the pathologic findings will predict a higher risk of cancer recurrence.

• Advise patients with adverse pathologic findings, including seminal vesicle invasion, positive surgical margins, and extraprostatic extension, that adjuvant radiation therapy compared with radical prostatectomy only reduces the risk of PSA recurrence, local recurrence, and clinical progression of cancer;

• Warn patients that they are a higher risk of developing metastatic prostate cancer or death from the disease if there is a PSA recurrence after surgery;

• Define biochemical recurrence as a detectable or rising PSA value after surgery that is greater than or equal to 0.2 ng/mL with a second confirmatory level greater than or equal to 0.2 ng/mL.

• Consider a restaging evaluation in patients with a PSA recurrence.

• Offer salvage radiation therapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease.

• Inform patients that the effectiveness of radiation therapy for PSA recurrence is greatest when given at lower levels of PSA. and

• Inform patients that in addition to the benefits of controlling disease recurrence, radiation therapy could produce possible short- and long-term urinary, bowel, and sexual side effects.

Before recommending adjuvant or salvage radiotherapy, "look at the patients’ biological information obtained from the radical prostatectomy specimen, and balance that with the overall health status of the patients [and] concerns about certain aspects of quality of life, whether it be sexual activity or urinary function. They also need to balance that with any other medical conditions or previous treatments that would preclude the use of radiation therapy," Dr. Valicenti said.

"The Adjuvant and Salvage Radiotherapy After Prostatectomy: ASTRO/AUA Guideline" is a comprehensive review of 324 research articles on patients with detectable and undetectable PSA levels, toxicity, optimal imaging strategies, and the impact on quality of life to determine the appropriateness of radiation therapy in patients suspected of recurrence. Only studies in which PSA data were provided for at least 75% of patients were included in the guideline. The panel was led by Dr. Valicenti and Dr. Ian M. Thompson of the University of Texas Health Science Center.

The guideline is available at www.redjournal.org and www.auanet.org.

Dr. Valicenti reported no relevant disclosures.

A new practice guideline released at the American Urological Association annual meeting presents the clinical framework to help weigh the risks and benefits of providing adjuvant and salvage radiation therapy after prostatectomy.

"There is now a document that guides us in offering the best clinical practices for anyone who undergoes radical prostatectomy regarding their follow-up care with radiotherapy," said Dr. Richard K. Valicenti of the department of radiation oncology at the University of California, Davis.

One practice standard in the guideline advises physicians to offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy, because studies have shown that this therapy can result in reductions in prostate-specific antigen (PSA) recurrence, local recurrence, and clinical progression. The adverse findings that would warrant this therapy include seminal vesicle invasion, positive surgical margins, or extraprostatic extension.

"The data are overwhelmingly consistent that it [radiotherapy] will improve on tumor control rates, as well as progression-free survival," Dr. Valicenti said, adding that these patients should also experience improved quality of life.

In addition to the above practice standard, the guideline, issued jointly by the American Society for Radiation Oncology (ASTRO) and the American Urological Association (AUA), made the following recommendations:

• Inform patients with localized prostate cancer considering radical prostatectomy about the possibility that the pathologic findings will predict a higher risk of cancer recurrence.

• Advise patients with adverse pathologic findings, including seminal vesicle invasion, positive surgical margins, and extraprostatic extension, that adjuvant radiation therapy compared with radical prostatectomy only reduces the risk of PSA recurrence, local recurrence, and clinical progression of cancer;

• Warn patients that they are a higher risk of developing metastatic prostate cancer or death from the disease if there is a PSA recurrence after surgery;

• Define biochemical recurrence as a detectable or rising PSA value after surgery that is greater than or equal to 0.2 ng/mL with a second confirmatory level greater than or equal to 0.2 ng/mL.

• Consider a restaging evaluation in patients with a PSA recurrence.

• Offer salvage radiation therapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease.

• Inform patients that the effectiveness of radiation therapy for PSA recurrence is greatest when given at lower levels of PSA. and

• Inform patients that in addition to the benefits of controlling disease recurrence, radiation therapy could produce possible short- and long-term urinary, bowel, and sexual side effects.

Before recommending adjuvant or salvage radiotherapy, "look at the patients’ biological information obtained from the radical prostatectomy specimen, and balance that with the overall health status of the patients [and] concerns about certain aspects of quality of life, whether it be sexual activity or urinary function. They also need to balance that with any other medical conditions or previous treatments that would preclude the use of radiation therapy," Dr. Valicenti said.

"The Adjuvant and Salvage Radiotherapy After Prostatectomy: ASTRO/AUA Guideline" is a comprehensive review of 324 research articles on patients with detectable and undetectable PSA levels, toxicity, optimal imaging strategies, and the impact on quality of life to determine the appropriateness of radiation therapy in patients suspected of recurrence. Only studies in which PSA data were provided for at least 75% of patients were included in the guideline. The panel was led by Dr. Valicenti and Dr. Ian M. Thompson of the University of Texas Health Science Center.

The guideline is available at www.redjournal.org and www.auanet.org.

Dr. Valicenti reported no relevant disclosures.

A new practice guideline released at the American Urological Association annual meeting presents the clinical framework to help weigh the risks and benefits of providing adjuvant and salvage radiation therapy after prostatectomy.

"There is now a document that guides us in offering the best clinical practices for anyone who undergoes radical prostatectomy regarding their follow-up care with radiotherapy," said Dr. Richard K. Valicenti of the department of radiation oncology at the University of California, Davis.

One practice standard in the guideline advises physicians to offer adjuvant radiotherapy to patients with adverse pathologic findings at prostatectomy, because studies have shown that this therapy can result in reductions in prostate-specific antigen (PSA) recurrence, local recurrence, and clinical progression. The adverse findings that would warrant this therapy include seminal vesicle invasion, positive surgical margins, or extraprostatic extension.

"The data are overwhelmingly consistent that it [radiotherapy] will improve on tumor control rates, as well as progression-free survival," Dr. Valicenti said, adding that these patients should also experience improved quality of life.

In addition to the above practice standard, the guideline, issued jointly by the American Society for Radiation Oncology (ASTRO) and the American Urological Association (AUA), made the following recommendations:

• Inform patients with localized prostate cancer considering radical prostatectomy about the possibility that the pathologic findings will predict a higher risk of cancer recurrence.

• Advise patients with adverse pathologic findings, including seminal vesicle invasion, positive surgical margins, and extraprostatic extension, that adjuvant radiation therapy compared with radical prostatectomy only reduces the risk of PSA recurrence, local recurrence, and clinical progression of cancer;

• Warn patients that they are a higher risk of developing metastatic prostate cancer or death from the disease if there is a PSA recurrence after surgery;

• Define biochemical recurrence as a detectable or rising PSA value after surgery that is greater than or equal to 0.2 ng/mL with a second confirmatory level greater than or equal to 0.2 ng/mL.

• Consider a restaging evaluation in patients with a PSA recurrence.

• Offer salvage radiation therapy to patients with PSA or local recurrence after radical prostatectomy in whom there is no evidence of distant metastatic disease.

• Inform patients that the effectiveness of radiation therapy for PSA recurrence is greatest when given at lower levels of PSA. and

• Inform patients that in addition to the benefits of controlling disease recurrence, radiation therapy could produce possible short- and long-term urinary, bowel, and sexual side effects.

Before recommending adjuvant or salvage radiotherapy, "look at the patients’ biological information obtained from the radical prostatectomy specimen, and balance that with the overall health status of the patients [and] concerns about certain aspects of quality of life, whether it be sexual activity or urinary function. They also need to balance that with any other medical conditions or previous treatments that would preclude the use of radiation therapy," Dr. Valicenti said.

"The Adjuvant and Salvage Radiotherapy After Prostatectomy: ASTRO/AUA Guideline" is a comprehensive review of 324 research articles on patients with detectable and undetectable PSA levels, toxicity, optimal imaging strategies, and the impact on quality of life to determine the appropriateness of radiation therapy in patients suspected of recurrence. Only studies in which PSA data were provided for at least 75% of patients were included in the guideline. The panel was led by Dr. Valicenti and Dr. Ian M. Thompson of the University of Texas Health Science Center.

The guideline is available at www.redjournal.org and www.auanet.org.

Dr. Valicenti reported no relevant disclosures.