Genitourinary Cancer

BOSTON – Stereotactic radiosurgery stabilized disease or induced tumor shrinkage on imaging in most patients with inoperable localized renal cancer in a phase I trial.

There were even hints of curative potential, investigators reported at the annual meeting of the American Society for Radiation Oncology.

"We’ve certainly seen encouraging results at this point: Two of the patients at the higher doses actually had negative biopsies," Dr. Rodney J. Ellis, director of urogenital oncology at the University Hospitals Seidman Cancer Center in Cleveland, said during a press briefing.

The combined radiographic tumor response rate – stable disease or tumor regression – was 94%, but treatment was found to be incomplete or refractory among most patients who had a post-treatment biopsy. This finding suggests that higher radiation doses would be required for better tumor control, Dr. Ellis said.

Dose escalation in the trial varied from 24 Gy divided into four 6-Gy fractions to 48 Gy in four 12-Gy fractions, with dose-limiting toxicities not yet reached.

Acute toxicities were limited to grade-1 acute fatigue in two patients. Late toxicities were limited to an increase in chronic renal failure in two patients who had a baseline mean estimated glomerular filtration rate of 19.5 mL/min, corresponding to stage-4 renal disease. There were no other significant grade-3 or higher toxicities and no gastrointestinal adverse effects, he said.

The investigators looked at 20 patients, mean age 80 years, with a radiologically or biopsy-determined diagnosis of localized primary renal cancer. All were considered to be poor candidates for surgery and had no history of pelvic or abdominal radiation.

The patients were assigned to receive stereotactic radiosurgery with the CyberKnife robotic system at an initial dose of 600 cGy per fraction, followed by dose escalation of 200-cGy increments per fraction to total doses up to 48 Gy.

The dose escalation was started if the patients had not developed dose-limiting toxicity within 180 days of treatment. In all, 20 patients were enrolled: 4 at 24 Gy, 6 at 32 Gy, 4 at 40 Gy, and 6 at 48 Gy.

The institutional review board for the trial has approved enrollment of 12 additional patients at doses ranging from 48 Gy in three fractions to 60 Gy in four fractions, Dr. Ellis said.

Dr. Ellis noted that the diagnosis of primary cancer has become much more common with the advent of CT scans, which detect incidental renal masses, some of which are likely to progress. Some people suggest that incidental renal cancers should be handled with watch and wait, he noted. Also, some of these cancers may be inoperable because of patient factors.

He said that sterotactic radiosurgery "will prolong life for patients, especially if we see the kind of efficacy at the higher doses that we anticipate."

The study is supported by the National Cancer Institute. Dr. Ellis reported no relevant disclosures.

BOSTON – Stereotactic radiosurgery stabilized disease or induced tumor shrinkage on imaging in most patients with inoperable localized renal cancer in a phase I trial.

There were even hints of curative potential, investigators reported at the annual meeting of the American Society for Radiation Oncology.

"We’ve certainly seen encouraging results at this point: Two of the patients at the higher doses actually had negative biopsies," Dr. Rodney J. Ellis, director of urogenital oncology at the University Hospitals Seidman Cancer Center in Cleveland, said during a press briefing.

The combined radiographic tumor response rate – stable disease or tumor regression – was 94%, but treatment was found to be incomplete or refractory among most patients who had a post-treatment biopsy. This finding suggests that higher radiation doses would be required for better tumor control, Dr. Ellis said.

Dose escalation in the trial varied from 24 Gy divided into four 6-Gy fractions to 48 Gy in four 12-Gy fractions, with dose-limiting toxicities not yet reached.

Acute toxicities were limited to grade-1 acute fatigue in two patients. Late toxicities were limited to an increase in chronic renal failure in two patients who had a baseline mean estimated glomerular filtration rate of 19.5 mL/min, corresponding to stage-4 renal disease. There were no other significant grade-3 or higher toxicities and no gastrointestinal adverse effects, he said.

The investigators looked at 20 patients, mean age 80 years, with a radiologically or biopsy-determined diagnosis of localized primary renal cancer. All were considered to be poor candidates for surgery and had no history of pelvic or abdominal radiation.

The patients were assigned to receive stereotactic radiosurgery with the CyberKnife robotic system at an initial dose of 600 cGy per fraction, followed by dose escalation of 200-cGy increments per fraction to total doses up to 48 Gy.

The dose escalation was started if the patients had not developed dose-limiting toxicity within 180 days of treatment. In all, 20 patients were enrolled: 4 at 24 Gy, 6 at 32 Gy, 4 at 40 Gy, and 6 at 48 Gy.

The institutional review board for the trial has approved enrollment of 12 additional patients at doses ranging from 48 Gy in three fractions to 60 Gy in four fractions, Dr. Ellis said.

Dr. Ellis noted that the diagnosis of primary cancer has become much more common with the advent of CT scans, which detect incidental renal masses, some of which are likely to progress. Some people suggest that incidental renal cancers should be handled with watch and wait, he noted. Also, some of these cancers may be inoperable because of patient factors.

He said that sterotactic radiosurgery "will prolong life for patients, especially if we see the kind of efficacy at the higher doses that we anticipate."

The study is supported by the National Cancer Institute. Dr. Ellis reported no relevant disclosures.

BOSTON – Stereotactic radiosurgery stabilized disease or induced tumor shrinkage on imaging in most patients with inoperable localized renal cancer in a phase I trial.

There were even hints of curative potential, investigators reported at the annual meeting of the American Society for Radiation Oncology.

"We’ve certainly seen encouraging results at this point: Two of the patients at the higher doses actually had negative biopsies," Dr. Rodney J. Ellis, director of urogenital oncology at the University Hospitals Seidman Cancer Center in Cleveland, said during a press briefing.

The combined radiographic tumor response rate – stable disease or tumor regression – was 94%, but treatment was found to be incomplete or refractory among most patients who had a post-treatment biopsy. This finding suggests that higher radiation doses would be required for better tumor control, Dr. Ellis said.

Dose escalation in the trial varied from 24 Gy divided into four 6-Gy fractions to 48 Gy in four 12-Gy fractions, with dose-limiting toxicities not yet reached.

Acute toxicities were limited to grade-1 acute fatigue in two patients. Late toxicities were limited to an increase in chronic renal failure in two patients who had a baseline mean estimated glomerular filtration rate of 19.5 mL/min, corresponding to stage-4 renal disease. There were no other significant grade-3 or higher toxicities and no gastrointestinal adverse effects, he said.

The investigators looked at 20 patients, mean age 80 years, with a radiologically or biopsy-determined diagnosis of localized primary renal cancer. All were considered to be poor candidates for surgery and had no history of pelvic or abdominal radiation.

The patients were assigned to receive stereotactic radiosurgery with the CyberKnife robotic system at an initial dose of 600 cGy per fraction, followed by dose escalation of 200-cGy increments per fraction to total doses up to 48 Gy.

The dose escalation was started if the patients had not developed dose-limiting toxicity within 180 days of treatment. In all, 20 patients were enrolled: 4 at 24 Gy, 6 at 32 Gy, 4 at 40 Gy, and 6 at 48 Gy.

The institutional review board for the trial has approved enrollment of 12 additional patients at doses ranging from 48 Gy in three fractions to 60 Gy in four fractions, Dr. Ellis said.

Dr. Ellis noted that the diagnosis of primary cancer has become much more common with the advent of CT scans, which detect incidental renal masses, some of which are likely to progress. Some people suggest that incidental renal cancers should be handled with watch and wait, he noted. Also, some of these cancers may be inoperable because of patient factors.

He said that sterotactic radiosurgery "will prolong life for patients, especially if we see the kind of efficacy at the higher doses that we anticipate."

The study is supported by the National Cancer Institute. Dr. Ellis reported no relevant disclosures.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

PRAGUE – Everolimus significantly improved the skin lesions of tuberous sclerosis complex in two phase-III clinical trials, Dr. Sergiusz Jozwiak reported at the annual congress of the European Academy of Dermatology and Venereology.

Tuberous sclerosis is a genetic disorder characterized by the growth of numerous nonmalignant tumors in various organs including the brain, kidneys, heart, and skin.

The most devastating skin lesions associated with tuberous sclerosis complex are facial angiofibromas. Hypopigmented spots are also common, said Dr. Jozwiak, a pediatric neurologist at the Children’s Memorial Health Institute of Warsaw.

In the first study, Examining Everolimus in a Study of Tuberous Sclerosis Complex (EXIST-1), about 100 patients with subependymal giant cell astrocytoma (SEGA) were randomized 2:1 to receive everolimus or placebo. In EXIST-2, approximately 100 patients with renal angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis were randomized to receive either everolimus or placebo. EXIST-1 participants averaged about 8 years of age; those in EXIST-2 had an average age of 30 years.

Both studies met their primary end points, with favorable effects documented in patients with SEGA and renal angiomyolipoma. This led the Food and Drug Administration to approve everolimus (Afinitor), an oral inhibitor of the mammalian target of rapamycin (mTOR), for the treatment of both conditions.

Dr. Jozwiak reported on the skin lesion response to everolimus, a prespecified secondary end point in EXIST-1 and -2.

Close to 95% of all participants – 224 subjects in the two trials – had skin lesions at baseline. Of those on everolimus, 42% in EXIST-1 and 26% in EXIST-2 had significant improvements in their skin lesions, compared with 11% and 0%, respectively, of those on placebo.

The skin response was partial in all cases as judged on a 7-point scale, but the response, when it occurred, was durable: All patients with a partial response to everolimus maintained that response at last follow-up, ranging from 2 to 20 months. Thus, the median duration of skin response has yet to be determined, Dr. Jozwiak noted.

Mouth ulcers were the most common and troublesome everolimus side effect, seen intermittently in 70% of the patients in the two phase-III trials. The side effect was managed by temporary reductions in dosing or suspension of therapy for a week.

"We were able to reinstitute full-dose therapy in all patients," he said.

There were no other serious treatment-related adverse events. The incidence of infections was similar in the everolimus and placebo arms of the studies.

Everolimus was dosed starting at 4.5 mg/m² per day, with a target trough level of 5-15 ng/mL in EXIST-1. In EXIST-2, which was limited to an adult patient population, the drug was dosed at 10 mg/day.

The EXIST trials were sponsored by Novartis. Dr. Jozwiak is a consultant to the company.

BOSTON – The combination of radiation and hormonal therapy for locally advanced prostate cancer results in significantly better overall and disease-specific survival outcomes than hormonal therapy alone, according to the final results of a long-term study.

At a median follow-up of 8 years, the addition of radiation therapy (RT) to androgen deprivation therapy (ADT) was associated with significantly better overall survival (hazard ratio 0.70, P = .0003) and disease-specific survival (HR 0.46, P less than .0001) compared with ADT alone, Dr. Padraig Warde reported at the annual meeting of the American Society for Radiation Oncology.

"We believe our study results support the recommendation that for patients with locally advanced prostate cancer who are suitable for a curative treatment approach, combined-modality treatment should be considered the standard of care," said Dr. Warde, a professor of radiation oncology at Princess Margaret Hospital and the University of Toronto.

"Clearly the optimal duration of androgen deprivation therapy needs to be defined. However, the benefit of radiation therapy may be greater in the modern era with dose escalation," he added.

The findings of the study are consistent with those of a similarly designed study, the randomized Scandinavian Prostate Cancer Group (SPCG) 7 study, noted Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital in Boston, the invited discussant.

"External-beam radiation and hormonal therapy should now be the gold standard against which interventions for high-risk and locally advanced prostate cancer are compared, including radical prostatectomy," he said.

The Final Word

Dr. Warde presented final data from the NCIC Clinical Trials Group (NCIC CTG) PR.3/Medical Research Council (MRC) UK PR07 trial. Results of an interim analysis of the trial published last year showed a similar benefit for adding RT to ADT at 7 years.

From 1995 through 2005, investigators enrolled a total of 1,205 patients, most of whom (1,057) had locally advanced (T3, T4, N0/NX stage) prostate cancer. A smaller number had organ-confined disease (T2, N0/NX) with either a prostate-specific antigen (PSA) level greater than 40 mcg/L or a PSA greater than 20 mcg/L and a Gleason score of 8 or higher.

The patients were randomly assigned to receive lifelong therapy with either a bilateral orchiectomy or a luteinizing hormone releasing hormone agonist with or without 65- to 69-Gy RT to the prostate (with or without a dose to the seminal vesicles), and with or without 45 Gy to pelvic lymph nodes. In all, 602 patients were assigned to ADT only, and 603 to both ADT and RT.

At a median follow-up of 8 years, 260 patients on ADT alone and 205 on the combined therapy had died. Of these patients, 199 (43%) died from disease and/or treatment; 134 had been treated with ADT alone, and 65 with ADT plus radiation.

The 10-year overall survival rates were 55% for the combined therapy, and 49% for RT alone.

Treatment Well Tolerated

Although the radiation group had a moderate worsening of bowel scores at 6 months, "consistent with clinical expectations," the men who received radiotherapy generally tolerated it well, Dr. Warde said.

By 24 months there were no significant between-group differences in bowel or rectum domain on the EORTC (European Organisation for Research and Treatment of Cancer) quality-of-life questionnaire. Results in the urinary function quality-of-life domain were similar, Dr. Warde said. He did not provide specifics.

An exploratory analysis within the radiation arm showed that there were no significant differences in either overall or disease-specific survival with the addition of pelvic radiation to prostate radiation; in this analysis the hazard ratio was adjusted for geographic region of treatment, PSA, Gleason score, nodal staging, and prior hormonal therapy.

The study was supported by grants from the U.S. National Cancer Institute, U.K. Medical Research Council, and U.K. National Cancer Research Network. Dr. Warde and Dr. Efstathiou reported having no conflicts of interest.

BOSTON – The combination of radiation and hormonal therapy for locally advanced prostate cancer results in significantly better overall and disease-specific survival outcomes than hormonal therapy alone, according to the final results of a long-term study.

At a median follow-up of 8 years, the addition of radiation therapy (RT) to androgen deprivation therapy (ADT) was associated with significantly better overall survival (hazard ratio 0.70, P = .0003) and disease-specific survival (HR 0.46, P less than .0001) compared with ADT alone, Dr. Padraig Warde reported at the annual meeting of the American Society for Radiation Oncology.

"We believe our study results support the recommendation that for patients with locally advanced prostate cancer who are suitable for a curative treatment approach, combined-modality treatment should be considered the standard of care," said Dr. Warde, a professor of radiation oncology at Princess Margaret Hospital and the University of Toronto.

"Clearly the optimal duration of androgen deprivation therapy needs to be defined. However, the benefit of radiation therapy may be greater in the modern era with dose escalation," he added.

The findings of the study are consistent with those of a similarly designed study, the randomized Scandinavian Prostate Cancer Group (SPCG) 7 study, noted Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital in Boston, the invited discussant.

"External-beam radiation and hormonal therapy should now be the gold standard against which interventions for high-risk and locally advanced prostate cancer are compared, including radical prostatectomy," he said.

The Final Word

Dr. Warde presented final data from the NCIC Clinical Trials Group (NCIC CTG) PR.3/Medical Research Council (MRC) UK PR07 trial. Results of an interim analysis of the trial published last year showed a similar benefit for adding RT to ADT at 7 years.

From 1995 through 2005, investigators enrolled a total of 1,205 patients, most of whom (1,057) had locally advanced (T3, T4, N0/NX stage) prostate cancer. A smaller number had organ-confined disease (T2, N0/NX) with either a prostate-specific antigen (PSA) level greater than 40 mcg/L or a PSA greater than 20 mcg/L and a Gleason score of 8 or higher.

The patients were randomly assigned to receive lifelong therapy with either a bilateral orchiectomy or a luteinizing hormone releasing hormone agonist with or without 65- to 69-Gy RT to the prostate (with or without a dose to the seminal vesicles), and with or without 45 Gy to pelvic lymph nodes. In all, 602 patients were assigned to ADT only, and 603 to both ADT and RT.

At a median follow-up of 8 years, 260 patients on ADT alone and 205 on the combined therapy had died. Of these patients, 199 (43%) died from disease and/or treatment; 134 had been treated with ADT alone, and 65 with ADT plus radiation.

The 10-year overall survival rates were 55% for the combined therapy, and 49% for RT alone.

Treatment Well Tolerated

Although the radiation group had a moderate worsening of bowel scores at 6 months, "consistent with clinical expectations," the men who received radiotherapy generally tolerated it well, Dr. Warde said.

By 24 months there were no significant between-group differences in bowel or rectum domain on the EORTC (European Organisation for Research and Treatment of Cancer) quality-of-life questionnaire. Results in the urinary function quality-of-life domain were similar, Dr. Warde said. He did not provide specifics.

An exploratory analysis within the radiation arm showed that there were no significant differences in either overall or disease-specific survival with the addition of pelvic radiation to prostate radiation; in this analysis the hazard ratio was adjusted for geographic region of treatment, PSA, Gleason score, nodal staging, and prior hormonal therapy.

The study was supported by grants from the U.S. National Cancer Institute, U.K. Medical Research Council, and U.K. National Cancer Research Network. Dr. Warde and Dr. Efstathiou reported having no conflicts of interest.

BOSTON – The combination of radiation and hormonal therapy for locally advanced prostate cancer results in significantly better overall and disease-specific survival outcomes than hormonal therapy alone, according to the final results of a long-term study.

At a median follow-up of 8 years, the addition of radiation therapy (RT) to androgen deprivation therapy (ADT) was associated with significantly better overall survival (hazard ratio 0.70, P = .0003) and disease-specific survival (HR 0.46, P less than .0001) compared with ADT alone, Dr. Padraig Warde reported at the annual meeting of the American Society for Radiation Oncology.

"We believe our study results support the recommendation that for patients with locally advanced prostate cancer who are suitable for a curative treatment approach, combined-modality treatment should be considered the standard of care," said Dr. Warde, a professor of radiation oncology at Princess Margaret Hospital and the University of Toronto.

"Clearly the optimal duration of androgen deprivation therapy needs to be defined. However, the benefit of radiation therapy may be greater in the modern era with dose escalation," he added.

The findings of the study are consistent with those of a similarly designed study, the randomized Scandinavian Prostate Cancer Group (SPCG) 7 study, noted Dr. Jason A. Efstathiou, a radiation oncologist at Massachusetts General Hospital in Boston, the invited discussant.

"External-beam radiation and hormonal therapy should now be the gold standard against which interventions for high-risk and locally advanced prostate cancer are compared, including radical prostatectomy," he said.

The Final Word

Dr. Warde presented final data from the NCIC Clinical Trials Group (NCIC CTG) PR.3/Medical Research Council (MRC) UK PR07 trial. Results of an interim analysis of the trial published last year showed a similar benefit for adding RT to ADT at 7 years.

From 1995 through 2005, investigators enrolled a total of 1,205 patients, most of whom (1,057) had locally advanced (T3, T4, N0/NX stage) prostate cancer. A smaller number had organ-confined disease (T2, N0/NX) with either a prostate-specific antigen (PSA) level greater than 40 mcg/L or a PSA greater than 20 mcg/L and a Gleason score of 8 or higher.

The patients were randomly assigned to receive lifelong therapy with either a bilateral orchiectomy or a luteinizing hormone releasing hormone agonist with or without 65- to 69-Gy RT to the prostate (with or without a dose to the seminal vesicles), and with or without 45 Gy to pelvic lymph nodes. In all, 602 patients were assigned to ADT only, and 603 to both ADT and RT.

At a median follow-up of 8 years, 260 patients on ADT alone and 205 on the combined therapy had died. Of these patients, 199 (43%) died from disease and/or treatment; 134 had been treated with ADT alone, and 65 with ADT plus radiation.

The 10-year overall survival rates were 55% for the combined therapy, and 49% for RT alone.

Treatment Well Tolerated

Although the radiation group had a moderate worsening of bowel scores at 6 months, "consistent with clinical expectations," the men who received radiotherapy generally tolerated it well, Dr. Warde said.

By 24 months there were no significant between-group differences in bowel or rectum domain on the EORTC (European Organisation for Research and Treatment of Cancer) quality-of-life questionnaire. Results in the urinary function quality-of-life domain were similar, Dr. Warde said. He did not provide specifics.

An exploratory analysis within the radiation arm showed that there were no significant differences in either overall or disease-specific survival with the addition of pelvic radiation to prostate radiation; in this analysis the hazard ratio was adjusted for geographic region of treatment, PSA, Gleason score, nodal staging, and prior hormonal therapy.

The study was supported by grants from the U.S. National Cancer Institute, U.K. Medical Research Council, and U.K. National Cancer Research Network. Dr. Warde and Dr. Efstathiou reported having no conflicts of interest.

BOSTON – Men who receive proton beam radiotherapy for prostate cancer have modestly better bowel function in the short term than do those who receive conformal or intensity-modulated radiation, but the effect is transient, investigators found.

At 2-3 months follow-up, patients treated with proton beam therapy (PBT) reported minimal decrements in bowel function, compared with patients treated with either 3D conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT), who reported modest yet clinically meaningful decrements in bowel function, lead author Dr. Phillip J. Gray reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

All three patient groups also had significantly lower urinary quality-of-life (QoL) scores at early follow-up compared with baseline, but these changes were considered clinically meaningful only for IMRT, said Dr. Gray, a resident in the Harvard Radiation Oncology program in Boston.

"Though significant, these differences appear transient, with all three groups showing clinically meaningful decrements in bowel quality of life at 2 years following the start of treatment, and minimally lingering urinary symptoms," he said.

The retrospective study looked at three cohorts of men treated with the different modalities: 153 treated with IMRT monotherapy in the PROST-QA consortium, 94 patients treated with PBT at Massachusetts General Hospital (MGH), and 123 treated with 3D-CRT at MGH and other Harvard-affiliated hospitals.

Patients treated with IMRT and PBT were evaluated with the Expanded Prostate Cancer Index Composite (EPIC) instrument; patients treated with 3D-CRT were assessed using the Prostate Cancer Symptoms Index (PCSI); PCSI scores were inverted to match those of the EPIC scale.

Treatment dose ranges were 75.6-79.2 Gy for IMRT, 74-82 Gy relative biological effectiveness values for PBT, and 66.4-79.2 Gy for 3D-CRT.

Mean patient-reported bowel QoL scores in the immediate post-treatment period were 93.3 on a scale of 0-100 for PBT, 78.5 for IMRT, and 88.2 for 3D-CRT (P vs. PBT less than .001 for both comparisons). The differences from baseline in IMRT and 3D-CRT, but not in PBT, were considered clinically significant.

At 24 months, mean respective bowel QoL scores were 91.8, 87.6, and 90.2, respectively, with clinically significant differences between PBT and the other two modalities.

Dr. Gray acknowledged that the retrospective nature of the study and the use of different scoring instruments muddy the comparison waters. He noted that things may become clearer when the results of a recently launched randomized trial comparing PBT and IMRT become available. The study will look at 6-month efficacy outcomes, cost effectiveness, and toxicities at 2 years, and survival and other end points out to 10 years.

Protons Are a Costly Choice

Although the relative long-term benefits of PBT for prostate cancer may not be known for several years, one thing is sure: PBT is about 70% more expensive than IMRT, said Dr. James Yu, a radiation oncologist at Yale University in New Haven, Conn.

Neil Osterweil/IMNG Medical Media

Dr. Yu and colleagues looked at data on patients who received IMRT or PBT as primary therapy for prostate cancer in the Medicare Chronic Condition Data Warehouse, a national database that captures 100% of Medicare fee-for-service claims for patients with specific chronic conditions.

They found that the median interquartile range amount that Medicare reimbursed for PBT was $32,428 vs. $18,575 for IMRT.

In early follow-up (0-6 months) genitourinary complications were significantly lower among 421 patients with who had received PBT than among 842 patients who received IMRT (5.9% vs. 9.5%; odds ratio 0.60; P = .03). Neither gastrointestinal nor other complications were significantly different, however, and at 12 months follow-up there were no significant differences between treatment types, Dr. Yu noted.

"A continued longitudinal study of the comparative effectiveness of proton radiation is needed, and we also believe that further study is needed before widespread application of proton radiation can be justified," he said.

PBT Benefit Proven in Other Cancers

A radiation oncologist who was not involved in the study commented that in the absence of evidence of a therapeutic benefit for PBT in prostate cancer over other modalities, proton therapy may better be reserved for the treatment of other cancers.

"If you have a resource that’s limited, you want to use it where you know there’s a benefit," said Dr, Jeffrey Bradley, professor of radiation oncology at Washington University in St. Louis.

His center is building a single-vault proton-beam facility that is expected to open in the summer of 2013. Dr. Bradley said that although they will likely treat patients with prostate cancer, he envisions the main role of the center to be treatment of pediatric and adult tumors of the central nervous system, sarcomas, ocular neoplasms, and other conditions where the benefits of PBT are better documented.

Dr Gray, Dr. Yu, and Dr. Bradley each reported no conflicts of interest.

BOSTON – Men who receive proton beam radiotherapy for prostate cancer have modestly better bowel function in the short term than do those who receive conformal or intensity-modulated radiation, but the effect is transient, investigators found.

At 2-3 months follow-up, patients treated with proton beam therapy (PBT) reported minimal decrements in bowel function, compared with patients treated with either 3D conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT), who reported modest yet clinically meaningful decrements in bowel function, lead author Dr. Phillip J. Gray reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

All three patient groups also had significantly lower urinary quality-of-life (QoL) scores at early follow-up compared with baseline, but these changes were considered clinically meaningful only for IMRT, said Dr. Gray, a resident in the Harvard Radiation Oncology program in Boston.

"Though significant, these differences appear transient, with all three groups showing clinically meaningful decrements in bowel quality of life at 2 years following the start of treatment, and minimally lingering urinary symptoms," he said.

The retrospective study looked at three cohorts of men treated with the different modalities: 153 treated with IMRT monotherapy in the PROST-QA consortium, 94 patients treated with PBT at Massachusetts General Hospital (MGH), and 123 treated with 3D-CRT at MGH and other Harvard-affiliated hospitals.

Patients treated with IMRT and PBT were evaluated with the Expanded Prostate Cancer Index Composite (EPIC) instrument; patients treated with 3D-CRT were assessed using the Prostate Cancer Symptoms Index (PCSI); PCSI scores were inverted to match those of the EPIC scale.

Treatment dose ranges were 75.6-79.2 Gy for IMRT, 74-82 Gy relative biological effectiveness values for PBT, and 66.4-79.2 Gy for 3D-CRT.

Mean patient-reported bowel QoL scores in the immediate post-treatment period were 93.3 on a scale of 0-100 for PBT, 78.5 for IMRT, and 88.2 for 3D-CRT (P vs. PBT less than .001 for both comparisons). The differences from baseline in IMRT and 3D-CRT, but not in PBT, were considered clinically significant.

At 24 months, mean respective bowel QoL scores were 91.8, 87.6, and 90.2, respectively, with clinically significant differences between PBT and the other two modalities.

Dr. Gray acknowledged that the retrospective nature of the study and the use of different scoring instruments muddy the comparison waters. He noted that things may become clearer when the results of a recently launched randomized trial comparing PBT and IMRT become available. The study will look at 6-month efficacy outcomes, cost effectiveness, and toxicities at 2 years, and survival and other end points out to 10 years.

Protons Are a Costly Choice

Although the relative long-term benefits of PBT for prostate cancer may not be known for several years, one thing is sure: PBT is about 70% more expensive than IMRT, said Dr. James Yu, a radiation oncologist at Yale University in New Haven, Conn.

Neil Osterweil/IMNG Medical Media

Dr. Yu and colleagues looked at data on patients who received IMRT or PBT as primary therapy for prostate cancer in the Medicare Chronic Condition Data Warehouse, a national database that captures 100% of Medicare fee-for-service claims for patients with specific chronic conditions.

They found that the median interquartile range amount that Medicare reimbursed for PBT was $32,428 vs. $18,575 for IMRT.

In early follow-up (0-6 months) genitourinary complications were significantly lower among 421 patients with who had received PBT than among 842 patients who received IMRT (5.9% vs. 9.5%; odds ratio 0.60; P = .03). Neither gastrointestinal nor other complications were significantly different, however, and at 12 months follow-up there were no significant differences between treatment types, Dr. Yu noted.

"A continued longitudinal study of the comparative effectiveness of proton radiation is needed, and we also believe that further study is needed before widespread application of proton radiation can be justified," he said.

PBT Benefit Proven in Other Cancers

A radiation oncologist who was not involved in the study commented that in the absence of evidence of a therapeutic benefit for PBT in prostate cancer over other modalities, proton therapy may better be reserved for the treatment of other cancers.

"If you have a resource that’s limited, you want to use it where you know there’s a benefit," said Dr, Jeffrey Bradley, professor of radiation oncology at Washington University in St. Louis.

His center is building a single-vault proton-beam facility that is expected to open in the summer of 2013. Dr. Bradley said that although they will likely treat patients with prostate cancer, he envisions the main role of the center to be treatment of pediatric and adult tumors of the central nervous system, sarcomas, ocular neoplasms, and other conditions where the benefits of PBT are better documented.

Dr Gray, Dr. Yu, and Dr. Bradley each reported no conflicts of interest.

BOSTON – Men who receive proton beam radiotherapy for prostate cancer have modestly better bowel function in the short term than do those who receive conformal or intensity-modulated radiation, but the effect is transient, investigators found.

At 2-3 months follow-up, patients treated with proton beam therapy (PBT) reported minimal decrements in bowel function, compared with patients treated with either 3D conformal radiotherapy (3D-CRT) or intensity-modulated radiotherapy (IMRT), who reported modest yet clinically meaningful decrements in bowel function, lead author Dr. Phillip J. Gray reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

All three patient groups also had significantly lower urinary quality-of-life (QoL) scores at early follow-up compared with baseline, but these changes were considered clinically meaningful only for IMRT, said Dr. Gray, a resident in the Harvard Radiation Oncology program in Boston.

"Though significant, these differences appear transient, with all three groups showing clinically meaningful decrements in bowel quality of life at 2 years following the start of treatment, and minimally lingering urinary symptoms," he said.

The retrospective study looked at three cohorts of men treated with the different modalities: 153 treated with IMRT monotherapy in the PROST-QA consortium, 94 patients treated with PBT at Massachusetts General Hospital (MGH), and 123 treated with 3D-CRT at MGH and other Harvard-affiliated hospitals.

Patients treated with IMRT and PBT were evaluated with the Expanded Prostate Cancer Index Composite (EPIC) instrument; patients treated with 3D-CRT were assessed using the Prostate Cancer Symptoms Index (PCSI); PCSI scores were inverted to match those of the EPIC scale.

Treatment dose ranges were 75.6-79.2 Gy for IMRT, 74-82 Gy relative biological effectiveness values for PBT, and 66.4-79.2 Gy for 3D-CRT.

Mean patient-reported bowel QoL scores in the immediate post-treatment period were 93.3 on a scale of 0-100 for PBT, 78.5 for IMRT, and 88.2 for 3D-CRT (P vs. PBT less than .001 for both comparisons). The differences from baseline in IMRT and 3D-CRT, but not in PBT, were considered clinically significant.

At 24 months, mean respective bowel QoL scores were 91.8, 87.6, and 90.2, respectively, with clinically significant differences between PBT and the other two modalities.

Dr. Gray acknowledged that the retrospective nature of the study and the use of different scoring instruments muddy the comparison waters. He noted that things may become clearer when the results of a recently launched randomized trial comparing PBT and IMRT become available. The study will look at 6-month efficacy outcomes, cost effectiveness, and toxicities at 2 years, and survival and other end points out to 10 years.

Protons Are a Costly Choice

Although the relative long-term benefits of PBT for prostate cancer may not be known for several years, one thing is sure: PBT is about 70% more expensive than IMRT, said Dr. James Yu, a radiation oncologist at Yale University in New Haven, Conn.

Neil Osterweil/IMNG Medical Media

Dr. Yu and colleagues looked at data on patients who received IMRT or PBT as primary therapy for prostate cancer in the Medicare Chronic Condition Data Warehouse, a national database that captures 100% of Medicare fee-for-service claims for patients with specific chronic conditions.

They found that the median interquartile range amount that Medicare reimbursed for PBT was $32,428 vs. $18,575 for IMRT.

In early follow-up (0-6 months) genitourinary complications were significantly lower among 421 patients with who had received PBT than among 842 patients who received IMRT (5.9% vs. 9.5%; odds ratio 0.60; P = .03). Neither gastrointestinal nor other complications were significantly different, however, and at 12 months follow-up there were no significant differences between treatment types, Dr. Yu noted.

"A continued longitudinal study of the comparative effectiveness of proton radiation is needed, and we also believe that further study is needed before widespread application of proton radiation can be justified," he said.

PBT Benefit Proven in Other Cancers

A radiation oncologist who was not involved in the study commented that in the absence of evidence of a therapeutic benefit for PBT in prostate cancer over other modalities, proton therapy may better be reserved for the treatment of other cancers.

"If you have a resource that’s limited, you want to use it where you know there’s a benefit," said Dr, Jeffrey Bradley, professor of radiation oncology at Washington University in St. Louis.

His center is building a single-vault proton-beam facility that is expected to open in the summer of 2013. Dr. Bradley said that although they will likely treat patients with prostate cancer, he envisions the main role of the center to be treatment of pediatric and adult tumors of the central nervous system, sarcomas, ocular neoplasms, and other conditions where the benefits of PBT are better documented.

Dr Gray, Dr. Yu, and Dr. Bradley each reported no conflicts of interest.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – Trastuzumab appears to have a limited impact on advanced HER2-positive bladder cancer, despite its transformative role in HER2-positive breast cancer.

In a multicenter, randomized phase II trial, no difference was observed in response, survival, or quality of life when gemcitabine (Gemzar) plus platinum-based chemotherapy was compared with the same gemcitabine-plus-platinum regimen plus trastuzumab (Herceptin) in 61 patients with stage IV advanced or metastatic urothelial cancer overexpressing HER2.

There was, however, the intriguing finding that overall survival was related to baseline platinum treatment, which included cisplatin or carboplatin.

Patients receiving cisplatin chemotherapy plus trastuzumab lived a median of 33.1 months, compared with 14.5 months in those receiving cisplatin without trastuzumab and just 9.4 months for patients given carboplatin chemotherapy with trastuzumab, Dr. Stéphane Oudard reported at the European Society for Medical Oncology Congress.

"Trastuzumab could have a synergistic effect with cisplatinum, leading to a longer overall survival," he said.

Urothelial cancer is the fourth most common cancer among men, with about 111,000 new cases reported in 2011. It has proven difficult to target with novel agents, despite the variety of molecular pathways that play a significant role in the formation of these tumors. The incidence of HER2 overexpression and/or amplification remains uncertain, ranging from 23% to 80% in various publications, Dr. Oudard observed.

An earlier phase II trial reported a response rate of 70%, including five complete and 26 partial responses, when trastuzumab was added to paclitaxel (Taxol), carboplatin, and gemcitabine chemotherapy in 44 patients with advanced urothelial cancer not previously treated with chemotherapy for metastasis. Median survival was 14 months, but 22% of patients experienced grades 1-3 cardiac toxicity (J. Clin. Oncol. 2007;25:2218-24).

A more recent phase II double-blind trial reported that adding the oral tyrosine kinase inhibitor vandetanib (Caprelsa) to second-line docetaxel (Taxotere) in advanced urothelial cancer did not significantly improve the overall response rate, progression-free survival, or overall survival, which reached a median of just 7 months (J. Clin. Oncol. 2012;30:507-512).

Treatment in the current trial included gemcitabine 1,000 mg/m² on days 1 and 8 every 21 days plus cisplatin 70 mg/m² on day 1 if creatinine clearance was more than 60 mL/min or carboplatin area under the curve (AUC) 5 on day 1 every 21 days if creatinine clearance was 60 mL/min or less, or the same chemotherapy regimen plus trastuzumab at a loading dose of 8 mg/kg then 6 mg/kg every 21 days until progression.

Prior neoadjuvant or adjuvant chemotherapy was allowed if it occurred at least 6 months prior to study entry. Prior trastuzumab therapy was not permitted.

Of the 563 patients tested for HER2 status, only 75 patients (13.3%) were positive on immunohistochemistry, and 14 of these were excluded from the trial for various reasons. The remaining 61 patients had an ECOG performance status of 2 or less, three-fourths had metastatic disease, and half received cisplatin-based chemotherapy.

The 32 patients in the trastuzumab arm received a median of eight chemotherapy cycles vs. a median of six cycles for the 29 patients in the control group, and their median time on therapy was longer, at 5.3 months vs. 3.9 months. Trastuzumab was given for a median of 10 months. Median follow-up was 33.3 months.

The median time to progression was 10.5 months in the control group and 8.3 months with trastuzumab (P = .33), and median overall survival was 15.7 months vs. 14.2 months (P = .56), said Dr. Oudard, of the Georges Pompidou European Hospital, Paris.

Using a Cox regression analysis, baseline serum HER2 was found to be predictive of progression-free survival, whatever the treatment arm (P = .03).

In multivariate Cox regression analysis, the main predictive factors for progression-free survival were ECOG performance status 0-1 vs. 2 (hazard ratio, 3.66) and baseline serum HER2 (HR, 1.01). Trastuzumab was not predictive (P = .49), nor was platinum analogue cisplatin vs. carboplatin (P = .77), he said.

Patients treated with trastuzumab did not have improved quality of life scores, and experienced more grade 3/4 febrile neutropenia (6.5% vs. 0%), dyspnea (3.2% vs. 0%), and decreased left ventricular ejection fraction (3.2% vs. 0%).

Future urothelial cancer trials with HER2-targeting therapy should be performed, but it is unclear whether a trastuzumab combination should be proposed for patients who can only receive cisplatin chemotherapy, whether patient selection should be based on baseline serum HER2, or whether a more powerful drug such as T-DM1 should be used, Dr. Oudard said.

Dr. Oudard reported honoraria from Sanofi-Aventis, Bayer, and other companies.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

VIENNA – The mammalian target of rapamycin inhibitors temsirolimus and everolimus have racked up a trio of negative trials in advanced renal cell carcinoma.

The phase IIIb INTORACT and phase II RECORD-2 trials show that combinations of bevacizumab (Avastin) and temsirolimus (Torisel) or everolimus (Afinitor) offer no response or survival advantage over existing first-line treatments. In addition, temsirolimus was not superior to sorafenib (Nexavar) as second-line therapy in the phase III INTORSECT trial.

All three trials were reported at the European Society for Medical Oncology Congress.

INTORACT: Temsirolimus

INTORACT randomly assigned 791 treatment naive patients with advanced, predominantly clear cell renal cell carcinoma (RCC) to bevacizumab 10 mg/kg every two weeks plus temsirolimus 25 mg IV weekly or bevacizumab plus interferon-alfa 9 MU three times per week until progression or unacceptable toxicity. Two-thirds of patients were Memorial Sloan-Kettering Cancer Center (MSKCC) intermediate risk, three-fourths were male, and about 85% had undergone a prior nephrectomy.

In INTORACT, the primary end point of progression free-survival by independent review reached 9.1 months with temsirolimus and bevacizumab and 9.3 months with interferon and bevacizumab (hazard ratio, 1.07; P = .759).

Median overall survival was nearly identical at 25.8 months with the temsirolimus combination and 25.5 months with interferon (HR, 1.04; P = .638), as were objective response rates at 27% and 28% (P = .965).

Median duration of response was longer in the interferon arm (17 months vs. 11 months), reported Dr. Brian Rini of the Cleveland Clinic.

According to a subset analysis, patients with a prior nephrectomy had a longer time to progression than did those without nephrectomy in the interferon arm (median 10.9 months vs. 6.8 months), but not in the temsirolimus arm (9.1 months vs. 9.2 months). Progression-free survival was similar between arms based on MSKCC risk status.

Temsirolimus is approved for the treatment of advanced RCC.

Patients receiving temsirolimus had significantly more grade 3/4 mucosal inflammation (8% vs. 0.3%), stomatitis (7% vs. 2%), as well as hypercholesterolemia, hyperglycemia and hypophosphatemia (all 6% vs. 1%). Pneumonitis was lower than expected based on previous trials (1% vs. 0%), he said.

Grade 3/4 neutropenia (8% vs. 2%), fatigue (11% vs. 5%), lymphopenia (6% vs. 3%) and asthenia (10% vs. 6%) were significantly more common in the interferon arm.

"Interferon plus bevacizumab remains a valid treatment option in metastatic renal cell carcinoma, but other combination therapies remain investigational," Dr. Rini concluded.

RECORD-2: Everolimus

The phase II, open-label RECORD-2 (Renal Cell Cancer Treatment With Oral RAD001 given daily–2) trial had a similar design, randomizing 365 treatment-naive patients metastatic RCC patients to bevacizumab 10 mg/kg every two weeks plus everolimus 10 mg/day or to bevacizumab plus interferon alfa-2a 3 to 9 MU three times/week. All patients had a prior nephrectomy, and more than 90% had a good to intermediate MSKCC performance status.

There was no significant difference between the everolimus and interferon groups in objective response rates (27% vs. 28%) or median progression-free survival based on central review (9.3 months vs. 10 months; HR, 0.91; P = .485).

Patients receiving bevacizumab with interferon lived for a median of 26 months, while the median was not yet available for those given everolimus and bevacizumab, reported Dr. Alain Ravaud of Bordeaux University Victor Segalen in France.

The combination of everolimus with bevacizumab was generally well tolerated and resulted in significantly better physical functioning on two quality of life measures, although no significant difference was observed between arms in a time to definitive deterioration analysis. Final overall survival and safety updates are expected later this year, he said.

Everolimus is approved for treatment of advanced RCC after failure of sunitinib (Sutent) or sorafenib.

Results Show Feasibility, Not Efficacy

Invited discussant Dr. Christian Kollmannsberger, senior scientist with the British Columbia Cancer Agency in Vancouver, said the two studies confirm phase I data that combining an mTOR inhibitor with bevacizumab is feasible, whereas combining bevacizumab with tyrosine kinase inhibitors or TKIs with mTOR inhibitors has proven too toxic because of overlapping toxicity profiles.

He said the current results clearly, and inexplicably, also contrast with the recently published French phase II TORAVA trial reporting treatment-limiting toxicity with temsirolimus plus bevacizumab and less clinical activity than the benefit expected from sequential use of each targeted therapy (Lancet Oncol. 2011;12:673-80).

Dr. Kollmannsberger said the overall negative results aren’t surprising since the rationale behind the INTORSECT and RECORD-2 combinations was based on very small phase I/II trials without complete responses and an absence of preclinical data showing an additive or synergistic effect with an mTOR inhibitor and bevacizumab.

He said future trials should combine agents with multiple mechanisms, and that vertical blockade of a single signaling pathway, in this case the vascular endothelial growth factor (VEGF) pathway, "is certainly not the way to go" with currently available agents because it is either too toxic or lacks convincing efficacy.

INTORSECT: Striking Finding

INTORSECT, the first head-to-head phase III trial comparing an mTOR inhibitor and a VEGF receptor inhibitor in second-line RCC, provided no easy answers regarding the optimal treatment sequence after sunitinib in advanced RCC.

The trial randomly assigned 512 patients to temsirolimus 25 mg weekly or sorafenib 400 mg twice daily until progressive disease or unacceptable toxicity. All patients had received first-line sunitinib, and about 82% had clear cell histology.

The confirmed objective response rates were 8% for both the temsirolimus and sorafenib groups, with stable disease reported in 61% of all patients.

Although patients receiving temsirolimus had a numerically longer progression-free survival by independent assessment (median 4.2 months vs. 3.9; HR 0.87; P = .193), those given sorafenib lived a median of four months longer (16.64 months vs. 12.27 months; HR 1.31, P = .014), reported Dr. Thomas Hutson, Pharm.D., of the Texas Oncology–Baylor Charles A. Sammons Cancer Center in Dallas.

Dr. Kollmannsberger described this as the most striking finding of the trial, and said it is likely the longest survival time observed in a randomized trial. The difference in survival is unlikely to be explained by patient characteristics, discontinuations because of adverse events with temsirolimus and sorafenib (17% vs. 14%), or subsequent therapies, since few patients had third-line therapy.

One possible explanation may be that prior VEGF therapy alters the biology of the disease. This hypothesis is supported by a recent analysis of sequential tissue samples suggesting that the protein expression in metastatic cell RCC changes with sunitinib therapy, Dr. Kollmannsberger said.

"I think in the end, the significant survival difference remains to be conclusively explained, but it at least gives rise to the hypothesis that the sequence of drugs does actually matter and matters more than we may think at the present time," he said.

INTORACT was sponsored by Pfizer Inc., which also provided funding for editorial support by Peloton Advantage. Dr. Rini reported research funding from and consulting for Pfizer. RECORD-2 was sponsored by Novartis. Dr. Ravaud reported financial ties with several firms including Pfizer and Novartis. Dr. Hutson reported serving as an adviser and investigator for Aveo, Bayer, GlaxoSmithKline, Novartis, and Pfizer, which sponsored INTORSECT. Dr. Kollmannsberger reported being an investigator on the INTORSECT study, and serving as an advisor for and travel support from Pfizer, Novartis and GSK.

Delivering radiation therapy immediately after radical prostatectomy resulted in fewer cases of biochemical progression of prostate cancer, compared with a "wait-and-see" approach, according to long-term data from a randomized phase III trial.

However, no such effect on overall survival was seen, with a possible detrimental effect in patients older than 70 years, investigators reported online Oct. 19 in the Lancet (doi: 10.1016/S0140-6736(12)61253-7).

Dr. Michel Bolla, of the Centre Hospitalier Universitaire A Michallon in Grenoble, France, and his colleagues looked at 1,005 men enrolled in the European Organisation for Research and Treatment of Cancer (EORTC) 22911 trial, who were followed for a median of 10.6 years.

The cohort (median age 65 years) included patients with untreated adenocarcinoma of the prostate and at least one of the following: capsular perforation, positive surgical margins, or seminal vesicle invasion.

All patients underwent radical prostatectomy, and were then randomly assigned either to receive immediate postoperative external irradiation (within 16 weeks of surgery) or to a "wait-and-see" policy, whereby subsequent treatment was delayed until biochemical or clinical relapse.

Overall, Dr. Bolla and his coauthors found that 198 patients (39.4%) in the postoperative radiation group had biochemical progression (defined as an increase in prostate-specific antigen concentration to more than 0.2 mcg/L measured on two occasions at least 2 weeks apart), clinical progression, or died.

In contrast, the "wait-and-see" group recorded 311 patients (61.8%) who either progressed or died, for a hazard ratio of 0.49 for the radiation approach (P less than .0001).

Stratifying the results by age showed that patients under 70 years old had improved biochemical progression-free survival (hazard ratio, 0.44; P less than .0001) and clinical progression-free survival (HR, 0.67; P = .0013) in the radiation cohort compared with wait-and-see patients.

However, "excess mortality was seen in patients aged 70 years or older who had received immediate radiation compared with those aged 70 years or older who were on the wait-and-see policy," they wrote, with 40 deaths out of 94 older patients in the radiation group versus 20 deaths out of 102 patients in the wait-and-see group (HR, 2.94; P less than .0001).

Finally, looking at the entire cohort, the authors found that overall all-cause 10-year survival did not differ substantially, at 76.9% for the postoperative radiation patients and 80.7% for the wait-and-see group.

"Prostate cancer mortality did not differ significantly between groups either," added the authors.

Dr. Bolla and his colleagues said they had no conflicts of interest related to this study, which was funded by the Ligue Nationale contre le Cancer and the EORTC Charitable Trust.

Delivering radiation therapy immediately after radical prostatectomy resulted in fewer cases of biochemical progression of prostate cancer, compared with a "wait-and-see" approach, according to long-term data from a randomized phase III trial.

However, no such effect on overall survival was seen, with a possible detrimental effect in patients older than 70 years, investigators reported online Oct. 19 in the Lancet (doi: 10.1016/S0140-6736(12)61253-7).

Dr. Michel Bolla, of the Centre Hospitalier Universitaire A Michallon in Grenoble, France, and his colleagues looked at 1,005 men enrolled in the European Organisation for Research and Treatment of Cancer (EORTC) 22911 trial, who were followed for a median of 10.6 years.

The cohort (median age 65 years) included patients with untreated adenocarcinoma of the prostate and at least one of the following: capsular perforation, positive surgical margins, or seminal vesicle invasion.

All patients underwent radical prostatectomy, and were then randomly assigned either to receive immediate postoperative external irradiation (within 16 weeks of surgery) or to a "wait-and-see" policy, whereby subsequent treatment was delayed until biochemical or clinical relapse.

Overall, Dr. Bolla and his coauthors found that 198 patients (39.4%) in the postoperative radiation group had biochemical progression (defined as an increase in prostate-specific antigen concentration to more than 0.2 mcg/L measured on two occasions at least 2 weeks apart), clinical progression, or died.

In contrast, the "wait-and-see" group recorded 311 patients (61.8%) who either progressed or died, for a hazard ratio of 0.49 for the radiation approach (P less than .0001).

Stratifying the results by age showed that patients under 70 years old had improved biochemical progression-free survival (hazard ratio, 0.44; P less than .0001) and clinical progression-free survival (HR, 0.67; P = .0013) in the radiation cohort compared with wait-and-see patients.

However, "excess mortality was seen in patients aged 70 years or older who had received immediate radiation compared with those aged 70 years or older who were on the wait-and-see policy," they wrote, with 40 deaths out of 94 older patients in the radiation group versus 20 deaths out of 102 patients in the wait-and-see group (HR, 2.94; P less than .0001).

Finally, looking at the entire cohort, the authors found that overall all-cause 10-year survival did not differ substantially, at 76.9% for the postoperative radiation patients and 80.7% for the wait-and-see group.

"Prostate cancer mortality did not differ significantly between groups either," added the authors.

Dr. Bolla and his colleagues said they had no conflicts of interest related to this study, which was funded by the Ligue Nationale contre le Cancer and the EORTC Charitable Trust.

Delivering radiation therapy immediately after radical prostatectomy resulted in fewer cases of biochemical progression of prostate cancer, compared with a "wait-and-see" approach, according to long-term data from a randomized phase III trial.

However, no such effect on overall survival was seen, with a possible detrimental effect in patients older than 70 years, investigators reported online Oct. 19 in the Lancet (doi: 10.1016/S0140-6736(12)61253-7).

Dr. Michel Bolla, of the Centre Hospitalier Universitaire A Michallon in Grenoble, France, and his colleagues looked at 1,005 men enrolled in the European Organisation for Research and Treatment of Cancer (EORTC) 22911 trial, who were followed for a median of 10.6 years.

The cohort (median age 65 years) included patients with untreated adenocarcinoma of the prostate and at least one of the following: capsular perforation, positive surgical margins, or seminal vesicle invasion.

All patients underwent radical prostatectomy, and were then randomly assigned either to receive immediate postoperative external irradiation (within 16 weeks of surgery) or to a "wait-and-see" policy, whereby subsequent treatment was delayed until biochemical or clinical relapse.

Overall, Dr. Bolla and his coauthors found that 198 patients (39.4%) in the postoperative radiation group had biochemical progression (defined as an increase in prostate-specific antigen concentration to more than 0.2 mcg/L measured on two occasions at least 2 weeks apart), clinical progression, or died.

In contrast, the "wait-and-see" group recorded 311 patients (61.8%) who either progressed or died, for a hazard ratio of 0.49 for the radiation approach (P less than .0001).

Stratifying the results by age showed that patients under 70 years old had improved biochemical progression-free survival (hazard ratio, 0.44; P less than .0001) and clinical progression-free survival (HR, 0.67; P = .0013) in the radiation cohort compared with wait-and-see patients.

However, "excess mortality was seen in patients aged 70 years or older who had received immediate radiation compared with those aged 70 years or older who were on the wait-and-see policy," they wrote, with 40 deaths out of 94 older patients in the radiation group versus 20 deaths out of 102 patients in the wait-and-see group (HR, 2.94; P less than .0001).

Finally, looking at the entire cohort, the authors found that overall all-cause 10-year survival did not differ substantially, at 76.9% for the postoperative radiation patients and 80.7% for the wait-and-see group.

"Prostate cancer mortality did not differ significantly between groups either," added the authors.

Dr. Bolla and his colleagues said they had no conflicts of interest related to this study, which was funded by the Ligue Nationale contre le Cancer and the EORTC Charitable Trust.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

When the U.S. Preventive Services Task Force recommended against prostate-specific antigen-based screening in men of any age this spring, an uproar swiftly followed. Evidence was dissected; cancer survivors and stakeholders lambasted the decision as shortsighted, and still others endorsed the recommendation as a long overdue nod to science.

Similar fallout erupted in November 2009 when the task force recommended against routine screening mammography in women younger than age 50 years. Only this time, critics charged that science had taken a back seat to politics, characterizing the decision as a harbinger of rationing under President Obama’s health care reform.

Less contentious so far are new recommendations that the annual Pap smear screening for cervical cancer should be pushed back to every 3 years and that low-dose lung CT screening be offered to heavy smokers. Time will tell whether the former is accepted in clinical practice and the latter can make the leap from clinical trial strategy to national guideline.

Given the complicated, emotionally charged nature of cancer screening and the political forces still at play, could another maelstrom be far off?

"There are a lot of misconceptions out there, in part because for so many decades, the messages have been so strong, they sometimes leaped ahead of the evidence," Dr. Barnett Kramer, director of the division of cancer prevention at the National Cancer Institute (NCI), Bethesda, Md., said in an interview.

When advocacy groups such as the American Cancer Society (ACS) first formed, strong, simple messages were needed to get Americans even to utter the word cancer out loud.

Over time, cancer screening messages have evolved into sound bites that almost always follow the very strong presumption that early detection means a better chance for survival, said Dr. Kramer, who described this as a serious oversimplification of the principles of screening. By its very nature, a screening test will always advance the date of diagnosis, but this may not benefit the patient.

"Simply saying that screening increases survival doesn’t convey any useful information," he said. "You really need to know what the effect of the screening test is on the risk of dying – that is the mortality rate, and that’s a different calculation from simply measuring the duration of life from the day of diagnosis to death."

Dr. Virginia Moyer, chair of the U.S. Preventive Services Task Force (USPSTF), agreed that some advocacy groups "absolutely oversell the benefits of screening and completely ignore the harms" that screening and medical interventions can cause. The perception among the general public is that if you screen and find something, you have therefore saved a life.

She argued in an interview that scientific groups such as the task force have provided a more balanced message, but admits the scientific community has made its own mistakes.

"Our concept at the time that PSA screening was developed was that if you had cancer in you, it would inevitably grow and kill you if you didn’t do something about it," she said. "That’s what we thought all cancer was about and we just turned out to be wrong. A huge proportion of cancers never do anything and that’s the piece we didn’t know."

Some physicians, however, may still not know. Dr. Moyer pointed out that risk communication experts recently reported that about one half (47%) of U.S. primary care physicians surveyed incorrectly said that finding more cases of cancer in screened vs. unscreened populations, "proves that screening saves lives" (Ann. Intern. Med. 2012;156:340-9).

The Push-Pull of Politics

Dr. Handel Reynolds, breast radiologist with Piedmont Hospital in Atlanta and author of the new book, "The Big Squeeze: A Social and Political History of the Controversial Mammogram," said in an interview that a series of crucial decisions made by health professionals set up screening mammography to be the controversial test it is today.

The first of these came in 1973 when, based on a single trial showing a mortality benefit in women under 50, the ACS and NCI decided to include women as young as 35 years in the National Breast Cancer Detection Demonstration Project (BCDDP), the first large-scale use of mammography as a screening tool involving some 280,000 women over 5 years (J. Natl. Cancer Inst. 1988;80:1540-7).

Just 3 years later, the National Institutes of Health (NIH) convened its first consensus conference to address screening in younger women, even though the BCDDP was not a clinical trial and demonstration projects are typically performed to show that activities with proven efficacy in clinical trials can be done on a large scale.

"1976 was the first time we had this huge blow-up about women under 50, and it has not gone away. In fact, it has become more acrimonious with each subsequent iteration," Dr. Reynolds said.

The most egregious example of political interference occurred in 1997. The NCI had broken with the ACS four years earlier and dropped its recommendation for mammography in women under 50. In 1997, however, the NCI reversed its position after a series of high-profile hearings held by then Sen. Arlen Specter (R-PA.), who chaired the subcommittee controlling funding for the NCI and who openly supported screening for women under 50, Dr. Reynolds said.

"The 1997 episode established the primacy of politics over science in the mammography debate and made it so much easier then for the 2009 controversy to be resolved in a matter of weeks," he contends.

Pap Test Changes Fly Under the Radar

Politics played a huge role in the uproar that surrounded the 2003 cervical cancer guidelines, said Dr. Alan G. Waxman, who recalled being accused of hating his mother because the 2003 guidelines he helped pen urged less frequent screening for cervical cancer.

Although the 2012 cervical screening guidelines essentially retire the annual Pap smear, Dr. Waxman said that he’s not expecting a huge backlash. Things have been relatively quiet since two separate groups released updates this March. The change between guidelines has been incremental, and women trust the science because it hasn’t gone through the permutations and "fluctuating truth" observed with the mammography data.

"With the Pap smear, the science has been pretty much in lockstep," said Dr. Waxman, president of the American Society for Colposcopy and Cervical Pathology, which partnered with the ACS and American Society for Clinical Pathology to release its guidelines in tandem with similar recommendations from the USPSTF.

Money Makes Its Voice Heard

The relative quiet following the changes to cervical cancer screening recommendations may also reflect the numbers. Only about 12,000 new cases of cervical cancer are diagnosed annually, compared with 214,633 new cases of prostate cancer in 2008, the most recent year for which numbers are available. Similarly, mammograms were ordered or provided in 20.3 million physician office visits and 2.3 million hospital outpatient department visits in 2009 alone.

The financial stakes are high in prostate and breast cancer and the rhetoric proportionate.

The American Urological Association expressed outrage after the release of the UPSTF PSA recommendation, warning that it could potentially turn back the clock to a time before PSA testing when "men presented with high-grade, metastatic disease for which there was little or no treatment beyond palliative care."

Dr. Otis Brawley, chief medical officer of the American Cancer Society, defended the USPSTF in a recent commentary, saying that unlike many of their critics, USPSTF members are ideally suited to assess the science objectively because they have no "emotional, ideological, or financial conflicts of interest" and understand the complicated science of screening.

He also expressed hope that the new PSA recommendations will end mass screenings, a "lucrative business" that offers tests outside the physician-patient relationship, often in shopping malls and parking lots with sponsorship from hospitals, medical practices, and even an adult diaper company.

For his part, Dr. Richard Albin, who discovered PSA, has been quoted as saying, "I never dreamed that my discovery 4 decades ago would lead to such a profit-driven public health disaster."

Some urologists have criticized the USPSTF for failing to include urologists on the panel and for the absence of a cost analysis.

"If you’re not saving any lives, then any money you’re spending is wasted, and you don’t need a complicated cost-effectiveness analysis to figure that out," countered Dr. Moyer.

Physicians and patients, however, may need a scorecard to wade through the rhetoric and conflicting data, frequently cherry-picked to argue for or against a particular screening test. In a recent study, 30% of women reported that the 2009 USPSTF mammography guidelines confused more than they helped them understand when to get a mammogram (Am. J. Prev. Med. 2011;40:497-504)

A More Nuanced Conversation

There’s little doubt that the task force’s recent decisions will dramatically reshape mammography and PSA screening in the United States, but the question is by how much.

"Largely what we’ve communicated is all the benefit, but I think the U.S. Preventive Services Task Force is communicating all the harms. And the right place is somewhere in between," Dr. Therese Bartholomew Bevers, medical director of the Cancer Prevention Center at the University of Texas M.D. Anderson Cancer Center in Houston, said in an interview.

What’s important is having a more balanced, nuanced conversation with patients. But is the American public ready for discussions of mortality rates or the changing calculus of risk/benefit ratios of screening as they age?

Nearly half of all American adults – 90 million people – have difficulty understanding and using health information, according to an Institute of Medicine report. In addition, the 2000 census counted 20 million people who speak poor English and 10 million who speak none.

The public is quite intelligent, but that part of the problem is that physicians don’t always know or understand the data. And if even when physicians understand the data, they often do not know how to communicate them in a way their patients can understand, says Dr. Bevers.

"That’s where there is a huge opportunity to create decision-making tools," she says.

With the help of communication experts, Dr. Bevers and her colleagues are developing a computerized tool that reviews the data from the National Lung Screening Trial (NLST) and spells out the benefits and harms of low-dose computed tomography screening for lung cancer in a very simplified fashion, using smiley faces for benefits and frowning faces for risks.

"It really advances my discussion when I walk in the room," said Dr. Bevers, a coinvestigator for the NLST. "I’m not explaining about the 20% mortality reduction, the associated harms. I’m now talking about: ‘What did you think about that?’ ‘What did you think about the harms?’ ‘How did it influence your decision about this?’ It’s a much more advanced discussion, and that’s helpful in a busy practice."

Another tool could then be used to walk patients through the next step of care to give physicians a sense of what concerns their patients most; for example, the risk of dying or that their cancer will return, she said.

The New Kid on the Block

Most experts agree that low-dose CT lung cancer screening is something of an anomaly in the cancer screening wars. Prior nonrandomized trials suggested a benefit with low-dose CT, but practice did not leapfrog the evidence. Only now that the randomized NLST has been completed is the screening machinery gearing up, but with significant questions about cost and high false-positive rates still unanswered (N. Engl. J. Med. 2011;365:395-409)

Moreover, CT lung screening would be an additional service offered to high-risk individuals, rather than the retraction of an entrenched screening practice.

The NCI has developed its own one-page, online NLST study guide for patients and physicians that provides specific data on low-dose CT vs. chest x-ray screening, "take-home" messages, and an educational component directing patients not to smoke.

"We don’t want to oversell the harms and undersell the benefits," said the NCI’s Dr. Kramer. "We don’t want the pendulum to swing completely in the opposite direction, and I think this sheet goes a long way."

In a busy primary care office, no doubt the various new recommendations will shift the conversation with patients, many of whom have been given the simple message for years to come back each year for their annual mammogram or PSA test. Depending on which recommendations their physicians advocate and what patients choose to follow, it will ultimately tip the balance sheet and outcomes data for years to come.

None of the physicians interviewed reported having relevant conflicts of interest.

Objectives: This randomized, open-label phase III trial asks whether adding bevacizumab (Avastin) to) everolimus (Afinitor) can improve overall survival of patients with advanced renal cell carcinoma that progressed after first-line vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment.

Key entry or exclusion criteria: Patients must have histologically confirmed renal cell carcinoma with some component of clear cell disease and their disease must be metastatic or unresectable. They also must have at least 1 prior VEGFR-TKI treatment and have progressed or been intolerant to treatment.

Locations: 400 sites.

Goal: 700 patients.

Study sponsor: Cancer and Leukemia Group B in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/NCT01198158

NIH clinical trials identifier: NCT01198158.

Objectives: This randomized, open-label phase III trial asks whether adding bevacizumab (Avastin) to) everolimus (Afinitor) can improve overall survival of patients with advanced renal cell carcinoma that progressed after first-line vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment.

Key entry or exclusion criteria: Patients must have histologically confirmed renal cell carcinoma with some component of clear cell disease and their disease must be metastatic or unresectable. They also must have at least 1 prior VEGFR-TKI treatment and have progressed or been intolerant to treatment.

Locations: 400 sites.

Goal: 700 patients.

Study sponsor: Cancer and Leukemia Group B in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/NCT01198158

NIH clinical trials identifier: NCT01198158.

Objectives: This randomized, open-label phase III trial asks whether adding bevacizumab (Avastin) to) everolimus (Afinitor) can improve overall survival of patients with advanced renal cell carcinoma that progressed after first-line vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) treatment.

Key entry or exclusion criteria: Patients must have histologically confirmed renal cell carcinoma with some component of clear cell disease and their disease must be metastatic or unresectable. They also must have at least 1 prior VEGFR-TKI treatment and have progressed or been intolerant to treatment.

Locations: 400 sites.

Goal: 700 patients.

Study sponsor: Cancer and Leukemia Group B in collaboration with the National Cancer Institute.

Link for more information: clinicaltrials.gov/ct2/show/NCT01198158

NIH clinical trials identifier: NCT01198158.

Objectives:Orteronel (TAK-700) is a novel, oral nonsteroidal androgen synthesis inhibitor. This randomized, double-blind phase III trial compares orteronel with placebo in men who have progression during or after docetaxel (Taxotere) therapy. Overall survival is the primary outcome measure.

Key entry or exclusion criteria: Patients who received prior therapy with orteronel, aminoglutethimide (Cytadren), ketoconazole (Nizoral, Xolegel), or abiraterone (Zytiga) are excluded.

Locations: 79 sites.

Goal: 1,083 patients.

Study sponsor: Millennium Pharmaceuticals, Inc.

Link for more information: clinicaltrials.gov/ct2/show/NCT01193257

NIH clinical trials identifier: NCT01193257

Objectives:Orteronel (TAK-700) is a novel, oral nonsteroidal androgen synthesis inhibitor. This randomized, double-blind phase III trial compares orteronel with placebo in men who have progression during or after docetaxel (Taxotere) therapy. Overall survival is the primary outcome measure.

Key entry or exclusion criteria: Patients who received prior therapy with orteronel, aminoglutethimide (Cytadren), ketoconazole (Nizoral, Xolegel), or abiraterone (Zytiga) are excluded.

Locations: 79 sites.

Goal: 1,083 patients.

Study sponsor: Millennium Pharmaceuticals, Inc.

Link for more information: clinicaltrials.gov/ct2/show/NCT01193257

NIH clinical trials identifier: NCT01193257

Objectives:Orteronel (TAK-700) is a novel, oral nonsteroidal androgen synthesis inhibitor. This randomized, double-blind phase III trial compares orteronel with placebo in men who have progression during or after docetaxel (Taxotere) therapy. Overall survival is the primary outcome measure.

Key entry or exclusion criteria: Patients who received prior therapy with orteronel, aminoglutethimide (Cytadren), ketoconazole (Nizoral, Xolegel), or abiraterone (Zytiga) are excluded.

Locations: 79 sites.

Goal: 1,083 patients.

Study sponsor: Millennium Pharmaceuticals, Inc.

Link for more information: clinicaltrials.gov/ct2/show/NCT01193257

NIH clinical trials identifier: NCT01193257