Genitourinary Cancer

ATLANTA – Men with intermediate-risk prostate cancer fared just as well over the long term with 8 weeks as with 28 weeks of neoadjuvant androgen suppression before receiving concomitant androgen suppression and radiation, said Dr. Thomas M. Pisansky at the annual meeting of the American Society for Radiation Oncology.

Based on follow-up data from the RTOG 9910 trial, 10-year disease-specific survival rates were virtually identical for the two groups at 95% and 96%. Further, 10-year biochemical failure rates were exactly the same at 27%. Nor were there any significant differences in either locoregional progression at 10 years (6% vs. 4%) or in distant metastases (6% in each group).

Neil Osterweil/IMNG Medical Media

"In 10-years of follow-up, the disease-specific survival of men treated in either fashion is extraordinarily high," said Dr. Pisansky, principal investigator for the trial, and a professor of radiation oncology at the Mayo Clinic in Rochester, Minn.

"It’s quite clear to us: The recommendation is that the preradiotherapy neoadjuvant androgen suppression need last no longer than 8 weeks. When you combine the preradiotherapy with the concurrent radiotherapy/androgen suppression, it need last no more than 16 weeks," he said at a media briefing before his presentation of the data in plenary session.

A radiation oncologist who was not involved in the study commented that it reinforces the importance of optimizing therapeutic regimens.

"From personal experience, when you shorten treatment, patients at least perceive that their quality of life is better," said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

Dr. Haffty moderated the briefing at which Dr. Pisansky discussed his data.

The investigators enrolled men with intermediate-risk prostate cancer into the trial, with accrual ranging from February 2000 through May 2004. The participants were randomly assigned to receive either 8 weeks (752 men) or 28 weeks (737 men) of neoadjuvant total androgen suppression with a luteinizing hormone-releasing-hormone analog and nonsteroidal antiandrogen. All patients then received radiation therapy of 70.2 Gy divided into 39 fractions with doses to the seminal vesicles and pelvic nodes as needed, concurrent with 8 additional weeks of total androgen suppression.

After a median follow-up of 8.7 years for all patients and 9.3 years for all survivors, 3% of all patients had died from prostate cancer. There were 30 prostate cancer deaths in the 8-week arm, and 24 in the 28-week arm, a difference that was not significant. Biochemical failures, defined as at least a 2 ng/dL rise in prostate specific antigen [PSA] from the PSA nadir), occurred in 192 of 752 patients assigned to 8 weeks neoadjuvant suppression, and in 185 of 737 assigned to 28 weeks.

Late radiation toxicities of grade 2 or greater occurred in 10% of patients in the 8-week arm, and in 8% of those in the 28-week arm. Sexual adverse events of grade 2 or greater occurred in 8% and 17%, respectively.

The evidence indicates that "there is little room for improvement in disease-specific survival and overall survival," and that studies seeking to show further benefit would be difficult to accomplish, Dr. Pisansky said.

He noted that as with breast cancer, there is likely to be a shift away from survival outcomes toward decreasing biochemical failure rates, reducing need for secondary therapies, and toward establishing an ideal radiation therapy dose.

The study was supported by grants from the National Cancer Institute. Dr. Pisansky and Dr. Haffty reported having no relevant conflicts of interest.

ATLANTA – Men with intermediate-risk prostate cancer fared just as well over the long term with 8 weeks as with 28 weeks of neoadjuvant androgen suppression before receiving concomitant androgen suppression and radiation, said Dr. Thomas M. Pisansky at the annual meeting of the American Society for Radiation Oncology.

Based on follow-up data from the RTOG 9910 trial, 10-year disease-specific survival rates were virtually identical for the two groups at 95% and 96%. Further, 10-year biochemical failure rates were exactly the same at 27%. Nor were there any significant differences in either locoregional progression at 10 years (6% vs. 4%) or in distant metastases (6% in each group).

Neil Osterweil/IMNG Medical Media

"In 10-years of follow-up, the disease-specific survival of men treated in either fashion is extraordinarily high," said Dr. Pisansky, principal investigator for the trial, and a professor of radiation oncology at the Mayo Clinic in Rochester, Minn.

"It’s quite clear to us: The recommendation is that the preradiotherapy neoadjuvant androgen suppression need last no longer than 8 weeks. When you combine the preradiotherapy with the concurrent radiotherapy/androgen suppression, it need last no more than 16 weeks," he said at a media briefing before his presentation of the data in plenary session.

A radiation oncologist who was not involved in the study commented that it reinforces the importance of optimizing therapeutic regimens.

"From personal experience, when you shorten treatment, patients at least perceive that their quality of life is better," said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

Dr. Haffty moderated the briefing at which Dr. Pisansky discussed his data.

The investigators enrolled men with intermediate-risk prostate cancer into the trial, with accrual ranging from February 2000 through May 2004. The participants were randomly assigned to receive either 8 weeks (752 men) or 28 weeks (737 men) of neoadjuvant total androgen suppression with a luteinizing hormone-releasing-hormone analog and nonsteroidal antiandrogen. All patients then received radiation therapy of 70.2 Gy divided into 39 fractions with doses to the seminal vesicles and pelvic nodes as needed, concurrent with 8 additional weeks of total androgen suppression.

After a median follow-up of 8.7 years for all patients and 9.3 years for all survivors, 3% of all patients had died from prostate cancer. There were 30 prostate cancer deaths in the 8-week arm, and 24 in the 28-week arm, a difference that was not significant. Biochemical failures, defined as at least a 2 ng/dL rise in prostate specific antigen [PSA] from the PSA nadir), occurred in 192 of 752 patients assigned to 8 weeks neoadjuvant suppression, and in 185 of 737 assigned to 28 weeks.

Late radiation toxicities of grade 2 or greater occurred in 10% of patients in the 8-week arm, and in 8% of those in the 28-week arm. Sexual adverse events of grade 2 or greater occurred in 8% and 17%, respectively.

The evidence indicates that "there is little room for improvement in disease-specific survival and overall survival," and that studies seeking to show further benefit would be difficult to accomplish, Dr. Pisansky said.

He noted that as with breast cancer, there is likely to be a shift away from survival outcomes toward decreasing biochemical failure rates, reducing need for secondary therapies, and toward establishing an ideal radiation therapy dose.

The study was supported by grants from the National Cancer Institute. Dr. Pisansky and Dr. Haffty reported having no relevant conflicts of interest.

ATLANTA – Men with intermediate-risk prostate cancer fared just as well over the long term with 8 weeks as with 28 weeks of neoadjuvant androgen suppression before receiving concomitant androgen suppression and radiation, said Dr. Thomas M. Pisansky at the annual meeting of the American Society for Radiation Oncology.

Based on follow-up data from the RTOG 9910 trial, 10-year disease-specific survival rates were virtually identical for the two groups at 95% and 96%. Further, 10-year biochemical failure rates were exactly the same at 27%. Nor were there any significant differences in either locoregional progression at 10 years (6% vs. 4%) or in distant metastases (6% in each group).

Neil Osterweil/IMNG Medical Media

"In 10-years of follow-up, the disease-specific survival of men treated in either fashion is extraordinarily high," said Dr. Pisansky, principal investigator for the trial, and a professor of radiation oncology at the Mayo Clinic in Rochester, Minn.

"It’s quite clear to us: The recommendation is that the preradiotherapy neoadjuvant androgen suppression need last no longer than 8 weeks. When you combine the preradiotherapy with the concurrent radiotherapy/androgen suppression, it need last no more than 16 weeks," he said at a media briefing before his presentation of the data in plenary session.

A radiation oncologist who was not involved in the study commented that it reinforces the importance of optimizing therapeutic regimens.

"From personal experience, when you shorten treatment, patients at least perceive that their quality of life is better," said Dr. Bruce G. Haffty, a radiation oncologist at the Cancer Institute of New Jersey in New Brunswick, and ASTRO president-elect.

Dr. Haffty moderated the briefing at which Dr. Pisansky discussed his data.

The investigators enrolled men with intermediate-risk prostate cancer into the trial, with accrual ranging from February 2000 through May 2004. The participants were randomly assigned to receive either 8 weeks (752 men) or 28 weeks (737 men) of neoadjuvant total androgen suppression with a luteinizing hormone-releasing-hormone analog and nonsteroidal antiandrogen. All patients then received radiation therapy of 70.2 Gy divided into 39 fractions with doses to the seminal vesicles and pelvic nodes as needed, concurrent with 8 additional weeks of total androgen suppression.

After a median follow-up of 8.7 years for all patients and 9.3 years for all survivors, 3% of all patients had died from prostate cancer. There were 30 prostate cancer deaths in the 8-week arm, and 24 in the 28-week arm, a difference that was not significant. Biochemical failures, defined as at least a 2 ng/dL rise in prostate specific antigen [PSA] from the PSA nadir), occurred in 192 of 752 patients assigned to 8 weeks neoadjuvant suppression, and in 185 of 737 assigned to 28 weeks.

Late radiation toxicities of grade 2 or greater occurred in 10% of patients in the 8-week arm, and in 8% of those in the 28-week arm. Sexual adverse events of grade 2 or greater occurred in 8% and 17%, respectively.

The evidence indicates that "there is little room for improvement in disease-specific survival and overall survival," and that studies seeking to show further benefit would be difficult to accomplish, Dr. Pisansky said.

He noted that as with breast cancer, there is likely to be a shift away from survival outcomes toward decreasing biochemical failure rates, reducing need for secondary therapies, and toward establishing an ideal radiation therapy dose.

The study was supported by grants from the National Cancer Institute. Dr. Pisansky and Dr. Haffty reported having no relevant conflicts of interest.

ATLANTA – Five common radiation therapy practices are not adequately supported by evidence and may not be the best choice for many patients, radiation oncology experts said at the annual meeting of the American Society for Radiation Oncology (ASTRO).

The evidence-based recommendations on radiation therapy for breast cancer, prostate cancer, and bone metastases are part of the national "Choosing Wisely" campaign, which is aimed at improving the quality of care by reducing or eliminating overuse of tests and procedures. This campaign is about "removal of waste to improve quality and safety, and doing no harm to patients," said Daniel Wolfson, executive vice president and chief operating officer of the American Board of Internal Medicine (ABIM) Foundation, which is leading the Choosing Wisely campaign.

Medical societies in various disciplines have released recommendations geared toward individual clinical disciplines, and now it’s ASTRO’s turn, said Dr. Michael L. Steinberg, chairman of ASTRO’s board of directors, in a briefing announcing the guidelines. "The list serves only as a starting point for a detailed conversation between a patient and physician, and to ensure patient-centered care, which is a core principle of ASTRO."

The five recommendations are:

• Don’t initiate whole-breast radiotherapy as a part of breast conservation therapy in women aged 50 years and older with early-stage invasive breast cancer without considering shorter treatment schedules.

"We’ve known for years that whole-breast radiation improves local control and improves survival, and has cosmetic advantages over mastectomy," Dr. Steinberg said. In recent years, however, randomized clinical trials have demonstrated that shorter courses of therapy – less than 4 weeks, compared with 5 weeks for conventionally fractionated radiation – produce equivalent tumor control and cosmetic outcomes.

• Don’t initiate management of patients who have low-risk prostate cancer without discussing active surveillance.

Patients with low-risk prostate cancer should discuss "reasonable management options" with their physicians, including active surveillance. With this recommendation, ASTRO is "reinforcing the shared decision-making model," Dr. Steinberg said.

• Don’t routinely use extended fractionation schemes (more than 10 fractions) for palliation of bone metastases.

Patients with bone metastases may derive equivalent pain relief from 30 Gy in 10 fractions, 20 Gy over 5 fractions, or even a single 8-Gy fraction, studies suggest. The single-fraction option is more convenient for patients, but it may be associated with a marginally higher need for retreatment of the same site. Patients who are not ambulatory, have transportation problems, or a limited prognosis may be good candidates for the single-fraction option, the guidelines say.

• Don’t routinely recommend proton-beam therapy for prostate cancer outside of a prospective clinical trial or registry.

"There is no clear evidence that proton-beam therapy for prostate cancer offers any clinical advantage over other forms of definitive radiation therapy. Clinical trials are necessary to establish a possible advantage of this expensive therapy," the Choosing Wisely guidelines state.

At ASTRO 2012, investigators reported that 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. In addition, proton-beam therapy is estimated to cost about 70% more than external-beam radiotherapy for the treatment of prostate cancer.

• Don’t routinely use intensity-modulated radiation therapy (IMRT) to deliver whole-breast radiotherapy as part of breast conservation therapy.

"Clinical trials have suggested lower rates of skin toxicity after using modern 3D conformal techniques relative to older methods of 2D planning. In these trials, the term ‘IMRT’ has generally been applied to describe methods that are more accurately defined as field-in-field 3D conformal radiotherapy. While IMRT may be of benefit in select cases where the anatomy is unusual, its routine use has not been demonstrated to provide significant clinical advantage," the guidelines note.

The cost difference between 3D conformal radiotherapy and IMRT for whole-breast radiotherapy is approximately $7,000, according to Dr. Steinberg.

"These are not ‘never do this’ recommendations, these are ‘engage the patient in the shared-decision paradigm’ guidelines, because there may be patients that are better treated with, let’s say, IMRT [for whole-breast radiotherapy]," he said.

Asked whether the Choosing Wisely guidelines in radiation oncology and other disciplines might be used by insurers to justify denying reimbursement for certain procedures, Mr. Wolfson said that "we haven’t seen that, and whether it comes to be will be the question, but we would sharply criticize that [approach]."

ATLANTA – Five common radiation therapy practices are not adequately supported by evidence and may not be the best choice for many patients, radiation oncology experts said at the annual meeting of the American Society for Radiation Oncology (ASTRO).

The evidence-based recommendations on radiation therapy for breast cancer, prostate cancer, and bone metastases are part of the national "Choosing Wisely" campaign, which is aimed at improving the quality of care by reducing or eliminating overuse of tests and procedures. This campaign is about "removal of waste to improve quality and safety, and doing no harm to patients," said Daniel Wolfson, executive vice president and chief operating officer of the American Board of Internal Medicine (ABIM) Foundation, which is leading the Choosing Wisely campaign.

Medical societies in various disciplines have released recommendations geared toward individual clinical disciplines, and now it’s ASTRO’s turn, said Dr. Michael L. Steinberg, chairman of ASTRO’s board of directors, in a briefing announcing the guidelines. "The list serves only as a starting point for a detailed conversation between a patient and physician, and to ensure patient-centered care, which is a core principle of ASTRO."

The five recommendations are:

• Don’t initiate whole-breast radiotherapy as a part of breast conservation therapy in women aged 50 years and older with early-stage invasive breast cancer without considering shorter treatment schedules.

"We’ve known for years that whole-breast radiation improves local control and improves survival, and has cosmetic advantages over mastectomy," Dr. Steinberg said. In recent years, however, randomized clinical trials have demonstrated that shorter courses of therapy – less than 4 weeks, compared with 5 weeks for conventionally fractionated radiation – produce equivalent tumor control and cosmetic outcomes.

• Don’t initiate management of patients who have low-risk prostate cancer without discussing active surveillance.

Patients with low-risk prostate cancer should discuss "reasonable management options" with their physicians, including active surveillance. With this recommendation, ASTRO is "reinforcing the shared decision-making model," Dr. Steinberg said.

• Don’t routinely use extended fractionation schemes (more than 10 fractions) for palliation of bone metastases.

Patients with bone metastases may derive equivalent pain relief from 30 Gy in 10 fractions, 20 Gy over 5 fractions, or even a single 8-Gy fraction, studies suggest. The single-fraction option is more convenient for patients, but it may be associated with a marginally higher need for retreatment of the same site. Patients who are not ambulatory, have transportation problems, or a limited prognosis may be good candidates for the single-fraction option, the guidelines say.

• Don’t routinely recommend proton-beam therapy for prostate cancer outside of a prospective clinical trial or registry.

"There is no clear evidence that proton-beam therapy for prostate cancer offers any clinical advantage over other forms of definitive radiation therapy. Clinical trials are necessary to establish a possible advantage of this expensive therapy," the Choosing Wisely guidelines state.

At ASTRO 2012, investigators reported that 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. In addition, proton-beam therapy is estimated to cost about 70% more than external-beam radiotherapy for the treatment of prostate cancer.

• Don’t routinely use intensity-modulated radiation therapy (IMRT) to deliver whole-breast radiotherapy as part of breast conservation therapy.

"Clinical trials have suggested lower rates of skin toxicity after using modern 3D conformal techniques relative to older methods of 2D planning. In these trials, the term ‘IMRT’ has generally been applied to describe methods that are more accurately defined as field-in-field 3D conformal radiotherapy. While IMRT may be of benefit in select cases where the anatomy is unusual, its routine use has not been demonstrated to provide significant clinical advantage," the guidelines note.

The cost difference between 3D conformal radiotherapy and IMRT for whole-breast radiotherapy is approximately $7,000, according to Dr. Steinberg.

"These are not ‘never do this’ recommendations, these are ‘engage the patient in the shared-decision paradigm’ guidelines, because there may be patients that are better treated with, let’s say, IMRT [for whole-breast radiotherapy]," he said.

Asked whether the Choosing Wisely guidelines in radiation oncology and other disciplines might be used by insurers to justify denying reimbursement for certain procedures, Mr. Wolfson said that "we haven’t seen that, and whether it comes to be will be the question, but we would sharply criticize that [approach]."

ATLANTA – Five common radiation therapy practices are not adequately supported by evidence and may not be the best choice for many patients, radiation oncology experts said at the annual meeting of the American Society for Radiation Oncology (ASTRO).

The evidence-based recommendations on radiation therapy for breast cancer, prostate cancer, and bone metastases are part of the national "Choosing Wisely" campaign, which is aimed at improving the quality of care by reducing or eliminating overuse of tests and procedures. This campaign is about "removal of waste to improve quality and safety, and doing no harm to patients," said Daniel Wolfson, executive vice president and chief operating officer of the American Board of Internal Medicine (ABIM) Foundation, which is leading the Choosing Wisely campaign.

Medical societies in various disciplines have released recommendations geared toward individual clinical disciplines, and now it’s ASTRO’s turn, said Dr. Michael L. Steinberg, chairman of ASTRO’s board of directors, in a briefing announcing the guidelines. "The list serves only as a starting point for a detailed conversation between a patient and physician, and to ensure patient-centered care, which is a core principle of ASTRO."

The five recommendations are:

• Don’t initiate whole-breast radiotherapy as a part of breast conservation therapy in women aged 50 years and older with early-stage invasive breast cancer without considering shorter treatment schedules.

"We’ve known for years that whole-breast radiation improves local control and improves survival, and has cosmetic advantages over mastectomy," Dr. Steinberg said. In recent years, however, randomized clinical trials have demonstrated that shorter courses of therapy – less than 4 weeks, compared with 5 weeks for conventionally fractionated radiation – produce equivalent tumor control and cosmetic outcomes.

• Don’t initiate management of patients who have low-risk prostate cancer without discussing active surveillance.

Patients with low-risk prostate cancer should discuss "reasonable management options" with their physicians, including active surveillance. With this recommendation, ASTRO is "reinforcing the shared decision-making model," Dr. Steinberg said.

• Don’t routinely use extended fractionation schemes (more than 10 fractions) for palliation of bone metastases.

Patients with bone metastases may derive equivalent pain relief from 30 Gy in 10 fractions, 20 Gy over 5 fractions, or even a single 8-Gy fraction, studies suggest. The single-fraction option is more convenient for patients, but it may be associated with a marginally higher need for retreatment of the same site. Patients who are not ambulatory, have transportation problems, or a limited prognosis may be good candidates for the single-fraction option, the guidelines say.

• Don’t routinely recommend proton-beam therapy for prostate cancer outside of a prospective clinical trial or registry.

"There is no clear evidence that proton-beam therapy for prostate cancer offers any clinical advantage over other forms of definitive radiation therapy. Clinical trials are necessary to establish a possible advantage of this expensive therapy," the Choosing Wisely guidelines state.

At ASTRO 2012, investigators reported that 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. In addition, proton-beam therapy is estimated to cost about 70% more than external-beam radiotherapy for the treatment of prostate cancer.

• Don’t routinely use intensity-modulated radiation therapy (IMRT) to deliver whole-breast radiotherapy as part of breast conservation therapy.

"Clinical trials have suggested lower rates of skin toxicity after using modern 3D conformal techniques relative to older methods of 2D planning. In these trials, the term ‘IMRT’ has generally been applied to describe methods that are more accurately defined as field-in-field 3D conformal radiotherapy. While IMRT may be of benefit in select cases where the anatomy is unusual, its routine use has not been demonstrated to provide significant clinical advantage," the guidelines note.

The cost difference between 3D conformal radiotherapy and IMRT for whole-breast radiotherapy is approximately $7,000, according to Dr. Steinberg.

"These are not ‘never do this’ recommendations, these are ‘engage the patient in the shared-decision paradigm’ guidelines, because there may be patients that are better treated with, let’s say, IMRT [for whole-breast radiotherapy]," he said.

Asked whether the Choosing Wisely guidelines in radiation oncology and other disciplines might be used by insurers to justify denying reimbursement for certain procedures, Mr. Wolfson said that "we haven’t seen that, and whether it comes to be will be the question, but we would sharply criticize that [approach]."

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Hypermethylation in novel DNA biomarkers for prostate cancer predicted the cancer’s return after radical prostatectomy, according to a study published online Aug. 5 in the Journal of Clinical Oncology.

"To the best of our knowledge, this is the first report of a validated prognostic multigene methylation signature for [prostate cancer]," said Christa Haldrup, Ph.D., of Aarhus (Denmark) University Hospital and her colleagues (J. Clin. Oncol. 2013 Aug. 5 [doi: 10.1200/JCO.2012.47.1847]).

The study investigators identified six DNA methylation markers – hypermethylation of AOX1, C1orf114, GAS6, HAPLN3, KLF8, and MOB3B – as highly cancer specific. One of the potential markers, C1orf114 hypermethylation, and a methylation signature including the three genes AOX1, C1orf114, and HAPLN3 were independent predictors of time to biochemical recurrence after radical prostatectomy.

The researchers identified the markers using microarray-based screening and bisulfate sequencing of 20 nonmalignant tissue specimens and 29 prostate cancer (PC) tissue specimens. They then evaluated the markers’ diagnostic potential in a training cohort of 293 radical prostatectomy (RP) samples and a validation cohort of 114 RP samples.

High methylation of C1orf114 was significantly associated with biochemical recurrence of disease, according to multivariate analysis of the training cohort (hazard ratio, 3.10). This finding was confirmed in the validation cohort (HR, 3.27).

Similarly, a two-gene prognostic methylation signature (C1orf114 and HAPLN3) and the three-gene prognostic methylation signature also were significantly associated with biochemical recurrence in the training and validation cohorts.

When researchers analyzed the three-gene signature in high- and low-methylation subgroups, hypermethylation was significantly associated with recurrence in the training cohort (HR, 1.91) and validation cohort (HR, 2.33), the investigators said.

The two- and three-gene signatures performed markedly better as recurrence predictors than C10rf114 alone, and the three-gene signature performed slightly better than the two-gene signature, "suggesting that incorporation of a few genes into a simple dichotomized methylation-based test can improve robustness compared with a single-marker test," the investigators said.

"Three years after surgery, 52% and 41% of patients in the high-methylation group had experienced biochemical recurrence, compared with only 19% and 14% of patients in the low-methylation group in cohorts 1 and 2, respectively," they said.

Tissue samples for the study were collected in Denmark, Switzerland, Germany, and Finland. The training cohort consisted of "consecutive curatively intended RP of histologically verified, clinically localized PC" collected between 1993 and 2005 and previously used for tissue microarray construction. The validation cohort consisted of such samples collected from 1992 to 2003.

The six candidate genes were the most promising of eight that were initially selected for validation.

"Gene selection was based on difference in methylation levels between ADJ-N [adjacent normal] and PC samples, fold change in methylation levels between ADJ-N and PC samples, and, when possible, the presence of more than one CpG site indicating cancer-associated hypermethylation," the investigators wrote. "We preferably included genes not previously investigated in relation to PC."

For all candidate biomarkers, RP samples were significantly hypermethylated, compared with nonmalignant samples, they said.

"C1orf114 methylation as a continuous variable, and models based on dichotomized C1orf114, HAPLN3, and AOX1 methylation had significant independent prognostic value for prediction of biochemical recurrence in two RP patient cohorts from four different countries," the study authors said.

"The novel candidate methylation biomarkers were highly cancer specific" and were at level with or exceeded the known candidate PC methylation marker GSTP1 in this sample set, they added.

"The precise clinical utility of these new candidate methylation markers for PC diagnosis should be further investigated in studies including prostate biopsy, urine, or blood samples," the investigators said.

Future studies also should evaluate the prognostic potential of the markers in diagnostic biopsies. "Because only preoperative clinicopathologic parameters are available at this time, molecular markers may contribute relatively more independent prognostic information than after RP and, importantly, could be used to guide treatment decisions," the investigators said.

The Lundbeck Foundation, the John and Birthe Meyer Foundation, the Danish Cancer Society, and the Danish Council for Strategic Research supported the study. The authors reported having no disclosures.

Metformin appears to have slowed, or perhaps even halted, the progression of prostate cancer in a retrospective, Canadian study of 3,837 diabetic men.

The study was published in the Journal of Clinical Oncology.

The longer the men were on the drug, the better they did; for each additional 6 months of treatment following diagnosis, prostate cancer mortality dropped 24% (adjusted hazard ratio 0.76). There was a 24% reduction in all-cause mortality in the first 6 months, as well (aHR, 0.76), but the association faded with time; 24-30 months out from diagnosis, metformin was associated with an all-cause mortality reduction of 7% (aHR, 0.93).

Although some of the men used other diabetes drugs such as sulfonylureas, thiazolidinediones, and insulin some of the time, only metformin improved prostate cancer outcomes, regardless of concomitant cancer treatments.

"We cannot conclude" that a nondiabetic population would see similar benefits, but the results "suggest that metformin may ... improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments. We believe an interventional study of the use of metformin to delay progression in prostate cancer is warranted," wrote Dr. David Margel, a uro-oncology fellow at the University of Toronto when the study was conducted, and now a urologist at the Rabin Medical Center in Petah-Tikva, Israel (J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2012.46.7043]).

Dr. Margel and his team are not the first to suggest that the ubiquitous diabetes drug might also be a potent cancer fighter. Metformin is being tested in dozens of trials not only for prostate tumors, but also for breast, brain, lung, uterine, colorectal, pancreatic, skin, blood, and thyroid cancers.

It probably doesn’t stop benign cells from turning cancerous, but may "influence cancer cells indirectly by decreasing insulin levels or directly by influencing cancer cell proliferation and apoptosis," the investigators wrote.

Study data came from health care databases kept by the province of Ontario, including the Ontario Cancer Registry and Ontario Diabetes Database.

The men were a median of 75 years old at diagnosis, and followed for a median of 4.64 years. About a quarter (976) presented with high-grade tumors, and almost 60% (2,167) with high-volume tumors. Thirty-five percent (1,343) died during the study period; prostate cancer was responsible for 7.6% (291) of the deaths.

"Overall, 1,251 (32.6%) and 1,619 (42.2%) were exposed to metformin before and after [prostate cancer] diagnosis, respectively. Patients were exposed to metformin for a median of 19 months before diagnosis and 8.9 months after diagnosis," Dr. Margel and his team noted.

The Ontario Ministry of Health and Long-Term Care funded the project. The authors have no conflicts of interest.

aotto@frontlinemedcom.com

Metformin appears to have slowed, or perhaps even halted, the progression of prostate cancer in a retrospective, Canadian study of 3,837 diabetic men.

The study was published in the Journal of Clinical Oncology.

The longer the men were on the drug, the better they did; for each additional 6 months of treatment following diagnosis, prostate cancer mortality dropped 24% (adjusted hazard ratio 0.76). There was a 24% reduction in all-cause mortality in the first 6 months, as well (aHR, 0.76), but the association faded with time; 24-30 months out from diagnosis, metformin was associated with an all-cause mortality reduction of 7% (aHR, 0.93).

Although some of the men used other diabetes drugs such as sulfonylureas, thiazolidinediones, and insulin some of the time, only metformin improved prostate cancer outcomes, regardless of concomitant cancer treatments.

"We cannot conclude" that a nondiabetic population would see similar benefits, but the results "suggest that metformin may ... improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments. We believe an interventional study of the use of metformin to delay progression in prostate cancer is warranted," wrote Dr. David Margel, a uro-oncology fellow at the University of Toronto when the study was conducted, and now a urologist at the Rabin Medical Center in Petah-Tikva, Israel (J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2012.46.7043]).

Dr. Margel and his team are not the first to suggest that the ubiquitous diabetes drug might also be a potent cancer fighter. Metformin is being tested in dozens of trials not only for prostate tumors, but also for breast, brain, lung, uterine, colorectal, pancreatic, skin, blood, and thyroid cancers.

It probably doesn’t stop benign cells from turning cancerous, but may "influence cancer cells indirectly by decreasing insulin levels or directly by influencing cancer cell proliferation and apoptosis," the investigators wrote.

Study data came from health care databases kept by the province of Ontario, including the Ontario Cancer Registry and Ontario Diabetes Database.

The men were a median of 75 years old at diagnosis, and followed for a median of 4.64 years. About a quarter (976) presented with high-grade tumors, and almost 60% (2,167) with high-volume tumors. Thirty-five percent (1,343) died during the study period; prostate cancer was responsible for 7.6% (291) of the deaths.

"Overall, 1,251 (32.6%) and 1,619 (42.2%) were exposed to metformin before and after [prostate cancer] diagnosis, respectively. Patients were exposed to metformin for a median of 19 months before diagnosis and 8.9 months after diagnosis," Dr. Margel and his team noted.

The Ontario Ministry of Health and Long-Term Care funded the project. The authors have no conflicts of interest.

aotto@frontlinemedcom.com

Metformin appears to have slowed, or perhaps even halted, the progression of prostate cancer in a retrospective, Canadian study of 3,837 diabetic men.

The study was published in the Journal of Clinical Oncology.

The longer the men were on the drug, the better they did; for each additional 6 months of treatment following diagnosis, prostate cancer mortality dropped 24% (adjusted hazard ratio 0.76). There was a 24% reduction in all-cause mortality in the first 6 months, as well (aHR, 0.76), but the association faded with time; 24-30 months out from diagnosis, metformin was associated with an all-cause mortality reduction of 7% (aHR, 0.93).

Although some of the men used other diabetes drugs such as sulfonylureas, thiazolidinediones, and insulin some of the time, only metformin improved prostate cancer outcomes, regardless of concomitant cancer treatments.

"We cannot conclude" that a nondiabetic population would see similar benefits, but the results "suggest that metformin may ... improve survival as an adjunct therapy, even among those already receiving optimal cancer treatments. We believe an interventional study of the use of metformin to delay progression in prostate cancer is warranted," wrote Dr. David Margel, a uro-oncology fellow at the University of Toronto when the study was conducted, and now a urologist at the Rabin Medical Center in Petah-Tikva, Israel (J. Clin. Oncol. 2013 Aug 5 [doi: 10.1200/JCO.2012.46.7043]).

Dr. Margel and his team are not the first to suggest that the ubiquitous diabetes drug might also be a potent cancer fighter. Metformin is being tested in dozens of trials not only for prostate tumors, but also for breast, brain, lung, uterine, colorectal, pancreatic, skin, blood, and thyroid cancers.

It probably doesn’t stop benign cells from turning cancerous, but may "influence cancer cells indirectly by decreasing insulin levels or directly by influencing cancer cell proliferation and apoptosis," the investigators wrote.

Study data came from health care databases kept by the province of Ontario, including the Ontario Cancer Registry and Ontario Diabetes Database.

The men were a median of 75 years old at diagnosis, and followed for a median of 4.64 years. About a quarter (976) presented with high-grade tumors, and almost 60% (2,167) with high-volume tumors. Thirty-five percent (1,343) died during the study period; prostate cancer was responsible for 7.6% (291) of the deaths.

"Overall, 1,251 (32.6%) and 1,619 (42.2%) were exposed to metformin before and after [prostate cancer] diagnosis, respectively. Patients were exposed to metformin for a median of 19 months before diagnosis and 8.9 months after diagnosis," Dr. Margel and his team noted.

The Ontario Ministry of Health and Long-Term Care funded the project. The authors have no conflicts of interest.

aotto@frontlinemedcom.com

Patients with metastatic clear cell renal cell carcinoma treated with first-line pazopanib used fewer medical resources than did those receiving sunitinib, according to new details from the phase III COMPARZ trial.

Over the first 6 months of treatment, patients on pazopanib (Votrient) had significantly fewer emergency department visits (cumulative mean, 0.037 vs. 0.067; P = .003) and monthly telephone consultations (mean, 0.279 vs. 0.312; P = .04) than did those receiving first-line sunitinib (Sutent).

Pazopanib patients also had a nonsignificant trend toward fewer days in hospital (mean, 0.402 vs. 0.562; P = .10) and non–study-related medical visits (0.726 vs. 0.779; P = .07), according to the full results of COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) published today in the New England Journal of Medicine (2013, Aug. 22;369:722-31).

"Our study showed lower monthly use of medical resources with pazopanib then with sunitinib," wrote lead author Dr. Robert J. Motzer of Memorial Sloan-Kettering Cancer Center in New York. "These endpoints, plus health-related quality of life and the safety profile, assume special importance in comparative-effectiveness research when clinically similar (noninferior) treatments are being considered."

Data presented by Dr. Motzer at the 2012 European Society for Medical Oncology (ESMO) Congress and reported by The Oncology Report show a median progression-free survival of 8.4 months with pazopanib and 9.5 months with sunitinib. Median overall survival also was similar at 28.4 months vs. 29.3 months, respectively.

Where pazopanib appeared to have the advantage was in the secondary endpoints of safety and quality of life. Patients treated with sunitinib had significantly more fatigue (63% vs. 55%), hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%), while those given pazopanib had a higher incidence of elevated alanine aminotransferase (60% vs. 43%), weight loss (15% vs. 6%), and changes in hair color (30% vs. 10%). The authors noted that fatigue, gastrointestinal events, hand-foot syndrome, and liver toxicity have been highlighted as "adverse events of particular concern to patients."

The article expands on the quality-of-life analyses, but the bottom line is that significant differences favored pazopanib over sunitinib for 11 of 14 comparisons. Two other studies, including the PISCES trial also reported at ESMO 2012, support the health-related quality of life results.

"Many oncologists, including the group at MSKCC, have switched their preferred first-line drug from sunitinib to pazopanib," Dr. Motzer said in an interview.

The renal cancer treatment field is crowded, with competitors, however, including sorafenib (Nexavar), bevacizumab (Avastin), temsirolimus (Torisel), and more recently, tivozanib. The hepatotoxicity associated with pazopanib may also deter some clinicians from making the switch.

As for whom sunitinib remains the best option for first-line therapy, Dr. Motzer said, "Sunitinib could be considered the preferred treatment, in my opinion, in patients with underlying liver dysfunction, and in non–clear cell subtypes of kidney cancer."

Officials at GlaxoSmithKline would not comment on the impact of the COMPARZ trial on pazopanib’s market share, noting that they are not marketing against it or using the data in the pazopanib label. Still, U.S. sales figures show pazopanib sales have increased steadily over the last year, doubling from $25 million in the first quarter of 2012 to $51 million for the same period in 2013. Sales in the second quarter of 2013 hit $56 million, according to Bernadette King, director of GSK’s U.S. external communications for oncology.

Earlier this month, GSK filed with the European Medicines Agency for an additional indication for pazopanib as maintenance treatment for advanced stage II-IV ovarian, fallopian tube, or primary peritoneal cancer. Phase III data reported earlier this year show pazopanib maintenance therapy extends progression-free survival by an average of 5.6 months, compared with placebo.

Pazopanib already is recommended by the National Institute for Health and Clinical Excellence (NICE) as first-line treatment for patients in the U.K. with advanced kidney cancer, after GSK officials agreed to a 12.5% discount on the list price and a possible second rebate following the outcome of COMPARZ.

GSK officials are in discussion with U.K. officials on that second "risk-sharing" agreement now that the COMPARZ data are published, but no details are available, Ms. King said.

She noted that the negotiations will not affect the price of pazopanib in the United States, but that GSK offers a range of patient assistance programs for eligible patients in the U.S. The average wholesale acquisition cost for a 30-day supply of pazopanib at the 800-mg dose used in COMPARZ is $7,163. A total of 1,110 patients were randomized to a continuous dose of pazopanib 800 mg once daily or sunitinib 50 mg once daily for 4 weeks, followed by a 2-week drug holiday.

GlaxoSmithKline Pharmaceuticals sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib.

pwendling@frontlinemedcom.com

Patients with metastatic clear cell renal cell carcinoma treated with first-line pazopanib used fewer medical resources than did those receiving sunitinib, according to new details from the phase III COMPARZ trial.

Over the first 6 months of treatment, patients on pazopanib (Votrient) had significantly fewer emergency department visits (cumulative mean, 0.037 vs. 0.067; P = .003) and monthly telephone consultations (mean, 0.279 vs. 0.312; P = .04) than did those receiving first-line sunitinib (Sutent).

Pazopanib patients also had a nonsignificant trend toward fewer days in hospital (mean, 0.402 vs. 0.562; P = .10) and non–study-related medical visits (0.726 vs. 0.779; P = .07), according to the full results of COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) published today in the New England Journal of Medicine (2013, Aug. 22;369:722-31).

"Our study showed lower monthly use of medical resources with pazopanib then with sunitinib," wrote lead author Dr. Robert J. Motzer of Memorial Sloan-Kettering Cancer Center in New York. "These endpoints, plus health-related quality of life and the safety profile, assume special importance in comparative-effectiveness research when clinically similar (noninferior) treatments are being considered."

Data presented by Dr. Motzer at the 2012 European Society for Medical Oncology (ESMO) Congress and reported by The Oncology Report show a median progression-free survival of 8.4 months with pazopanib and 9.5 months with sunitinib. Median overall survival also was similar at 28.4 months vs. 29.3 months, respectively.

Where pazopanib appeared to have the advantage was in the secondary endpoints of safety and quality of life. Patients treated with sunitinib had significantly more fatigue (63% vs. 55%), hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%), while those given pazopanib had a higher incidence of elevated alanine aminotransferase (60% vs. 43%), weight loss (15% vs. 6%), and changes in hair color (30% vs. 10%). The authors noted that fatigue, gastrointestinal events, hand-foot syndrome, and liver toxicity have been highlighted as "adverse events of particular concern to patients."

The article expands on the quality-of-life analyses, but the bottom line is that significant differences favored pazopanib over sunitinib for 11 of 14 comparisons. Two other studies, including the PISCES trial also reported at ESMO 2012, support the health-related quality of life results.

"Many oncologists, including the group at MSKCC, have switched their preferred first-line drug from sunitinib to pazopanib," Dr. Motzer said in an interview.

The renal cancer treatment field is crowded, with competitors, however, including sorafenib (Nexavar), bevacizumab (Avastin), temsirolimus (Torisel), and more recently, tivozanib. The hepatotoxicity associated with pazopanib may also deter some clinicians from making the switch.

As for whom sunitinib remains the best option for first-line therapy, Dr. Motzer said, "Sunitinib could be considered the preferred treatment, in my opinion, in patients with underlying liver dysfunction, and in non–clear cell subtypes of kidney cancer."

Officials at GlaxoSmithKline would not comment on the impact of the COMPARZ trial on pazopanib’s market share, noting that they are not marketing against it or using the data in the pazopanib label. Still, U.S. sales figures show pazopanib sales have increased steadily over the last year, doubling from $25 million in the first quarter of 2012 to $51 million for the same period in 2013. Sales in the second quarter of 2013 hit $56 million, according to Bernadette King, director of GSK’s U.S. external communications for oncology.

Earlier this month, GSK filed with the European Medicines Agency for an additional indication for pazopanib as maintenance treatment for advanced stage II-IV ovarian, fallopian tube, or primary peritoneal cancer. Phase III data reported earlier this year show pazopanib maintenance therapy extends progression-free survival by an average of 5.6 months, compared with placebo.

Pazopanib already is recommended by the National Institute for Health and Clinical Excellence (NICE) as first-line treatment for patients in the U.K. with advanced kidney cancer, after GSK officials agreed to a 12.5% discount on the list price and a possible second rebate following the outcome of COMPARZ.

GSK officials are in discussion with U.K. officials on that second "risk-sharing" agreement now that the COMPARZ data are published, but no details are available, Ms. King said.

She noted that the negotiations will not affect the price of pazopanib in the United States, but that GSK offers a range of patient assistance programs for eligible patients in the U.S. The average wholesale acquisition cost for a 30-day supply of pazopanib at the 800-mg dose used in COMPARZ is $7,163. A total of 1,110 patients were randomized to a continuous dose of pazopanib 800 mg once daily or sunitinib 50 mg once daily for 4 weeks, followed by a 2-week drug holiday.

GlaxoSmithKline Pharmaceuticals sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib.

pwendling@frontlinemedcom.com

Patients with metastatic clear cell renal cell carcinoma treated with first-line pazopanib used fewer medical resources than did those receiving sunitinib, according to new details from the phase III COMPARZ trial.

Over the first 6 months of treatment, patients on pazopanib (Votrient) had significantly fewer emergency department visits (cumulative mean, 0.037 vs. 0.067; P = .003) and monthly telephone consultations (mean, 0.279 vs. 0.312; P = .04) than did those receiving first-line sunitinib (Sutent).

Pazopanib patients also had a nonsignificant trend toward fewer days in hospital (mean, 0.402 vs. 0.562; P = .10) and non–study-related medical visits (0.726 vs. 0.779; P = .07), according to the full results of COMPARZ (Comparing the Efficacy, Safety and Tolerability of Pazopanib vs. Sunitinib) published today in the New England Journal of Medicine (2013, Aug. 22;369:722-31).

"Our study showed lower monthly use of medical resources with pazopanib then with sunitinib," wrote lead author Dr. Robert J. Motzer of Memorial Sloan-Kettering Cancer Center in New York. "These endpoints, plus health-related quality of life and the safety profile, assume special importance in comparative-effectiveness research when clinically similar (noninferior) treatments are being considered."

Data presented by Dr. Motzer at the 2012 European Society for Medical Oncology (ESMO) Congress and reported by The Oncology Report show a median progression-free survival of 8.4 months with pazopanib and 9.5 months with sunitinib. Median overall survival also was similar at 28.4 months vs. 29.3 months, respectively.

Where pazopanib appeared to have the advantage was in the secondary endpoints of safety and quality of life. Patients treated with sunitinib had significantly more fatigue (63% vs. 55%), hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%), while those given pazopanib had a higher incidence of elevated alanine aminotransferase (60% vs. 43%), weight loss (15% vs. 6%), and changes in hair color (30% vs. 10%). The authors noted that fatigue, gastrointestinal events, hand-foot syndrome, and liver toxicity have been highlighted as "adverse events of particular concern to patients."

The article expands on the quality-of-life analyses, but the bottom line is that significant differences favored pazopanib over sunitinib for 11 of 14 comparisons. Two other studies, including the PISCES trial also reported at ESMO 2012, support the health-related quality of life results.

"Many oncologists, including the group at MSKCC, have switched their preferred first-line drug from sunitinib to pazopanib," Dr. Motzer said in an interview.

The renal cancer treatment field is crowded, with competitors, however, including sorafenib (Nexavar), bevacizumab (Avastin), temsirolimus (Torisel), and more recently, tivozanib. The hepatotoxicity associated with pazopanib may also deter some clinicians from making the switch.

As for whom sunitinib remains the best option for first-line therapy, Dr. Motzer said, "Sunitinib could be considered the preferred treatment, in my opinion, in patients with underlying liver dysfunction, and in non–clear cell subtypes of kidney cancer."

Officials at GlaxoSmithKline would not comment on the impact of the COMPARZ trial on pazopanib’s market share, noting that they are not marketing against it or using the data in the pazopanib label. Still, U.S. sales figures show pazopanib sales have increased steadily over the last year, doubling from $25 million in the first quarter of 2012 to $51 million for the same period in 2013. Sales in the second quarter of 2013 hit $56 million, according to Bernadette King, director of GSK’s U.S. external communications for oncology.

Earlier this month, GSK filed with the European Medicines Agency for an additional indication for pazopanib as maintenance treatment for advanced stage II-IV ovarian, fallopian tube, or primary peritoneal cancer. Phase III data reported earlier this year show pazopanib maintenance therapy extends progression-free survival by an average of 5.6 months, compared with placebo.

Pazopanib already is recommended by the National Institute for Health and Clinical Excellence (NICE) as first-line treatment for patients in the U.K. with advanced kidney cancer, after GSK officials agreed to a 12.5% discount on the list price and a possible second rebate following the outcome of COMPARZ.

GSK officials are in discussion with U.K. officials on that second "risk-sharing" agreement now that the COMPARZ data are published, but no details are available, Ms. King said.

She noted that the negotiations will not affect the price of pazopanib in the United States, but that GSK offers a range of patient assistance programs for eligible patients in the U.S. The average wholesale acquisition cost for a 30-day supply of pazopanib at the 800-mg dose used in COMPARZ is $7,163. A total of 1,110 patients were randomized to a continuous dose of pazopanib 800 mg once daily or sunitinib 50 mg once daily for 4 weeks, followed by a 2-week drug holiday.

GlaxoSmithKline Pharmaceuticals sponsored the trial. Dr. Motzer and his coauthors report financial relationships with several firms, including Pfizer and GSK, the manufacturer of pazopanib.

pwendling@frontlinemedcom.com

Men who took finasteride to prevent prostate cancer as part of a randomized clinical trial that ended in 2003 had the same long-term mortality as did those who took placebo, according to a report published online Aug. 14 in the New England Journal of Medicine.

The 15-year survival was approximately 78% in both groups, said Dr. Ian M. Thompson Jr. of the Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, and his associates.

"The use of finasteride over a period of 7 years in a general population of men with a median age at study entry of 63.2 years reduced the risk of prostate cancer but did not significantly affect mortality. This reduction in risk was due entirely to a relative reduction of 43% in the risk of low-grade cancer among men receiving finasteride, as compared with placebo," the researchers wrote

The original randomized controlled study, the Prostate Cancer Prevention Trial, enrolled 18,882 men in 1994-1997 and followed them regularly for the development of the disease. Approximately half were randomly assigned to take the 5-alpha-reductase inhibitor finasteride and half to take placebo for 7 years. Data collection and prostate-cancer assessments continued for up to 10 years for most of the study participants.

In the initial analysis of the data in 2004, finasteride had reduced the relative risk of prostate cancer by 24.8%. However, it also appeared to raise the relative risk of high-grade tumors by 26.9%.

In 2011, the Food & Drug Administration mandated labeling changes for all 5-alpha-reductase inhibitors, stating that the drugs are not approved for use as preventives and they may raise the risk of high-grade prostate cancers.

Finasteride likely reduced prostate-specific antigen (PSA) levels in men who had benign enlargement of the prostate, causing the prostate to shrink. This is probably the reason why the drug improved the sensitivity of PSA testing, prostate biopsy, and digital rectal examination for the detection of high-grade disease, Dr. Thompson and his colleagues said.

"Despite multiple analyses suggesting that [such] detection bias accounted, at least in part, for the observed increase in the rate of high-grade tumors in the finasteride group, concern regarding this potential risk has all but eliminated the use of finasteride for prostate-cancer prevention," they noted.

Dr. Thompson and his associates reasoned that if the increase in high-grade prostate cancers wasn’t just an artifact of detection but in fact reflected finasteride-induced tumors "some increase in mortality among men receiving finasteride should become obvious during long-term follow-up." They therefore performed a post hoc analysis of long-term survival in the study population "to seek any evidence of an increased risk of death among men in the finasteride group, since such an increase would be a potentially accurate indicator of an increase in the risk of high-grade (and hence more lethal) cancer."

Long-term follow-up was hampered by the fact that many of the study centers closed, and direct contact with many participants was lost. The Social Security Death Index was used to assess the subjects’ survival status through 2011. The cause of death was not available for most of the men, so prostate-cancer-specific mortality could not be assessed. In addition, "since the total number of high-grade cancers was small and there were only a total of 177 deaths in this subgroup, there was not enough information to formally test noninferiority," the researchers said.

Nevertheless, they found that prostate cancer developed in 10.5% of the finasteride group and 14.9% of the placebo group, confirming that finasteride significantly reduced the risk of the disease.

A total of 3.5% of the tumors in the finasteride group and 3% in the placebo group were high-grade cancers.

Fifteen-year survival was 78% with finasteride and 78.2% with placebo, a nonsignificant difference. The median age at which prostate cancer was diagnosed also was the same in both groups: 70 years, the researchers said (N. Engl. J. Med. 2013 Aug. 14;369:603-10).

"Although the prevention of these tumors did not appear to reduce overall mortality, increased diagnosis of low-grade prostate cancer is a problematic byproduct of PSA testing, in that treatment adds little, if any, benefit and in that all forms of therapy cause considerable burden to the patient and to society," they concluded.

This study was funded by the National Cancer Institute. Merck provided the finasteride and placebo for the PCPT but wasn\'t involved in the design, oversight, data analysis, or decision to publish that trial. Dr. Thompson reported ties to Ferring and is listed as an inventor on 2 patent applications concerning prostate cancer and erectile dysfunction. One of his associates reported being a consultant for Amgen and Eli Lilly.

Men who took finasteride to prevent prostate cancer as part of a randomized clinical trial that ended in 2003 had the same long-term mortality as did those who took placebo, according to a report published online Aug. 14 in the New England Journal of Medicine.

The 15-year survival was approximately 78% in both groups, said Dr. Ian M. Thompson Jr. of the Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, and his associates.

"The use of finasteride over a period of 7 years in a general population of men with a median age at study entry of 63.2 years reduced the risk of prostate cancer but did not significantly affect mortality. This reduction in risk was due entirely to a relative reduction of 43% in the risk of low-grade cancer among men receiving finasteride, as compared with placebo," the researchers wrote

The original randomized controlled study, the Prostate Cancer Prevention Trial, enrolled 18,882 men in 1994-1997 and followed them regularly for the development of the disease. Approximately half were randomly assigned to take the 5-alpha-reductase inhibitor finasteride and half to take placebo for 7 years. Data collection and prostate-cancer assessments continued for up to 10 years for most of the study participants.

In the initial analysis of the data in 2004, finasteride had reduced the relative risk of prostate cancer by 24.8%. However, it also appeared to raise the relative risk of high-grade tumors by 26.9%.

In 2011, the Food & Drug Administration mandated labeling changes for all 5-alpha-reductase inhibitors, stating that the drugs are not approved for use as preventives and they may raise the risk of high-grade prostate cancers.

Finasteride likely reduced prostate-specific antigen (PSA) levels in men who had benign enlargement of the prostate, causing the prostate to shrink. This is probably the reason why the drug improved the sensitivity of PSA testing, prostate biopsy, and digital rectal examination for the detection of high-grade disease, Dr. Thompson and his colleagues said.

"Despite multiple analyses suggesting that [such] detection bias accounted, at least in part, for the observed increase in the rate of high-grade tumors in the finasteride group, concern regarding this potential risk has all but eliminated the use of finasteride for prostate-cancer prevention," they noted.

Dr. Thompson and his associates reasoned that if the increase in high-grade prostate cancers wasn’t just an artifact of detection but in fact reflected finasteride-induced tumors "some increase in mortality among men receiving finasteride should become obvious during long-term follow-up." They therefore performed a post hoc analysis of long-term survival in the study population "to seek any evidence of an increased risk of death among men in the finasteride group, since such an increase would be a potentially accurate indicator of an increase in the risk of high-grade (and hence more lethal) cancer."

Long-term follow-up was hampered by the fact that many of the study centers closed, and direct contact with many participants was lost. The Social Security Death Index was used to assess the subjects’ survival status through 2011. The cause of death was not available for most of the men, so prostate-cancer-specific mortality could not be assessed. In addition, "since the total number of high-grade cancers was small and there were only a total of 177 deaths in this subgroup, there was not enough information to formally test noninferiority," the researchers said.

Nevertheless, they found that prostate cancer developed in 10.5% of the finasteride group and 14.9% of the placebo group, confirming that finasteride significantly reduced the risk of the disease.

A total of 3.5% of the tumors in the finasteride group and 3% in the placebo group were high-grade cancers.

Fifteen-year survival was 78% with finasteride and 78.2% with placebo, a nonsignificant difference. The median age at which prostate cancer was diagnosed also was the same in both groups: 70 years, the researchers said (N. Engl. J. Med. 2013 Aug. 14;369:603-10).

"Although the prevention of these tumors did not appear to reduce overall mortality, increased diagnosis of low-grade prostate cancer is a problematic byproduct of PSA testing, in that treatment adds little, if any, benefit and in that all forms of therapy cause considerable burden to the patient and to society," they concluded.

This study was funded by the National Cancer Institute. Merck provided the finasteride and placebo for the PCPT but wasn\'t involved in the design, oversight, data analysis, or decision to publish that trial. Dr. Thompson reported ties to Ferring and is listed as an inventor on 2 patent applications concerning prostate cancer and erectile dysfunction. One of his associates reported being a consultant for Amgen and Eli Lilly.

Men who took finasteride to prevent prostate cancer as part of a randomized clinical trial that ended in 2003 had the same long-term mortality as did those who took placebo, according to a report published online Aug. 14 in the New England Journal of Medicine.

The 15-year survival was approximately 78% in both groups, said Dr. Ian M. Thompson Jr. of the Cancer Research and Therapy Center, University of Texas Health Science Center at San Antonio, and his associates.

"The use of finasteride over a period of 7 years in a general population of men with a median age at study entry of 63.2 years reduced the risk of prostate cancer but did not significantly affect mortality. This reduction in risk was due entirely to a relative reduction of 43% in the risk of low-grade cancer among men receiving finasteride, as compared with placebo," the researchers wrote

The original randomized controlled study, the Prostate Cancer Prevention Trial, enrolled 18,882 men in 1994-1997 and followed them regularly for the development of the disease. Approximately half were randomly assigned to take the 5-alpha-reductase inhibitor finasteride and half to take placebo for 7 years. Data collection and prostate-cancer assessments continued for up to 10 years for most of the study participants.

In the initial analysis of the data in 2004, finasteride had reduced the relative risk of prostate cancer by 24.8%. However, it also appeared to raise the relative risk of high-grade tumors by 26.9%.

In 2011, the Food & Drug Administration mandated labeling changes for all 5-alpha-reductase inhibitors, stating that the drugs are not approved for use as preventives and they may raise the risk of high-grade prostate cancers.

Finasteride likely reduced prostate-specific antigen (PSA) levels in men who had benign enlargement of the prostate, causing the prostate to shrink. This is probably the reason why the drug improved the sensitivity of PSA testing, prostate biopsy, and digital rectal examination for the detection of high-grade disease, Dr. Thompson and his colleagues said.

"Despite multiple analyses suggesting that [such] detection bias accounted, at least in part, for the observed increase in the rate of high-grade tumors in the finasteride group, concern regarding this potential risk has all but eliminated the use of finasteride for prostate-cancer prevention," they noted.

Dr. Thompson and his associates reasoned that if the increase in high-grade prostate cancers wasn’t just an artifact of detection but in fact reflected finasteride-induced tumors "some increase in mortality among men receiving finasteride should become obvious during long-term follow-up." They therefore performed a post hoc analysis of long-term survival in the study population "to seek any evidence of an increased risk of death among men in the finasteride group, since such an increase would be a potentially accurate indicator of an increase in the risk of high-grade (and hence more lethal) cancer."

Long-term follow-up was hampered by the fact that many of the study centers closed, and direct contact with many participants was lost. The Social Security Death Index was used to assess the subjects’ survival status through 2011. The cause of death was not available for most of the men, so prostate-cancer-specific mortality could not be assessed. In addition, "since the total number of high-grade cancers was small and there were only a total of 177 deaths in this subgroup, there was not enough information to formally test noninferiority," the researchers said.

Nevertheless, they found that prostate cancer developed in 10.5% of the finasteride group and 14.9% of the placebo group, confirming that finasteride significantly reduced the risk of the disease.

A total of 3.5% of the tumors in the finasteride group and 3% in the placebo group were high-grade cancers.

Fifteen-year survival was 78% with finasteride and 78.2% with placebo, a nonsignificant difference. The median age at which prostate cancer was diagnosed also was the same in both groups: 70 years, the researchers said (N. Engl. J. Med. 2013 Aug. 14;369:603-10).

"Although the prevention of these tumors did not appear to reduce overall mortality, increased diagnosis of low-grade prostate cancer is a problematic byproduct of PSA testing, in that treatment adds little, if any, benefit and in that all forms of therapy cause considerable burden to the patient and to society," they concluded.

This study was funded by the National Cancer Institute. Merck provided the finasteride and placebo for the PCPT but wasn\'t involved in the design, oversight, data analysis, or decision to publish that trial. Dr. Thompson reported ties to Ferring and is listed as an inventor on 2 patent applications concerning prostate cancer and erectile dysfunction. One of his associates reported being a consultant for Amgen and Eli Lilly.

The proportion of advanced prostate cancers has declined by more than sixfold over the last 2 decades; however, the proportion of high Gleason grade tumors has not followed suit.

The findings from a 22-year review of two large databases suggest that most low-grade prostate tumors do not progress over time. They further suggest that men can be successfully managed with active watchful waiting – repeated, close follow-up that could spare many from unnecessary and possibly harmful interventions, reported Kathryn Penney, Sc.D. The study was published in the Aug. 14 issue of Cancer Research (Cancer Res. 2013;73:5163-8).

"Men with low-grade disease are being encouraged more and more to do this sort of active surveillance, which isn’t just watching and waiting, but returning for regular visits, additional blood tests, or additional biopsies," Dr. Penney said in an interview. "This is an encouraging trend, because men who are candidates for this kind of follow-up may not end up being candidates for radiation or surgery, which can have long-term side effects."

Dr. Penney, an associate epidemiologist at Brigham and Women’s Hospital, Boston, examined prostate tumor characteristics among 1,207 men who were included in two longitudinal studies: 420 in the Physicians’ Health Study (PHS) and 787 in the ongoing Health Professionals Follow-Up Study (HPFS). All of the men had undergone radical prostatectomy. Dr. Penney and her colleagues analyzed tissue from each tumor and categorized the results from four epochs: 1982-1993, 1993-1996, 1996-2000, and 2000-2004.

Mean age at diagnosis was 66 years in both studies. Information about prostate specific antigen was not available for the PHS, since it was an earlier cohort examined from 1982 to 2004. For the HPFS data, PSA results were available from 1994 onward. In 1994, 42% of the entire study group had been tested in the previous 2 years; that increased to 81% by 2000.

From 1982 to 1993, the earliest epoch, 20% of tumors were stage T3 or higher. This proportion decreased over all four epochs, declining to 3% by the last period – an 85% drop. There were no T4 tumors in that epoch.

There was a 30% decrease in tumors with a Gleason score of 8 or more, dropping from 25% in the first epoch to 17.6% in the last.

"When restricting [the analysis] to men with stage T1/T2, the proportion of Gleason score 8-10 decreased even less across time periods, from 19.5% to 16%," the researchers wrote.

While there was a significant age/grade relationship, with older men having higher Gleason scores, it primarily occurred during the pre-PSA screening epochs. "This suggests that the change over time we observe for Gleason score is not due to a change in age at diagnosis and may represent an increase in screening of younger men detecting more indolent, lower grade tumors," they wrote. "Widespread PSA screening not only advanced the time of diagnosis of prostate cancer, but also has increased the prevalence of detected indolent tumors that would otherwise never have been diagnosed ... Although we cannot rule out the possibility that Gleason grade progresses within an individual, we conclude that it is not a major feature of prostate cancer."

The study speaks to the biology of prostate cancer as well, Dr. Penney and her coinvestigators noted. If Gleason score "seems set early in the disease," then later, potentially modifiable risk factors might be a trigger for progression in low-grade disease. "If we suppose that a Gleason score 3+3 will remain 3+3 for the entire course of the disease, active surveillance could be considered a definitive treatment for selected patients with [10 or fewer years life expectancy] and could significantly delay (potentially forever) the treatment of selected patients with [more than] 10 years life expectancy."

"Alternatively, earlier influences, such as genetics, may drive the development of a subtype of cancer that is more aggressive in a way that is not related to differentiation status," they said.

The study was funded by the Dana-Farber/Harvard Cancer Center, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. Dr. Penney had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

The proportion of advanced prostate cancers has declined by more than sixfold over the last 2 decades; however, the proportion of high Gleason grade tumors has not followed suit.

The findings from a 22-year review of two large databases suggest that most low-grade prostate tumors do not progress over time. They further suggest that men can be successfully managed with active watchful waiting – repeated, close follow-up that could spare many from unnecessary and possibly harmful interventions, reported Kathryn Penney, Sc.D. The study was published in the Aug. 14 issue of Cancer Research (Cancer Res. 2013;73:5163-8).

"Men with low-grade disease are being encouraged more and more to do this sort of active surveillance, which isn’t just watching and waiting, but returning for regular visits, additional blood tests, or additional biopsies," Dr. Penney said in an interview. "This is an encouraging trend, because men who are candidates for this kind of follow-up may not end up being candidates for radiation or surgery, which can have long-term side effects."

Dr. Penney, an associate epidemiologist at Brigham and Women’s Hospital, Boston, examined prostate tumor characteristics among 1,207 men who were included in two longitudinal studies: 420 in the Physicians’ Health Study (PHS) and 787 in the ongoing Health Professionals Follow-Up Study (HPFS). All of the men had undergone radical prostatectomy. Dr. Penney and her colleagues analyzed tissue from each tumor and categorized the results from four epochs: 1982-1993, 1993-1996, 1996-2000, and 2000-2004.

Mean age at diagnosis was 66 years in both studies. Information about prostate specific antigen was not available for the PHS, since it was an earlier cohort examined from 1982 to 2004. For the HPFS data, PSA results were available from 1994 onward. In 1994, 42% of the entire study group had been tested in the previous 2 years; that increased to 81% by 2000.

From 1982 to 1993, the earliest epoch, 20% of tumors were stage T3 or higher. This proportion decreased over all four epochs, declining to 3% by the last period – an 85% drop. There were no T4 tumors in that epoch.

There was a 30% decrease in tumors with a Gleason score of 8 or more, dropping from 25% in the first epoch to 17.6% in the last.

"When restricting [the analysis] to men with stage T1/T2, the proportion of Gleason score 8-10 decreased even less across time periods, from 19.5% to 16%," the researchers wrote.

While there was a significant age/grade relationship, with older men having higher Gleason scores, it primarily occurred during the pre-PSA screening epochs. "This suggests that the change over time we observe for Gleason score is not due to a change in age at diagnosis and may represent an increase in screening of younger men detecting more indolent, lower grade tumors," they wrote. "Widespread PSA screening not only advanced the time of diagnosis of prostate cancer, but also has increased the prevalence of detected indolent tumors that would otherwise never have been diagnosed ... Although we cannot rule out the possibility that Gleason grade progresses within an individual, we conclude that it is not a major feature of prostate cancer."

The study speaks to the biology of prostate cancer as well, Dr. Penney and her coinvestigators noted. If Gleason score "seems set early in the disease," then later, potentially modifiable risk factors might be a trigger for progression in low-grade disease. "If we suppose that a Gleason score 3+3 will remain 3+3 for the entire course of the disease, active surveillance could be considered a definitive treatment for selected patients with [10 or fewer years life expectancy] and could significantly delay (potentially forever) the treatment of selected patients with [more than] 10 years life expectancy."

"Alternatively, earlier influences, such as genetics, may drive the development of a subtype of cancer that is more aggressive in a way that is not related to differentiation status," they said.

The study was funded by the Dana-Farber/Harvard Cancer Center, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. Dr. Penney had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

The proportion of advanced prostate cancers has declined by more than sixfold over the last 2 decades; however, the proportion of high Gleason grade tumors has not followed suit.

The findings from a 22-year review of two large databases suggest that most low-grade prostate tumors do not progress over time. They further suggest that men can be successfully managed with active watchful waiting – repeated, close follow-up that could spare many from unnecessary and possibly harmful interventions, reported Kathryn Penney, Sc.D. The study was published in the Aug. 14 issue of Cancer Research (Cancer Res. 2013;73:5163-8).

"Men with low-grade disease are being encouraged more and more to do this sort of active surveillance, which isn’t just watching and waiting, but returning for regular visits, additional blood tests, or additional biopsies," Dr. Penney said in an interview. "This is an encouraging trend, because men who are candidates for this kind of follow-up may not end up being candidates for radiation or surgery, which can have long-term side effects."

Dr. Penney, an associate epidemiologist at Brigham and Women’s Hospital, Boston, examined prostate tumor characteristics among 1,207 men who were included in two longitudinal studies: 420 in the Physicians’ Health Study (PHS) and 787 in the ongoing Health Professionals Follow-Up Study (HPFS). All of the men had undergone radical prostatectomy. Dr. Penney and her colleagues analyzed tissue from each tumor and categorized the results from four epochs: 1982-1993, 1993-1996, 1996-2000, and 2000-2004.

Mean age at diagnosis was 66 years in both studies. Information about prostate specific antigen was not available for the PHS, since it was an earlier cohort examined from 1982 to 2004. For the HPFS data, PSA results were available from 1994 onward. In 1994, 42% of the entire study group had been tested in the previous 2 years; that increased to 81% by 2000.

From 1982 to 1993, the earliest epoch, 20% of tumors were stage T3 or higher. This proportion decreased over all four epochs, declining to 3% by the last period – an 85% drop. There were no T4 tumors in that epoch.

There was a 30% decrease in tumors with a Gleason score of 8 or more, dropping from 25% in the first epoch to 17.6% in the last.

"When restricting [the analysis] to men with stage T1/T2, the proportion of Gleason score 8-10 decreased even less across time periods, from 19.5% to 16%," the researchers wrote.

While there was a significant age/grade relationship, with older men having higher Gleason scores, it primarily occurred during the pre-PSA screening epochs. "This suggests that the change over time we observe for Gleason score is not due to a change in age at diagnosis and may represent an increase in screening of younger men detecting more indolent, lower grade tumors," they wrote. "Widespread PSA screening not only advanced the time of diagnosis of prostate cancer, but also has increased the prevalence of detected indolent tumors that would otherwise never have been diagnosed ... Although we cannot rule out the possibility that Gleason grade progresses within an individual, we conclude that it is not a major feature of prostate cancer."

The study speaks to the biology of prostate cancer as well, Dr. Penney and her coinvestigators noted. If Gleason score "seems set early in the disease," then later, potentially modifiable risk factors might be a trigger for progression in low-grade disease. "If we suppose that a Gleason score 3+3 will remain 3+3 for the entire course of the disease, active surveillance could be considered a definitive treatment for selected patients with [10 or fewer years life expectancy] and could significantly delay (potentially forever) the treatment of selected patients with [more than] 10 years life expectancy."

"Alternatively, earlier influences, such as genetics, may drive the development of a subtype of cancer that is more aggressive in a way that is not related to differentiation status," they said.

The study was funded by the Dana-Farber/Harvard Cancer Center, the National Cancer Institute, and the National Heart, Lung, and Blood Institute. Dr. Penney had no financial disclosures.

msullivan@frontlinemedcom.com

On Twitter @Alz_Gal

African American men with very-low-risk prostate cancer undergoing prostatectomy still have a higher likelihood of poor oncologic outcomes that should be discussed during counseling, according to results from a retrospective cohort study appearing in the Journal of Clinical Oncology.

Investigators at Johns Hopkins University, Baltimore, studied 1,801 men – 14% African American, 82% white, and 4% other races/ethnicities – treated in the prostate-specific antigen era who met criteria for very-low-risk disease but opted for an immediate radical prostatectomy instead.

Study results showed that relative to white peers, African American men were significantly more likely to have tumors with adverse pathologic features, upgrading at prostatectomy, positive surgical margins, and scores predicting a higher risk of recurrence, Dr. Debasish Sundi and his colleagues reported.

In a multivariate analysis restricted to the 359 men treated with modern practices (extended biopsy sampling and contemporary Gleason grading), African American men had a more than tripling of the odds of adverse tumor features and a more than doubling of the odds of pathologic upgrading relative to men of other races/ethnicities.

The investigators wrote that the study "shows a disparity in outcomes for African American men after radical prostatectomy by multiple metrics, even within a highly selected and contemporary cohort of very-low–risk patients. This underscores the need to develop and use race-based risk classifiers when counseling patients about different management strategies."

"African American men with very low risk of prostate cancer should be counseled about increased oncologic risk when deciding among their disease management options," they recommended.

However, "the results of our study do not support the universal rejection of active surveillance in African American men but rather should promote future studies to address whether alternate race-specific surveillance entry criteria should be used for African American men to ensure oncologic parity with their white counterparts."

The investigators retrospectively studied men undergoing radical prostatectomy at Johns Hopkins since 1992, excluding any who received neoadjuvant hormonal therapy and restricting analyses to those who met National Comprehensive Cancer Network criteria for very-low-risk disease.

Relative to their white peers, African American men were more likely to have upgrading at prostatectomy (27.3% vs. 14.4%), positive surgical margins (9.8% vs. 5.9%), adverse pathologic features (14.1% vs. 7.7%), and a CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical scoring system) score of 3 or higher, indicating a higher risk of biochemical recurrence (14.8% vs. 6.9%), the investigators reported (J. Clin. Oncol. 2013 June 17 [doi: 10.1200/JCO.2012.47.0302]).

With a median follow-up of 3 years, African Americans also had a higher rate of biochemical recurrence (4% vs. 1.4%), but the two groups were statistically indistinguishable with respect to metastasis-free, cancer-specific, or overall survival.

In the subset of men treated with modern clinical practices, compared with white men, African American men again had higher rates of upgrading (32.7% vs. 12.6%), positive margins (19% vs. 6.3%), adverse pathology (19.8% vs. 7.2%), and higher CAPRA-S scores (21% vs. 5.7%).

A multivariate analysis in this subset showed that compared with white men and other men combined, African American men still had higher odds of upgrading at prostatectomy (odds ratio, 2.26; P = .03), adverse pathology (OR, 3.23; P = .03), and higher CAPRA-S scores (OR, 6.57; P = .001).

The authors disclosed no potential conflicts of interest.

African American men with very-low-risk prostate cancer undergoing prostatectomy still have a higher likelihood of poor oncologic outcomes that should be discussed during counseling, according to results from a retrospective cohort study appearing in the Journal of Clinical Oncology.

Investigators at Johns Hopkins University, Baltimore, studied 1,801 men – 14% African American, 82% white, and 4% other races/ethnicities – treated in the prostate-specific antigen era who met criteria for very-low-risk disease but opted for an immediate radical prostatectomy instead.

Study results showed that relative to white peers, African American men were significantly more likely to have tumors with adverse pathologic features, upgrading at prostatectomy, positive surgical margins, and scores predicting a higher risk of recurrence, Dr. Debasish Sundi and his colleagues reported.

In a multivariate analysis restricted to the 359 men treated with modern practices (extended biopsy sampling and contemporary Gleason grading), African American men had a more than tripling of the odds of adverse tumor features and a more than doubling of the odds of pathologic upgrading relative to men of other races/ethnicities.

The investigators wrote that the study "shows a disparity in outcomes for African American men after radical prostatectomy by multiple metrics, even within a highly selected and contemporary cohort of very-low–risk patients. This underscores the need to develop and use race-based risk classifiers when counseling patients about different management strategies."

"African American men with very low risk of prostate cancer should be counseled about increased oncologic risk when deciding among their disease management options," they recommended.

However, "the results of our study do not support the universal rejection of active surveillance in African American men but rather should promote future studies to address whether alternate race-specific surveillance entry criteria should be used for African American men to ensure oncologic parity with their white counterparts."

The investigators retrospectively studied men undergoing radical prostatectomy at Johns Hopkins since 1992, excluding any who received neoadjuvant hormonal therapy and restricting analyses to those who met National Comprehensive Cancer Network criteria for very-low-risk disease.

Relative to their white peers, African American men were more likely to have upgrading at prostatectomy (27.3% vs. 14.4%), positive surgical margins (9.8% vs. 5.9%), adverse pathologic features (14.1% vs. 7.7%), and a CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical scoring system) score of 3 or higher, indicating a higher risk of biochemical recurrence (14.8% vs. 6.9%), the investigators reported (J. Clin. Oncol. 2013 June 17 [doi: 10.1200/JCO.2012.47.0302]).

With a median follow-up of 3 years, African Americans also had a higher rate of biochemical recurrence (4% vs. 1.4%), but the two groups were statistically indistinguishable with respect to metastasis-free, cancer-specific, or overall survival.

In the subset of men treated with modern clinical practices, compared with white men, African American men again had higher rates of upgrading (32.7% vs. 12.6%), positive margins (19% vs. 6.3%), adverse pathology (19.8% vs. 7.2%), and higher CAPRA-S scores (21% vs. 5.7%).

A multivariate analysis in this subset showed that compared with white men and other men combined, African American men still had higher odds of upgrading at prostatectomy (odds ratio, 2.26; P = .03), adverse pathology (OR, 3.23; P = .03), and higher CAPRA-S scores (OR, 6.57; P = .001).

The authors disclosed no potential conflicts of interest.

African American men with very-low-risk prostate cancer undergoing prostatectomy still have a higher likelihood of poor oncologic outcomes that should be discussed during counseling, according to results from a retrospective cohort study appearing in the Journal of Clinical Oncology.

Investigators at Johns Hopkins University, Baltimore, studied 1,801 men – 14% African American, 82% white, and 4% other races/ethnicities – treated in the prostate-specific antigen era who met criteria for very-low-risk disease but opted for an immediate radical prostatectomy instead.

Study results showed that relative to white peers, African American men were significantly more likely to have tumors with adverse pathologic features, upgrading at prostatectomy, positive surgical margins, and scores predicting a higher risk of recurrence, Dr. Debasish Sundi and his colleagues reported.

In a multivariate analysis restricted to the 359 men treated with modern practices (extended biopsy sampling and contemporary Gleason grading), African American men had a more than tripling of the odds of adverse tumor features and a more than doubling of the odds of pathologic upgrading relative to men of other races/ethnicities.

The investigators wrote that the study "shows a disparity in outcomes for African American men after radical prostatectomy by multiple metrics, even within a highly selected and contemporary cohort of very-low–risk patients. This underscores the need to develop and use race-based risk classifiers when counseling patients about different management strategies."

"African American men with very low risk of prostate cancer should be counseled about increased oncologic risk when deciding among their disease management options," they recommended.

However, "the results of our study do not support the universal rejection of active surveillance in African American men but rather should promote future studies to address whether alternate race-specific surveillance entry criteria should be used for African American men to ensure oncologic parity with their white counterparts."

The investigators retrospectively studied men undergoing radical prostatectomy at Johns Hopkins since 1992, excluding any who received neoadjuvant hormonal therapy and restricting analyses to those who met National Comprehensive Cancer Network criteria for very-low-risk disease.

Relative to their white peers, African American men were more likely to have upgrading at prostatectomy (27.3% vs. 14.4%), positive surgical margins (9.8% vs. 5.9%), adverse pathologic features (14.1% vs. 7.7%), and a CAPRA-S (Cancer of the Prostate Risk Assessment Post-Surgical scoring system) score of 3 or higher, indicating a higher risk of biochemical recurrence (14.8% vs. 6.9%), the investigators reported (J. Clin. Oncol. 2013 June 17 [doi: 10.1200/JCO.2012.47.0302]).

With a median follow-up of 3 years, African Americans also had a higher rate of biochemical recurrence (4% vs. 1.4%), but the two groups were statistically indistinguishable with respect to metastasis-free, cancer-specific, or overall survival.

In the subset of men treated with modern clinical practices, compared with white men, African American men again had higher rates of upgrading (32.7% vs. 12.6%), positive margins (19% vs. 6.3%), adverse pathology (19.8% vs. 7.2%), and higher CAPRA-S scores (21% vs. 5.7%).

A multivariate analysis in this subset showed that compared with white men and other men combined, African American men still had higher odds of upgrading at prostatectomy (odds ratio, 2.26; P = .03), adverse pathology (OR, 3.23; P = .03), and higher CAPRA-S scores (OR, 6.57; P = .001).

The authors disclosed no potential conflicts of interest.