Genitourinary Cancer

Smoking causes death from many diseases that until now have not been linked officially to tobacco use, including digestive disorders, liver cirrhosis, infections, renal failure, and breast and prostate cancers, according to a report published online Feb. 11 in the New England Journal of Medicine.

“Our results suggest that the number of persons in the United States who die each year as a result of smoking cigarettes may be substantially greater than currently estimated,” said Brian D. Carter of the epidemiology research program, American Cancer Society, Atlanta, and his associates.

The 2014 Surgeon General’s report estimated that smoking causes more than 480,000 deaths every year in the United States, based on mortality figures from 21 diseases that have been formally established as caused by smoking: 12 types of cancer, 6 types of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia. Mr. Carter and his associates pooled data from five large cohort studies to examine possible associations between smoking and an additional 31 cause-of-death categories. They now estimate that an additional 60,000-120,000 deaths each year can be attributed to smoking.

For their study, the investigators assessed 421,378 men and 532,651 women aged 55 years and older at baseline whose smoking status was carefully recorded and who were followed from 2000 to 2011 in the Cancer Prevention Study II Nutrition Cohort, the Nurses’ Health Study I, the Health Professionals Follow-up Study, the Women’s Health Initiative, and the National Institutes of Health-AARP Diet and Health Study.

As expected, smokers had a twofold to threefold higher mortality from any cause, compared with nonsmokers. Smokers also had a markedly higher risk of death than nonsmokers from all 21 causes already established as attributable to tobacco use, such as lung cancer, oral cancer, ischemic heart disease, atherosclerosis, and stroke. But approximately 17% of smokers’ excess mortality was accounted for by several diseases that previously have not been attributable to tobacco use.

For example, the risk of death due to intestinal ischemia was approximately six times higher among smokers than among nonsmokers, a remarkably strong association that was also reported in the Million Women Study. “Smoking acutely reduces blood flow to the intestines, and evidence suggests that smoking causes risk factors that can often lead to intestinal ischemia, including atherosclerosis, platelet aggregation, and congestive heart failure,” Mr. Carter and his associates said (N. Engl. J. Med. 2015 Feb. 12 [doi:10.1056/NEJMsa140721]).  In this study, smoking also more than doubled the risk of dying from other digestive diseases. Previous studies have suggested a link between smoking and digestive disorders such as Crohn’s disease, peptic ulcers, acute pancreatitis, paralytic ileus, bowel obstruction, choletlithiasis, diverticulitis, and gastrointestinal hemorrhage. “Although these diseases are not common causes of death, they account for millions of hospitalizations each year,” the investigators noted.

The mortality risk from liver cirrhosis, after the data were adjusted to account for alcohol consumption, was more than three times higher in smokers than in nonsmokers. Even smokers who did not drink alcohol were at significantly increased risk of cirrhosis, compared with nonsmokers.

The risk of death due to infection was 2.3 times higher in smokers than in nonsmokers. This strong association was dose-dependent, as infection-related mortality rose with increasing smoking intensity. And among study participants who had quit smoking, infection-related mortality declined as the number of years since cessation increased.

The rate of death due to renal failure was twice as high among smokers as among nonsmokers. And the rate of death due to hypertensive heart disease, the only category of heart disease not already established as smoking related, was 2.4 times higher in smokers. The latter association “is relevant for assessing the public health burden of smoking, since a considerable number of deaths in the United States are attributable to hypertensive heart disease,” according to Mr. Carter and his associates.

Smoking also was strongly associated with “multiple diseases too uncommon to examine individually.” This included all rare cancers combined, rare digestive diseases, and respiratory diseases other than those already known to stem from smoking.

In women, smoking raised breast cancer mortality, with a relative risk of 1.3. This association was strongly dose dependent. In men, smoking raised prostate cancer mortality, with a relative risk of 1.4.

This study was limited in that most of the participants were white and better educated than the general population, which may affect the applicability of the results to other populations.

Smoking causes death from many diseases that until now have not been linked officially to tobacco use, including digestive disorders, liver cirrhosis, infections, renal failure, and breast and prostate cancers, according to a report published online Feb. 11 in the New England Journal of Medicine.

“Our results suggest that the number of persons in the United States who die each year as a result of smoking cigarettes may be substantially greater than currently estimated,” said Brian D. Carter of the epidemiology research program, American Cancer Society, Atlanta, and his associates.

The 2014 Surgeon General’s report estimated that smoking causes more than 480,000 deaths every year in the United States, based on mortality figures from 21 diseases that have been formally established as caused by smoking: 12 types of cancer, 6 types of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia. Mr. Carter and his associates pooled data from five large cohort studies to examine possible associations between smoking and an additional 31 cause-of-death categories. They now estimate that an additional 60,000-120,000 deaths each year can be attributed to smoking.

For their study, the investigators assessed 421,378 men and 532,651 women aged 55 years and older at baseline whose smoking status was carefully recorded and who were followed from 2000 to 2011 in the Cancer Prevention Study II Nutrition Cohort, the Nurses’ Health Study I, the Health Professionals Follow-up Study, the Women’s Health Initiative, and the National Institutes of Health-AARP Diet and Health Study.

As expected, smokers had a twofold to threefold higher mortality from any cause, compared with nonsmokers. Smokers also had a markedly higher risk of death than nonsmokers from all 21 causes already established as attributable to tobacco use, such as lung cancer, oral cancer, ischemic heart disease, atherosclerosis, and stroke. But approximately 17% of smokers’ excess mortality was accounted for by several diseases that previously have not been attributable to tobacco use.

For example, the risk of death due to intestinal ischemia was approximately six times higher among smokers than among nonsmokers, a remarkably strong association that was also reported in the Million Women Study. “Smoking acutely reduces blood flow to the intestines, and evidence suggests that smoking causes risk factors that can often lead to intestinal ischemia, including atherosclerosis, platelet aggregation, and congestive heart failure,” Mr. Carter and his associates said (N. Engl. J. Med. 2015 Feb. 12 [doi:10.1056/NEJMsa140721]).  In this study, smoking also more than doubled the risk of dying from other digestive diseases. Previous studies have suggested a link between smoking and digestive disorders such as Crohn’s disease, peptic ulcers, acute pancreatitis, paralytic ileus, bowel obstruction, choletlithiasis, diverticulitis, and gastrointestinal hemorrhage. “Although these diseases are not common causes of death, they account for millions of hospitalizations each year,” the investigators noted.

The mortality risk from liver cirrhosis, after the data were adjusted to account for alcohol consumption, was more than three times higher in smokers than in nonsmokers. Even smokers who did not drink alcohol were at significantly increased risk of cirrhosis, compared with nonsmokers.

The risk of death due to infection was 2.3 times higher in smokers than in nonsmokers. This strong association was dose-dependent, as infection-related mortality rose with increasing smoking intensity. And among study participants who had quit smoking, infection-related mortality declined as the number of years since cessation increased.

The rate of death due to renal failure was twice as high among smokers as among nonsmokers. And the rate of death due to hypertensive heart disease, the only category of heart disease not already established as smoking related, was 2.4 times higher in smokers. The latter association “is relevant for assessing the public health burden of smoking, since a considerable number of deaths in the United States are attributable to hypertensive heart disease,” according to Mr. Carter and his associates.

Smoking also was strongly associated with “multiple diseases too uncommon to examine individually.” This included all rare cancers combined, rare digestive diseases, and respiratory diseases other than those already known to stem from smoking.

In women, smoking raised breast cancer mortality, with a relative risk of 1.3. This association was strongly dose dependent. In men, smoking raised prostate cancer mortality, with a relative risk of 1.4.

This study was limited in that most of the participants were white and better educated than the general population, which may affect the applicability of the results to other populations.

Smoking causes death from many diseases that until now have not been linked officially to tobacco use, including digestive disorders, liver cirrhosis, infections, renal failure, and breast and prostate cancers, according to a report published online Feb. 11 in the New England Journal of Medicine.

“Our results suggest that the number of persons in the United States who die each year as a result of smoking cigarettes may be substantially greater than currently estimated,” said Brian D. Carter of the epidemiology research program, American Cancer Society, Atlanta, and his associates.

The 2014 Surgeon General’s report estimated that smoking causes more than 480,000 deaths every year in the United States, based on mortality figures from 21 diseases that have been formally established as caused by smoking: 12 types of cancer, 6 types of cardiovascular disease, diabetes, chronic obstructive pulmonary disease, and pneumonia. Mr. Carter and his associates pooled data from five large cohort studies to examine possible associations between smoking and an additional 31 cause-of-death categories. They now estimate that an additional 60,000-120,000 deaths each year can be attributed to smoking.

For their study, the investigators assessed 421,378 men and 532,651 women aged 55 years and older at baseline whose smoking status was carefully recorded and who were followed from 2000 to 2011 in the Cancer Prevention Study II Nutrition Cohort, the Nurses’ Health Study I, the Health Professionals Follow-up Study, the Women’s Health Initiative, and the National Institutes of Health-AARP Diet and Health Study.

As expected, smokers had a twofold to threefold higher mortality from any cause, compared with nonsmokers. Smokers also had a markedly higher risk of death than nonsmokers from all 21 causes already established as attributable to tobacco use, such as lung cancer, oral cancer, ischemic heart disease, atherosclerosis, and stroke. But approximately 17% of smokers’ excess mortality was accounted for by several diseases that previously have not been attributable to tobacco use.

For example, the risk of death due to intestinal ischemia was approximately six times higher among smokers than among nonsmokers, a remarkably strong association that was also reported in the Million Women Study. “Smoking acutely reduces blood flow to the intestines, and evidence suggests that smoking causes risk factors that can often lead to intestinal ischemia, including atherosclerosis, platelet aggregation, and congestive heart failure,” Mr. Carter and his associates said (N. Engl. J. Med. 2015 Feb. 12 [doi:10.1056/NEJMsa140721]).  In this study, smoking also more than doubled the risk of dying from other digestive diseases. Previous studies have suggested a link between smoking and digestive disorders such as Crohn’s disease, peptic ulcers, acute pancreatitis, paralytic ileus, bowel obstruction, choletlithiasis, diverticulitis, and gastrointestinal hemorrhage. “Although these diseases are not common causes of death, they account for millions of hospitalizations each year,” the investigators noted.

The mortality risk from liver cirrhosis, after the data were adjusted to account for alcohol consumption, was more than three times higher in smokers than in nonsmokers. Even smokers who did not drink alcohol were at significantly increased risk of cirrhosis, compared with nonsmokers.

The risk of death due to infection was 2.3 times higher in smokers than in nonsmokers. This strong association was dose-dependent, as infection-related mortality rose with increasing smoking intensity. And among study participants who had quit smoking, infection-related mortality declined as the number of years since cessation increased.

The rate of death due to renal failure was twice as high among smokers as among nonsmokers. And the rate of death due to hypertensive heart disease, the only category of heart disease not already established as smoking related, was 2.4 times higher in smokers. The latter association “is relevant for assessing the public health burden of smoking, since a considerable number of deaths in the United States are attributable to hypertensive heart disease,” according to Mr. Carter and his associates.

Smoking also was strongly associated with “multiple diseases too uncommon to examine individually.” This included all rare cancers combined, rare digestive diseases, and respiratory diseases other than those already known to stem from smoking.

In women, smoking raised breast cancer mortality, with a relative risk of 1.3. This association was strongly dose dependent. In men, smoking raised prostate cancer mortality, with a relative risk of 1.4.

This study was limited in that most of the participants were white and better educated than the general population, which may affect the applicability of the results to other populations.

Targeted biopsy using magnetic resonance/ultrasound fusion imaging increased the detection of high-risk prostate cancer by 30% and decreased the detection of low-risk prostate cancer by 17%, compared with standard biopsy, according to a report published online Jan. 27 in JAMA.

Researchers compared the two approaches in a prospective cohort study involving 1,003 men referred to the National Cancer Institute during a 7-year period for evaluation of suspected prostate cancer. All the study participants had an elevated PSA or abnormal findings on digital rectal exam plus a multiparametric MRI showing at least 1 lesion in the prostate, said Dr. M. Minhaj Siddiqui of the urologic oncology branch, National Cancer Institute, Bethesda, Md., and his associates.

roobcio/Thinkstock.com

All the patients underwent both standard extended-sextant ultrasound-guided biopsy and targeted magnetic resonance/ultrasound fusion biopsy at the same visit. The latter technique involves electronically superimposing multiparametric MR images in real time onto transrectal ultrasound images, which improves spatial localization and capture of location in three planes. The lesions were separately categorized as low-risk, intermediate-risk, or high-risk by highly experienced genitourinary radiologists.

The two image-guided biopsy techniques agreed on these classifications in 69% of cases and identified a similar number of cancers. However, targeted biopsy detected 173 high-risk tumors, compared with only 122 identified on standard biopsy, and targeted biopsy detected 213 low-risk tumors, compared with 258 identified on standard biopsy. In a subset of 170 cases, these biopsy results could be compared against pathology found at whole-gland prostatectomy. Targeted biopsy proved to be much more accurate than standard biopsy, with sensitivities of 77% and 53%, respectively, the investigators said (JAMA 2015 Jan. 27 [doi:10.1001/jama.2014.17942]).

These findings show that targeted biopsy “could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high-risk disease. Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary” and didn’t include clinical end points such as cancer recurrence or prostate cancer–specific mortality, Dr. Siddiqui and his associates said.

Targeted biopsy using magnetic resonance/ultrasound fusion imaging increased the detection of high-risk prostate cancer by 30% and decreased the detection of low-risk prostate cancer by 17%, compared with standard biopsy, according to a report published online Jan. 27 in JAMA.

Researchers compared the two approaches in a prospective cohort study involving 1,003 men referred to the National Cancer Institute during a 7-year period for evaluation of suspected prostate cancer. All the study participants had an elevated PSA or abnormal findings on digital rectal exam plus a multiparametric MRI showing at least 1 lesion in the prostate, said Dr. M. Minhaj Siddiqui of the urologic oncology branch, National Cancer Institute, Bethesda, Md., and his associates.

roobcio/Thinkstock.com

All the patients underwent both standard extended-sextant ultrasound-guided biopsy and targeted magnetic resonance/ultrasound fusion biopsy at the same visit. The latter technique involves electronically superimposing multiparametric MR images in real time onto transrectal ultrasound images, which improves spatial localization and capture of location in three planes. The lesions were separately categorized as low-risk, intermediate-risk, or high-risk by highly experienced genitourinary radiologists.

The two image-guided biopsy techniques agreed on these classifications in 69% of cases and identified a similar number of cancers. However, targeted biopsy detected 173 high-risk tumors, compared with only 122 identified on standard biopsy, and targeted biopsy detected 213 low-risk tumors, compared with 258 identified on standard biopsy. In a subset of 170 cases, these biopsy results could be compared against pathology found at whole-gland prostatectomy. Targeted biopsy proved to be much more accurate than standard biopsy, with sensitivities of 77% and 53%, respectively, the investigators said (JAMA 2015 Jan. 27 [doi:10.1001/jama.2014.17942]).

These findings show that targeted biopsy “could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high-risk disease. Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary” and didn’t include clinical end points such as cancer recurrence or prostate cancer–specific mortality, Dr. Siddiqui and his associates said.

Targeted biopsy using magnetic resonance/ultrasound fusion imaging increased the detection of high-risk prostate cancer by 30% and decreased the detection of low-risk prostate cancer by 17%, compared with standard biopsy, according to a report published online Jan. 27 in JAMA.

Researchers compared the two approaches in a prospective cohort study involving 1,003 men referred to the National Cancer Institute during a 7-year period for evaluation of suspected prostate cancer. All the study participants had an elevated PSA or abnormal findings on digital rectal exam plus a multiparametric MRI showing at least 1 lesion in the prostate, said Dr. M. Minhaj Siddiqui of the urologic oncology branch, National Cancer Institute, Bethesda, Md., and his associates.

roobcio/Thinkstock.com

All the patients underwent both standard extended-sextant ultrasound-guided biopsy and targeted magnetic resonance/ultrasound fusion biopsy at the same visit. The latter technique involves electronically superimposing multiparametric MR images in real time onto transrectal ultrasound images, which improves spatial localization and capture of location in three planes. The lesions were separately categorized as low-risk, intermediate-risk, or high-risk by highly experienced genitourinary radiologists.

The two image-guided biopsy techniques agreed on these classifications in 69% of cases and identified a similar number of cancers. However, targeted biopsy detected 173 high-risk tumors, compared with only 122 identified on standard biopsy, and targeted biopsy detected 213 low-risk tumors, compared with 258 identified on standard biopsy. In a subset of 170 cases, these biopsy results could be compared against pathology found at whole-gland prostatectomy. Targeted biopsy proved to be much more accurate than standard biopsy, with sensitivities of 77% and 53%, respectively, the investigators said (JAMA 2015 Jan. 27 [doi:10.1001/jama.2014.17942]).

These findings show that targeted biopsy “could significantly change the distribution of risk in men newly diagnosed with prostate cancer toward diagnosis of more high-risk disease. Although these improvements in risk stratification could translate into substantial clinical benefits, it is important to recognize that this study is preliminary” and didn’t include clinical end points such as cancer recurrence or prostate cancer–specific mortality, Dr. Siddiqui and his associates said.

A reproducible quantitative definition of radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer was highly consistent and highly associated with overall survival in the Cougar-Abiraterone Acetate Study 302.

The findings could have implications for the interim measurement of treatment response in future studies, according to Dr. Michael J. Morris of Memorial Sloan Kettering Cancer Center, New York, and his colleagues.

Radiographic progression-free survival (rPFS) – defined in the Cougar-Abiraterone Acetate Study 302 (COU-AA-302) as the time from randomization to the first occurrence of progression by bone scan, progression by computed tomography or magnetic resonance imaging as defined by modified RECIST 1.0, or death resulting from any cause – was highly positively associated with overall survival in the randomized, placebo-controlled phase III study of 1,088 patients with metastatic castration-resistant prostate cancer (mCRPC) who were assigned to receive treatment with abiraterone plus prednisone or prednisone alone (Spearman’s correlation coefficient, 0.72), Dr. Morris and his colleagues reported online Jan. 26 in the Journal of Clinical Oncology.

Most men with mCRPC will succumb to the disease as a result of overwhelming osseous metastases; thus, approved treatments are prescribed to control or relieve pain and to delay or prevent skeletal-related events or death.

“There has long been a need to develop additional time-to-event endpoints short of [overall survival] to accelerate drug development,” the authors wrote, noting that the need is particularly urgent given the recent approval of numerous life-prolonging therapies for mCRPC (J. Clin. Oncol. 2015 Jan. 26 [doi:10.1200/JCO.2014.55.3875]).

A specific unmet need is a reproducible assay that can be interpreted and reported consistently and quantitatively as a biomarker in the assessment of bone disease with radionuclide bone scans, the investigators said.

A Prostate Cancer Working Group 2 (PCSG2) proposal to use a time-to-event progression endpoint for bone scan interpretation – with progression defined as two or more new lesions on an initial posttreatment bone scan, followed by two additional lesions on the subsequent scan – was evaluated along with a bone scan data capture assay developed through the Prostate Cancer Clinical Consortium in COU-AA-302.

Chemotherapy-naive patients were randomly assigned to receive 1,000 mg abiraterone plus prednisone daily or prednisone alone. At the first interim analysis for overall survival, independent review recorded 401 rPFS events. A 57% reduction in radiographic progression or death was seen in the abiraterone-treated group vs. the prednisone group (hazard ratio, 0.43); when rPFS was based on investigator-reviewed assessments of scans at that analysis, the decrease in the hazard of radiographic progression or death in the abiraterone group vs. the prednisone-only group was similar at 51% (hazard ratio, 0.49), the investigators reported.

At the second interim analysis for overall survival, 607 rPFS events were observed on investigator review. Treatment with abiraterone plus prednisone led to a 47% reduction in the risk of radiographic progression or death, compared with prednisone (hazard ratio, 0.53). This finding also closely matched the findings from the independent review at the first interim analysis.

Of note, the definition of radiographic progression used in the study prevented premature treatment discontinuation in 166 of 229 patients (72%) with two or more new lesions on their initial scan, because they did not develop two additional new lesions as of the subsequent scan, the investigators said.

The study – the first to use rPFS as a registration endpoint for evaluating chemotherapy-naive mCRPC patients per Food and Drug Administration approval of a supplemental new drug application – provides the highest level of evidence to date that rPFS is highly associated with overall survival in such patients, they said, noting that “the rigor of the independently validated data showing significant benefit in rPFS and a strong trend in [overall survival] as co-primary endpoints in combination with clinically relevant secondary endpoints” supported the regulatory approval of abiraterone acetate plus prednisone in chemotherapy-naive mCRPC patients.

“The results suggest that this objective, prospectively defined endpoint may serve as a response indicator biomarker that is evaluable in future studies,” they said, adding that while the findings demonstrate a highly positive association between rPFS and overall survival in mCRPC, they do not provide support for the use of rPFS as a substitute for overall survival.

This study was supported by Ortho Biotech Oncology Research and Development, the Prostate Cancer Clinical Trials Consortium, sponsored by the Department of Defense, and by Janssen Global Services, which provided writing assistance. Dr. Morris reported having no disclosures; his coauthors reported holding employment or leadership positions, serving in consultant or advisory roles, having stock ownership, and/or receiving honoraria or research funding from numerous pharmaceutical and other companies.

A reproducible quantitative definition of radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer was highly consistent and highly associated with overall survival in the Cougar-Abiraterone Acetate Study 302.

The findings could have implications for the interim measurement of treatment response in future studies, according to Dr. Michael J. Morris of Memorial Sloan Kettering Cancer Center, New York, and his colleagues.

Radiographic progression-free survival (rPFS) – defined in the Cougar-Abiraterone Acetate Study 302 (COU-AA-302) as the time from randomization to the first occurrence of progression by bone scan, progression by computed tomography or magnetic resonance imaging as defined by modified RECIST 1.0, or death resulting from any cause – was highly positively associated with overall survival in the randomized, placebo-controlled phase III study of 1,088 patients with metastatic castration-resistant prostate cancer (mCRPC) who were assigned to receive treatment with abiraterone plus prednisone or prednisone alone (Spearman’s correlation coefficient, 0.72), Dr. Morris and his colleagues reported online Jan. 26 in the Journal of Clinical Oncology.

Most men with mCRPC will succumb to the disease as a result of overwhelming osseous metastases; thus, approved treatments are prescribed to control or relieve pain and to delay or prevent skeletal-related events or death.

“There has long been a need to develop additional time-to-event endpoints short of [overall survival] to accelerate drug development,” the authors wrote, noting that the need is particularly urgent given the recent approval of numerous life-prolonging therapies for mCRPC (J. Clin. Oncol. 2015 Jan. 26 [doi:10.1200/JCO.2014.55.3875]).

A specific unmet need is a reproducible assay that can be interpreted and reported consistently and quantitatively as a biomarker in the assessment of bone disease with radionuclide bone scans, the investigators said.

A Prostate Cancer Working Group 2 (PCSG2) proposal to use a time-to-event progression endpoint for bone scan interpretation – with progression defined as two or more new lesions on an initial posttreatment bone scan, followed by two additional lesions on the subsequent scan – was evaluated along with a bone scan data capture assay developed through the Prostate Cancer Clinical Consortium in COU-AA-302.

Chemotherapy-naive patients were randomly assigned to receive 1,000 mg abiraterone plus prednisone daily or prednisone alone. At the first interim analysis for overall survival, independent review recorded 401 rPFS events. A 57% reduction in radiographic progression or death was seen in the abiraterone-treated group vs. the prednisone group (hazard ratio, 0.43); when rPFS was based on investigator-reviewed assessments of scans at that analysis, the decrease in the hazard of radiographic progression or death in the abiraterone group vs. the prednisone-only group was similar at 51% (hazard ratio, 0.49), the investigators reported.

At the second interim analysis for overall survival, 607 rPFS events were observed on investigator review. Treatment with abiraterone plus prednisone led to a 47% reduction in the risk of radiographic progression or death, compared with prednisone (hazard ratio, 0.53). This finding also closely matched the findings from the independent review at the first interim analysis.

Of note, the definition of radiographic progression used in the study prevented premature treatment discontinuation in 166 of 229 patients (72%) with two or more new lesions on their initial scan, because they did not develop two additional new lesions as of the subsequent scan, the investigators said.

The study – the first to use rPFS as a registration endpoint for evaluating chemotherapy-naive mCRPC patients per Food and Drug Administration approval of a supplemental new drug application – provides the highest level of evidence to date that rPFS is highly associated with overall survival in such patients, they said, noting that “the rigor of the independently validated data showing significant benefit in rPFS and a strong trend in [overall survival] as co-primary endpoints in combination with clinically relevant secondary endpoints” supported the regulatory approval of abiraterone acetate plus prednisone in chemotherapy-naive mCRPC patients.

“The results suggest that this objective, prospectively defined endpoint may serve as a response indicator biomarker that is evaluable in future studies,” they said, adding that while the findings demonstrate a highly positive association between rPFS and overall survival in mCRPC, they do not provide support for the use of rPFS as a substitute for overall survival.

This study was supported by Ortho Biotech Oncology Research and Development, the Prostate Cancer Clinical Trials Consortium, sponsored by the Department of Defense, and by Janssen Global Services, which provided writing assistance. Dr. Morris reported having no disclosures; his coauthors reported holding employment or leadership positions, serving in consultant or advisory roles, having stock ownership, and/or receiving honoraria or research funding from numerous pharmaceutical and other companies.

A reproducible quantitative definition of radiographic progression-free survival in patients with metastatic castration-resistant prostate cancer was highly consistent and highly associated with overall survival in the Cougar-Abiraterone Acetate Study 302.

The findings could have implications for the interim measurement of treatment response in future studies, according to Dr. Michael J. Morris of Memorial Sloan Kettering Cancer Center, New York, and his colleagues.

Radiographic progression-free survival (rPFS) – defined in the Cougar-Abiraterone Acetate Study 302 (COU-AA-302) as the time from randomization to the first occurrence of progression by bone scan, progression by computed tomography or magnetic resonance imaging as defined by modified RECIST 1.0, or death resulting from any cause – was highly positively associated with overall survival in the randomized, placebo-controlled phase III study of 1,088 patients with metastatic castration-resistant prostate cancer (mCRPC) who were assigned to receive treatment with abiraterone plus prednisone or prednisone alone (Spearman’s correlation coefficient, 0.72), Dr. Morris and his colleagues reported online Jan. 26 in the Journal of Clinical Oncology.

Most men with mCRPC will succumb to the disease as a result of overwhelming osseous metastases; thus, approved treatments are prescribed to control or relieve pain and to delay or prevent skeletal-related events or death.

“There has long been a need to develop additional time-to-event endpoints short of [overall survival] to accelerate drug development,” the authors wrote, noting that the need is particularly urgent given the recent approval of numerous life-prolonging therapies for mCRPC (J. Clin. Oncol. 2015 Jan. 26 [doi:10.1200/JCO.2014.55.3875]).

A specific unmet need is a reproducible assay that can be interpreted and reported consistently and quantitatively as a biomarker in the assessment of bone disease with radionuclide bone scans, the investigators said.

A Prostate Cancer Working Group 2 (PCSG2) proposal to use a time-to-event progression endpoint for bone scan interpretation – with progression defined as two or more new lesions on an initial posttreatment bone scan, followed by two additional lesions on the subsequent scan – was evaluated along with a bone scan data capture assay developed through the Prostate Cancer Clinical Consortium in COU-AA-302.

Chemotherapy-naive patients were randomly assigned to receive 1,000 mg abiraterone plus prednisone daily or prednisone alone. At the first interim analysis for overall survival, independent review recorded 401 rPFS events. A 57% reduction in radiographic progression or death was seen in the abiraterone-treated group vs. the prednisone group (hazard ratio, 0.43); when rPFS was based on investigator-reviewed assessments of scans at that analysis, the decrease in the hazard of radiographic progression or death in the abiraterone group vs. the prednisone-only group was similar at 51% (hazard ratio, 0.49), the investigators reported.

At the second interim analysis for overall survival, 607 rPFS events were observed on investigator review. Treatment with abiraterone plus prednisone led to a 47% reduction in the risk of radiographic progression or death, compared with prednisone (hazard ratio, 0.53). This finding also closely matched the findings from the independent review at the first interim analysis.

Of note, the definition of radiographic progression used in the study prevented premature treatment discontinuation in 166 of 229 patients (72%) with two or more new lesions on their initial scan, because they did not develop two additional new lesions as of the subsequent scan, the investigators said.

The study – the first to use rPFS as a registration endpoint for evaluating chemotherapy-naive mCRPC patients per Food and Drug Administration approval of a supplemental new drug application – provides the highest level of evidence to date that rPFS is highly associated with overall survival in such patients, they said, noting that “the rigor of the independently validated data showing significant benefit in rPFS and a strong trend in [overall survival] as co-primary endpoints in combination with clinically relevant secondary endpoints” supported the regulatory approval of abiraterone acetate plus prednisone in chemotherapy-naive mCRPC patients.

“The results suggest that this objective, prospectively defined endpoint may serve as a response indicator biomarker that is evaluable in future studies,” they said, adding that while the findings demonstrate a highly positive association between rPFS and overall survival in mCRPC, they do not provide support for the use of rPFS as a substitute for overall survival.

This study was supported by Ortho Biotech Oncology Research and Development, the Prostate Cancer Clinical Trials Consortium, sponsored by the Department of Defense, and by Janssen Global Services, which provided writing assistance. Dr. Morris reported having no disclosures; his coauthors reported holding employment or leadership positions, serving in consultant or advisory roles, having stock ownership, and/or receiving honoraria or research funding from numerous pharmaceutical and other companies.

Among older men with high-risk prostate cancer, receiving androgen-deprivation therapy in combination with radiotherapy reduced cause-specific and all-cause mortality by as much as 50% when compared with those who received androgen-deprivation therapy alone, results from a large-scale data review showed.

In fact, men over the age of 65 with locally advanced prostate cancer risk significantly higher mortality rates if they are treated with androgen-deprivation therapy (ADT) without accompanying radiotherapy (RT), according to the authors of a study published online Jan. 5 in the Journal of Clinical Oncology.

“Our findings raise a provocative hypothesis that in the United States, men age 75 years (or older) with locally advanced prostate cancer or men age 65 years (or older) with high-risk screen-detected prostate cancer who receive ADT alone risk decrements in cause-specific and overall survival,” wrote Dr. Justin E. Bekelman and his associates (J. Clin. Oncol. 2015 Jan. 5 [doi:10.1200/JCO.2014.57.2743]).

The large-scale data review, led by Dr. Bekelman of the University of Pennsylvania, Philadelphia, examined 31,451 men who developed prostate cancer between the ages of 65 and 85 whose medical records were included in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The men were diagnosed between 1995 and 2007 and observed through 2009.

The patients examined in the study were divided into three cohorts, including a primary cohort (which included men aged 65 to 75 years and was consistent with participants in randomized, controlled trials); an elderly cohort (which included men from 75 to 85 years old with locally advanced prostate cancer); and a screen-detected cohort (which included men over 65 years old with screen-detected high-risk prostate cancer).

Among men aged 76-85, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 5.0% of patients, compared with ADT alone at 7 years follow-up. Among men aged 65-75, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 4.4% compared with ADT alone at 7 years follow-up.

Though a number of studies have examined the effects of combination therapy for prostate cancer, the authors noted that geriatric patients are underrepresented in efficacy trials for prostate cancer therapy. In addition, androgen-deprivation therapy by itself is particularly common among patients older than 75, with 40% of patients in that age group receiving ADT without accompanying RT.

“The lack of evidence to guide prostate cancer treatment decisions among older men and those with screen-detected high-risk tumors stands as a special priority among the many evidence gaps in the treatment of prostate cancer,” the authors wrote.

mbock@frontlinemedcom.com

Among older men with high-risk prostate cancer, receiving androgen-deprivation therapy in combination with radiotherapy reduced cause-specific and all-cause mortality by as much as 50% when compared with those who received androgen-deprivation therapy alone, results from a large-scale data review showed.

In fact, men over the age of 65 with locally advanced prostate cancer risk significantly higher mortality rates if they are treated with androgen-deprivation therapy (ADT) without accompanying radiotherapy (RT), according to the authors of a study published online Jan. 5 in the Journal of Clinical Oncology.

“Our findings raise a provocative hypothesis that in the United States, men age 75 years (or older) with locally advanced prostate cancer or men age 65 years (or older) with high-risk screen-detected prostate cancer who receive ADT alone risk decrements in cause-specific and overall survival,” wrote Dr. Justin E. Bekelman and his associates (J. Clin. Oncol. 2015 Jan. 5 [doi:10.1200/JCO.2014.57.2743]).

The large-scale data review, led by Dr. Bekelman of the University of Pennsylvania, Philadelphia, examined 31,451 men who developed prostate cancer between the ages of 65 and 85 whose medical records were included in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The men were diagnosed between 1995 and 2007 and observed through 2009.

The patients examined in the study were divided into three cohorts, including a primary cohort (which included men aged 65 to 75 years and was consistent with participants in randomized, controlled trials); an elderly cohort (which included men from 75 to 85 years old with locally advanced prostate cancer); and a screen-detected cohort (which included men over 65 years old with screen-detected high-risk prostate cancer).

Among men aged 76-85, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 5.0% of patients, compared with ADT alone at 7 years follow-up. Among men aged 65-75, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 4.4% compared with ADT alone at 7 years follow-up.

Though a number of studies have examined the effects of combination therapy for prostate cancer, the authors noted that geriatric patients are underrepresented in efficacy trials for prostate cancer therapy. In addition, androgen-deprivation therapy by itself is particularly common among patients older than 75, with 40% of patients in that age group receiving ADT without accompanying RT.

“The lack of evidence to guide prostate cancer treatment decisions among older men and those with screen-detected high-risk tumors stands as a special priority among the many evidence gaps in the treatment of prostate cancer,” the authors wrote.

mbock@frontlinemedcom.com

Among older men with high-risk prostate cancer, receiving androgen-deprivation therapy in combination with radiotherapy reduced cause-specific and all-cause mortality by as much as 50% when compared with those who received androgen-deprivation therapy alone, results from a large-scale data review showed.

In fact, men over the age of 65 with locally advanced prostate cancer risk significantly higher mortality rates if they are treated with androgen-deprivation therapy (ADT) without accompanying radiotherapy (RT), according to the authors of a study published online Jan. 5 in the Journal of Clinical Oncology.

“Our findings raise a provocative hypothesis that in the United States, men age 75 years (or older) with locally advanced prostate cancer or men age 65 years (or older) with high-risk screen-detected prostate cancer who receive ADT alone risk decrements in cause-specific and overall survival,” wrote Dr. Justin E. Bekelman and his associates (J. Clin. Oncol. 2015 Jan. 5 [doi:10.1200/JCO.2014.57.2743]).

The large-scale data review, led by Dr. Bekelman of the University of Pennsylvania, Philadelphia, examined 31,451 men who developed prostate cancer between the ages of 65 and 85 whose medical records were included in the Surveillance, Epidemiology, and End Results (SEER) Medicare database. The men were diagnosed between 1995 and 2007 and observed through 2009.

The patients examined in the study were divided into three cohorts, including a primary cohort (which included men aged 65 to 75 years and was consistent with participants in randomized, controlled trials); an elderly cohort (which included men from 75 to 85 years old with locally advanced prostate cancer); and a screen-detected cohort (which included men over 65 years old with screen-detected high-risk prostate cancer).

Among men aged 76-85, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 5.0% of patients, compared with ADT alone at 7 years follow-up. Among men aged 65-75, ADT plus RT reduced cause-specific and all-cause mortality from 9.8% to 4.4% compared with ADT alone at 7 years follow-up.

Though a number of studies have examined the effects of combination therapy for prostate cancer, the authors noted that geriatric patients are underrepresented in efficacy trials for prostate cancer therapy. In addition, androgen-deprivation therapy by itself is particularly common among patients older than 75, with 40% of patients in that age group receiving ADT without accompanying RT.

“The lack of evidence to guide prostate cancer treatment decisions among older men and those with screen-detected high-risk tumors stands as a special priority among the many evidence gaps in the treatment of prostate cancer,” the authors wrote.

mbock@frontlinemedcom.com

Patients with prostate cancer who have elevated levels of testosterone should be investigated for use of topical androgens taken either by themselves or by their sexual partners, investigators suggested in reporting an unusual case history.

They found increasing levels of testosterone above the normal range, consistent with exogenous receipt of androgens, in a 68-year-old patient with prostate cancer who denied the use of androgens. Prostate-specific antigen at baseline was 4.8 ng/mL. After treatment with radical prostatectomy, the PSA never became undetectable, but it declined to a nadir of 0.05, reported Dr. Mhd Yaser Al-Marrawi and his colleagues. The results were published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2015 Jan 5. [doi: 10.1200/JCO.2014.59.7773]).

A year later, PSA increased to 0.18 and the patient underwent salvage external beam radiotherapy. However, his PSA continued to increase, and 2 months later it was 0.53, consistent with failure of local therapy, noted Dr. Al-Marrawi of Penn State University and the Hershey Cancer Institute in Hershey, Pa., and associates.

They eventually discovered that the persistently high testosterone levels were caused by the spouse’s use of topical testosterone cream vaginally as a lubricant before intercourse, to relieve dryness, unbeknownst to the patient.

“Topically applied testosterone gels are absorbed rather slowly, and they presumably form a reservoir in the stratum corneum of the skin. This reservoir of testosterone is then leached into the capillary circulation. Theoretically, more testosterone absorption will occur in the presence of a profuse vasculature. This situation is present in both male and female genitals during sexual intercourse,” the authors speculated.

The patient’s PSA continued to rise after his wife ceased using the testosterone cream, and he ultimately began androgen-deprivation therapy.

mbock@frontlinemedcom.com

Patients with prostate cancer who have elevated levels of testosterone should be investigated for use of topical androgens taken either by themselves or by their sexual partners, investigators suggested in reporting an unusual case history.

They found increasing levels of testosterone above the normal range, consistent with exogenous receipt of androgens, in a 68-year-old patient with prostate cancer who denied the use of androgens. Prostate-specific antigen at baseline was 4.8 ng/mL. After treatment with radical prostatectomy, the PSA never became undetectable, but it declined to a nadir of 0.05, reported Dr. Mhd Yaser Al-Marrawi and his colleagues. The results were published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2015 Jan 5. [doi: 10.1200/JCO.2014.59.7773]).

A year later, PSA increased to 0.18 and the patient underwent salvage external beam radiotherapy. However, his PSA continued to increase, and 2 months later it was 0.53, consistent with failure of local therapy, noted Dr. Al-Marrawi of Penn State University and the Hershey Cancer Institute in Hershey, Pa., and associates.

They eventually discovered that the persistently high testosterone levels were caused by the spouse’s use of topical testosterone cream vaginally as a lubricant before intercourse, to relieve dryness, unbeknownst to the patient.

“Topically applied testosterone gels are absorbed rather slowly, and they presumably form a reservoir in the stratum corneum of the skin. This reservoir of testosterone is then leached into the capillary circulation. Theoretically, more testosterone absorption will occur in the presence of a profuse vasculature. This situation is present in both male and female genitals during sexual intercourse,” the authors speculated.

The patient’s PSA continued to rise after his wife ceased using the testosterone cream, and he ultimately began androgen-deprivation therapy.

mbock@frontlinemedcom.com

Patients with prostate cancer who have elevated levels of testosterone should be investigated for use of topical androgens taken either by themselves or by their sexual partners, investigators suggested in reporting an unusual case history.

They found increasing levels of testosterone above the normal range, consistent with exogenous receipt of androgens, in a 68-year-old patient with prostate cancer who denied the use of androgens. Prostate-specific antigen at baseline was 4.8 ng/mL. After treatment with radical prostatectomy, the PSA never became undetectable, but it declined to a nadir of 0.05, reported Dr. Mhd Yaser Al-Marrawi and his colleagues. The results were published online in the Journal of Clinical Oncology (J. Clin. Oncol. 2015 Jan 5. [doi: 10.1200/JCO.2014.59.7773]).

A year later, PSA increased to 0.18 and the patient underwent salvage external beam radiotherapy. However, his PSA continued to increase, and 2 months later it was 0.53, consistent with failure of local therapy, noted Dr. Al-Marrawi of Penn State University and the Hershey Cancer Institute in Hershey, Pa., and associates.

They eventually discovered that the persistently high testosterone levels were caused by the spouse’s use of topical testosterone cream vaginally as a lubricant before intercourse, to relieve dryness, unbeknownst to the patient.

“Topically applied testosterone gels are absorbed rather slowly, and they presumably form a reservoir in the stratum corneum of the skin. This reservoir of testosterone is then leached into the capillary circulation. Theoretically, more testosterone absorption will occur in the presence of a profuse vasculature. This situation is present in both male and female genitals during sexual intercourse,” the authors speculated.

The patient’s PSA continued to rise after his wife ceased using the testosterone cream, and he ultimately began androgen-deprivation therapy.

mbock@frontlinemedcom.com

Mounting evidence suggests that there may be an increased risk of prostate cancer among men with the highest levels of vitamin D.

At a public conference on vitamin D sponsored by the National Institutes of Health, Dr. Demetrius Albanes highlighted several studies in the medical literature, including a meta-analysis which found a 1.17-fold increased risk of prostate cancer among men in the highest categories of 25-hydroxy vitamin D [25(OH)D] status. That analysis was based on a review of 21 prospective cohorts involving 11,941 incident cases of prostate cancer (J. Cancer Res. Clin. Oncol. 2014;140:1465-77). Similar findings were observed in an earlier Swedish study (Cancer Causes Control; 2012;23:1377-85).

Genetic variants in four genes have been shown to predict circulating levels of vitamin D: GC, CYP24A1, CYP2R1, and DHCR7. However, a large analysis of cases and controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium failed to demonstrate a protective association between loci known to influence vitamin D levels and prostate cancer risk (Cancer Epidemiol. Biomarkers Prev. 2013;22:688-96). In another study, Dr. Albanes and his associates found that serum vitamin D–binding protein (DBP) modified the association between serum 25-hydroxy vitamin D and prostate cancer, with higher risk for elevated 25-hydroxy vitamin D levels observed mainly among men having DBP concentrations above the median (odds ratio, 1.81 for highest vs. lowest quintile; P = .001) (Int. J. Cancer 2013; 132:2940-7).

“This adds to the serologic evidence that we have seen mounting for an adverse association between higher vitamin D status and prostate cancer risk,” said Dr. Albanes, a senior investigator in the Nutritional Epidemiology Branch of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. “Many mechanisms could be put forward to be related to this. One is related to the association between a higher 25-hydroxy vitamin D status and total testosterone.” Researchers involved in an Oxford-based biomarkers project are currently analyzing vitamin D data from 12,500 cases and 15,000 controls in 32 cohorts (http://www.ceu.ox.ac.uk/research/27/). Investigators from that effort “will weigh in on this topic,” he said. But for now, “there are no large trial data regarding vitamin D and prostate cancer; those would be very useful. Androgens and cell metabolism proliferation would be key targets as to how this might be coming about. I think it indicates that caution is indicated for this highly incident cancer worldwide.”

As for the impact of 25-hydroxy vitamin D on other cancers, most reports from observational studies are indicating an inverse (protective) association between 25-hydroxyvitamin D and the risk of colorectal cancer, yet data from the controlled trial component of the Women’s Health Initiative found no impact of the 400 IU dose combined with calcium after 8 years of supplementation (N. Engl. J. Med. 2006; 354:684-96). Possible mechanisms of actions include the fact that 1,600 chromatin vitamin D response elements impact target genes in the colon and that vitamin D3 receptor and 1a-hydroxylase is expressed in extrarenal tissues including the colon. The anti-inflammation impact of higher vitamin D status or detoxification of secondary bile acids may also play a role.

With regard to pancreatic cancer, studies have shown an association between high concentrations of circulating levels of serum vitamin D and an elevated risk of this cancer type. A recent analysis by researchers including Dr. Albanes found that men with higher 25-hydroxy vitamin D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR, 5.01 for highest vs. lowest quartile; P less than .0001), while risk was weakly inversely associated with serum 25-hydroxy vitamin D when DBP concentrations were higher (P = .001) (Cancer Research 2012; 72:1190-98).

“The organ site differences are likely,” Dr. Albanes concluded. “Adverse associations do seem possible for prostate and pancreas, particularly strong at this point for prostate. We need additional targeted mechanistic research based on these observations. How is it that higher 25-hydroxy vitamin D status is related to a lowering of risk in colorectal cancer whereas in prostate cancer it’s elevated risk? Is it the androgen pathway? Is it cell proliferation? Consideration of cancer in the ranking of outcomes would have clinical and public health relevance, but that’s a [different] discussion.”

Dr. Albanes reported having no financial disclosures.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Mounting evidence suggests that there may be an increased risk of prostate cancer among men with the highest levels of vitamin D.

At a public conference on vitamin D sponsored by the National Institutes of Health, Dr. Demetrius Albanes highlighted several studies in the medical literature, including a meta-analysis which found a 1.17-fold increased risk of prostate cancer among men in the highest categories of 25-hydroxy vitamin D [25(OH)D] status. That analysis was based on a review of 21 prospective cohorts involving 11,941 incident cases of prostate cancer (J. Cancer Res. Clin. Oncol. 2014;140:1465-77). Similar findings were observed in an earlier Swedish study (Cancer Causes Control; 2012;23:1377-85).

Genetic variants in four genes have been shown to predict circulating levels of vitamin D: GC, CYP24A1, CYP2R1, and DHCR7. However, a large analysis of cases and controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium failed to demonstrate a protective association between loci known to influence vitamin D levels and prostate cancer risk (Cancer Epidemiol. Biomarkers Prev. 2013;22:688-96). In another study, Dr. Albanes and his associates found that serum vitamin D–binding protein (DBP) modified the association between serum 25-hydroxy vitamin D and prostate cancer, with higher risk for elevated 25-hydroxy vitamin D levels observed mainly among men having DBP concentrations above the median (odds ratio, 1.81 for highest vs. lowest quintile; P = .001) (Int. J. Cancer 2013; 132:2940-7).

“This adds to the serologic evidence that we have seen mounting for an adverse association between higher vitamin D status and prostate cancer risk,” said Dr. Albanes, a senior investigator in the Nutritional Epidemiology Branch of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. “Many mechanisms could be put forward to be related to this. One is related to the association between a higher 25-hydroxy vitamin D status and total testosterone.” Researchers involved in an Oxford-based biomarkers project are currently analyzing vitamin D data from 12,500 cases and 15,000 controls in 32 cohorts (http://www.ceu.ox.ac.uk/research/27/). Investigators from that effort “will weigh in on this topic,” he said. But for now, “there are no large trial data regarding vitamin D and prostate cancer; those would be very useful. Androgens and cell metabolism proliferation would be key targets as to how this might be coming about. I think it indicates that caution is indicated for this highly incident cancer worldwide.”

As for the impact of 25-hydroxy vitamin D on other cancers, most reports from observational studies are indicating an inverse (protective) association between 25-hydroxyvitamin D and the risk of colorectal cancer, yet data from the controlled trial component of the Women’s Health Initiative found no impact of the 400 IU dose combined with calcium after 8 years of supplementation (N. Engl. J. Med. 2006; 354:684-96). Possible mechanisms of actions include the fact that 1,600 chromatin vitamin D response elements impact target genes in the colon and that vitamin D3 receptor and 1a-hydroxylase is expressed in extrarenal tissues including the colon. The anti-inflammation impact of higher vitamin D status or detoxification of secondary bile acids may also play a role.

With regard to pancreatic cancer, studies have shown an association between high concentrations of circulating levels of serum vitamin D and an elevated risk of this cancer type. A recent analysis by researchers including Dr. Albanes found that men with higher 25-hydroxy vitamin D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR, 5.01 for highest vs. lowest quartile; P less than .0001), while risk was weakly inversely associated with serum 25-hydroxy vitamin D when DBP concentrations were higher (P = .001) (Cancer Research 2012; 72:1190-98).

“The organ site differences are likely,” Dr. Albanes concluded. “Adverse associations do seem possible for prostate and pancreas, particularly strong at this point for prostate. We need additional targeted mechanistic research based on these observations. How is it that higher 25-hydroxy vitamin D status is related to a lowering of risk in colorectal cancer whereas in prostate cancer it’s elevated risk? Is it the androgen pathway? Is it cell proliferation? Consideration of cancer in the ranking of outcomes would have clinical and public health relevance, but that’s a [different] discussion.”

Dr. Albanes reported having no financial disclosures.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Mounting evidence suggests that there may be an increased risk of prostate cancer among men with the highest levels of vitamin D.

At a public conference on vitamin D sponsored by the National Institutes of Health, Dr. Demetrius Albanes highlighted several studies in the medical literature, including a meta-analysis which found a 1.17-fold increased risk of prostate cancer among men in the highest categories of 25-hydroxy vitamin D [25(OH)D] status. That analysis was based on a review of 21 prospective cohorts involving 11,941 incident cases of prostate cancer (J. Cancer Res. Clin. Oncol. 2014;140:1465-77). Similar findings were observed in an earlier Swedish study (Cancer Causes Control; 2012;23:1377-85).

Genetic variants in four genes have been shown to predict circulating levels of vitamin D: GC, CYP24A1, CYP2R1, and DHCR7. However, a large analysis of cases and controls from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium failed to demonstrate a protective association between loci known to influence vitamin D levels and prostate cancer risk (Cancer Epidemiol. Biomarkers Prev. 2013;22:688-96). In another study, Dr. Albanes and his associates found that serum vitamin D–binding protein (DBP) modified the association between serum 25-hydroxy vitamin D and prostate cancer, with higher risk for elevated 25-hydroxy vitamin D levels observed mainly among men having DBP concentrations above the median (odds ratio, 1.81 for highest vs. lowest quintile; P = .001) (Int. J. Cancer 2013; 132:2940-7).

“This adds to the serologic evidence that we have seen mounting for an adverse association between higher vitamin D status and prostate cancer risk,” said Dr. Albanes, a senior investigator in the Nutritional Epidemiology Branch of the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. “Many mechanisms could be put forward to be related to this. One is related to the association between a higher 25-hydroxy vitamin D status and total testosterone.” Researchers involved in an Oxford-based biomarkers project are currently analyzing vitamin D data from 12,500 cases and 15,000 controls in 32 cohorts (http://www.ceu.ox.ac.uk/research/27/). Investigators from that effort “will weigh in on this topic,” he said. But for now, “there are no large trial data regarding vitamin D and prostate cancer; those would be very useful. Androgens and cell metabolism proliferation would be key targets as to how this might be coming about. I think it indicates that caution is indicated for this highly incident cancer worldwide.”

As for the impact of 25-hydroxy vitamin D on other cancers, most reports from observational studies are indicating an inverse (protective) association between 25-hydroxyvitamin D and the risk of colorectal cancer, yet data from the controlled trial component of the Women’s Health Initiative found no impact of the 400 IU dose combined with calcium after 8 years of supplementation (N. Engl. J. Med. 2006; 354:684-96). Possible mechanisms of actions include the fact that 1,600 chromatin vitamin D response elements impact target genes in the colon and that vitamin D3 receptor and 1a-hydroxylase is expressed in extrarenal tissues including the colon. The anti-inflammation impact of higher vitamin D status or detoxification of secondary bile acids may also play a role.

With regard to pancreatic cancer, studies have shown an association between high concentrations of circulating levels of serum vitamin D and an elevated risk of this cancer type. A recent analysis by researchers including Dr. Albanes found that men with higher 25-hydroxy vitamin D concentrations and serum DBP below the median showed greatly elevated risk of pancreatic cancer (OR, 5.01 for highest vs. lowest quartile; P less than .0001), while risk was weakly inversely associated with serum 25-hydroxy vitamin D when DBP concentrations were higher (P = .001) (Cancer Research 2012; 72:1190-98).

“The organ site differences are likely,” Dr. Albanes concluded. “Adverse associations do seem possible for prostate and pancreas, particularly strong at this point for prostate. We need additional targeted mechanistic research based on these observations. How is it that higher 25-hydroxy vitamin D status is related to a lowering of risk in colorectal cancer whereas in prostate cancer it’s elevated risk? Is it the androgen pathway? Is it cell proliferation? Consideration of cancer in the ranking of outcomes would have clinical and public health relevance, but that’s a [different] discussion.”

Dr. Albanes reported having no financial disclosures.

dbrunk@frontlinemedcom.com

On Twitter @dougbrunk

Active surveillance appears to be safe through 15 years of follow-up for men who have low-risk prostate cancer, according to a report published online Dec. 15 in the Journal of Clinical Oncology.

In extended follow-up of a prospective cohort study begun in 1995, 993 men (current median age, 68 years; range, 41-89 years) with low-risk prostate cancer were assessed. Active surveillance consisted of PSA testing every 3 months for the first 2 years after diagnosis and then every 6 months thereafter, with repeat biopsy at 1 year and then every 3-4 years until the age of 80. These study participants were offered radical intervention only if the disease showed signs of progression, said Dr. Laurence Klotz of Sunnybrook Health Sciences Centre, University of Toronto, and his associates.

A total of 149 patients died, 819 were alive, and 25 were lost to follow-up. Only 15 men (1.5%) died from prostate cancer, and an additional 13 men with confirmed metastases either are alive (9 patients) or died from other causes (4 patients). Overall, the risk of dying from another cause was nearly 10 times greater than that for dying from prostate cancer (HR, 9.2). Even among men younger than 70, who had lower competing risks of death from other causes than older men, the risk of death from another cause was almost six times greater than that for death from prostate cancer (HR, 5.8), the investigators said (J. Clin. Oncol. 2014 Dec. 15 [doi:10.1200/JCO.2014.55.1192]).

The rate of patients who developed PSA failure during follow-up was 2.8% at 5 years and 10.2% at 10 years after diagnosis. These outcomes are consistent with those in low-risk patients managed with initial definitive intervention such as radiotherapy and surgery, Dr. Klotz and his associates added.

This study was supported by the Prostate Cancer Research Foundation of Canada. Dr. Klotz and his associates reported having no financial conflicts of interest.

Active surveillance appears to be safe through 15 years of follow-up for men who have low-risk prostate cancer, according to a report published online Dec. 15 in the Journal of Clinical Oncology.

In extended follow-up of a prospective cohort study begun in 1995, 993 men (current median age, 68 years; range, 41-89 years) with low-risk prostate cancer were assessed. Active surveillance consisted of PSA testing every 3 months for the first 2 years after diagnosis and then every 6 months thereafter, with repeat biopsy at 1 year and then every 3-4 years until the age of 80. These study participants were offered radical intervention only if the disease showed signs of progression, said Dr. Laurence Klotz of Sunnybrook Health Sciences Centre, University of Toronto, and his associates.

A total of 149 patients died, 819 were alive, and 25 were lost to follow-up. Only 15 men (1.5%) died from prostate cancer, and an additional 13 men with confirmed metastases either are alive (9 patients) or died from other causes (4 patients). Overall, the risk of dying from another cause was nearly 10 times greater than that for dying from prostate cancer (HR, 9.2). Even among men younger than 70, who had lower competing risks of death from other causes than older men, the risk of death from another cause was almost six times greater than that for death from prostate cancer (HR, 5.8), the investigators said (J. Clin. Oncol. 2014 Dec. 15 [doi:10.1200/JCO.2014.55.1192]).

The rate of patients who developed PSA failure during follow-up was 2.8% at 5 years and 10.2% at 10 years after diagnosis. These outcomes are consistent with those in low-risk patients managed with initial definitive intervention such as radiotherapy and surgery, Dr. Klotz and his associates added.

This study was supported by the Prostate Cancer Research Foundation of Canada. Dr. Klotz and his associates reported having no financial conflicts of interest.

Active surveillance appears to be safe through 15 years of follow-up for men who have low-risk prostate cancer, according to a report published online Dec. 15 in the Journal of Clinical Oncology.

In extended follow-up of a prospective cohort study begun in 1995, 993 men (current median age, 68 years; range, 41-89 years) with low-risk prostate cancer were assessed. Active surveillance consisted of PSA testing every 3 months for the first 2 years after diagnosis and then every 6 months thereafter, with repeat biopsy at 1 year and then every 3-4 years until the age of 80. These study participants were offered radical intervention only if the disease showed signs of progression, said Dr. Laurence Klotz of Sunnybrook Health Sciences Centre, University of Toronto, and his associates.

A total of 149 patients died, 819 were alive, and 25 were lost to follow-up. Only 15 men (1.5%) died from prostate cancer, and an additional 13 men with confirmed metastases either are alive (9 patients) or died from other causes (4 patients). Overall, the risk of dying from another cause was nearly 10 times greater than that for dying from prostate cancer (HR, 9.2). Even among men younger than 70, who had lower competing risks of death from other causes than older men, the risk of death from another cause was almost six times greater than that for death from prostate cancer (HR, 5.8), the investigators said (J. Clin. Oncol. 2014 Dec. 15 [doi:10.1200/JCO.2014.55.1192]).

The rate of patients who developed PSA failure during follow-up was 2.8% at 5 years and 10.2% at 10 years after diagnosis. These outcomes are consistent with those in low-risk patients managed with initial definitive intervention such as radiotherapy and surgery, Dr. Klotz and his associates added.

This study was supported by the Prostate Cancer Research Foundation of Canada. Dr. Klotz and his associates reported having no financial conflicts of interest.

POINT: Dr. Epstein

The pathologic answer favoring [calling Gleason pattern 3 and Gleason score 6] cancer is that morphologically, it is cancer. There is a loss of basal cells, which is not seen in benign glands. Psychologically and architecturally, it is indistinguishable from higher-grade cancer. You can see perineural invasion, you can see extraprostatic extension – which you don’t see with benign glands – and it merges in with higher-grade cancer. If we look at Gleason score 6 cancer wrapping around a nerve, and if we look at Gleason score 6 invading outside the prostate around the seminal vesicles – this is cancer. Benign glands don’t invade out of the prostate.

Gleason score 6 tumors exist on a molecular continuum with higher-grade cancers; it’s not that they don’t have any molecular features with cancer. If you look at PTEN loss, which is something associated with more aggressive cancer, it’s present in about 5% of Gleason score 6 cancers. Obviously Gleason score 6 has less PTEN loss than higher-grade cancers, but it’s a continuum; it’s not that they don’t have any PTEN loss.

Also, if you look at copy number alterations across the genome, it’s a spectrum across Gleason score 6. Of course, there is an increase [in copy number alterations] among the higher-grade cancers, but it’s not as if there are no copy number alterations among Gleason score 6. That is cancer, it’s just a lower-grade cancer.

Sometimes, in important molecular markers that we look at, Gleason score 6 cancer actually has the same hallmarks as higher-grade cancer: ERG rearrangement is just as common in Gleason score 6 cancer as in Gleason score 7 cancer and above; the relative risk of even Gleason score 8-10 vs. Gleason score 6 for ERG-positive tumors is identical in Gleason score 7 as well. If you look at mutation numbers, Gleason score 6 tumors have mutation numbers similar to those of higher-grade cancers. Again, the emphasis is [that] Gleason score 6 has some of the molecular alterations of cancer, just less so, compared with higher-grade cancer.

Now, let’s take the argument that we’re not going to call it cancer – so what would we call it? One of the terms that has been proposed is “IDLE tumor,” meaning indolent lesion of epithelial origin, or maybe a low malignant potential tumor. Would this make sense if you’re a urologist and you receive a pathology report? An IDLE tumor involving eight cores, 60%-80%, and the patient has a palpable lesion with a PSA [prostate-specific antigen ] above 20? Of course not; you know the patient has cancer, it’s probably an aggressive cancer, and the biopsy just missed the higher-grade lesion.

Also, what happens if you have some cores that have a Gleason score 6 and others of a higher grade? Now, all of a sudden, we don’t call it Gleason score 6 cancer. You’re going to get a pathology report where some of the cores are called an IDLE tumor and some are called Gleason score 7, but we all know that they’re the same tumor. And what happens when we have a tumor that has a mixture of well-formed glands of pattern 3, and poorly formed glands of pattern 4? Is it 3+4 or 4+3? We know it’s all one tumor, and we know that [pattern] 3 has an effect on the tumor, but suddenly we’re saying that if a tumor is all pattern 3, it’s not cancer. If we mix it with pattern 4, then it’s cancer. Again, this is not consistent, and intellectually does not make any sense.

Probably the biggest reason why we want to continue calling Gleason score 6 cancer is the issue of sampling error. If I could have a crystal ball and say that [a] patient has only a Gleason score 6 on the radical prostatectomy, and I’m 100% sure there’s nothing else, I would entertain potentially calling it something other than cancer. But the answer is that about 20% of the time, when we call something Gleason score 6 on a biopsy, it’s Gleason score 7 or higher because of a sampling error. If we don’t call it cancer, and instead use some euphemism for cancer, there will be a significant number of men with Gleason score 6 cancer who won’t be followed as closely, who will drop out of the system, and who will potentially progress to incurable cancer.

The way I look at it, Gleason score 6 cancer is similar to other indolent cancers we have in the body: squamous cell carcinoma, basal cell carcinoma, etc. We call these cancers, but patients have been educated that these are not very aggressive and, for the most part, are not particularly lethal. But they still need to be followed, and patients can deal with this in a rational manner.

So what I think we need is public education. We have to educate patients that most Gleason score 6 cancers can be followed with active surveillance, that they could have a good form of cancer that generally does not cause harm, but that they have to emphasize that there is a risk of having a more aggressive type of cancer that might have been missed, that the cancer could potentially change over time, and that the patient must be followed closely.

I think more and more patients are asking for active surveillance, compared with prior years, and I think urologists need to buy into the concept of “good cancer” to educate the appropriate patients for active surveillance because urologists are the first clinicians that patients typically see following their diagnosis.

One of the problems is that we don’t see Gleason patterns 1 and 2 anymore, so we don’t diagnose Gleason scores 2-5 anymore, for the most part. This makes Gleason score 6 pretty much the lowest cancer we see. The problem is that patients hear they have a Gleason score 6 tumor, they go on the Internet and find out the scale goes from 2-10, and they think their tumor is somewhere in the middle of the range.

Therefore, we are proposing a new grading system. We recently had a meeting in Chicago, which was attended by 85 prostate cancer experts, and this new grading system was accepted to be used, initially, in conjunction with the current Gleason scale. Basically, in the new scale, Gleason scores 2-6 are graded 1 out of 5; Gleason score 3+4=7 would be 2 out of 5; 4+3=7 would be 3 out of 5; Gleason score 8 would be a 4 out of 5; and Gleason scores 9-10 would be a 5 out of 5.

In summary, I don’t think we need to change calling Gleason score 6 cancer. We need to change what patients think when they hear that they have Gleason score 6 cancer. Urologists have to reassure and educate patients, and if you modify the grading system to tell someone that they have a grade 1 tumor out of 5 instead of a 6 out of 10, it will help reassure patients and realign the grading system in prostate cancer so Gleason score 6 tumors are more appropriately considered as indolent, but something that still needs following.

Dr. Jonathan I. Epstein is a professor of pathology, urology and oncology at Johns Hopkins University Hospital, Baltimore. He reported no relevant financial disclosures.

COUNTERPOINT: Dr. Rubin

If we were to name Gleason pattern 3 and Gleason score 6 today, we might go with something different. For me, the term “adenoma” comes to mind because adenomas are neoplastic, but we don’t call them cancer.

It’s very important to remind ourselves that if we look at a spectrum of cancer, ranging from indolent to aggressive, many of the [pertinent] studies that we’ve read or heard about are taken from a very discrete, carefully culled set of cancers in patients who were undergoing radical prostatectomies. One should consider that population-based studies are important for this type of evaluation. We should also remind ourselves that nothing in life is zero risk; even going to the gym and running has some risk associated with it, so the fact that we choose to classify something as cancer or an adenoma will always have some risk associated with it.

In a multi-institutional study that Dr. Epstein published recently, he described the risk of Gleason score 6 cancer progressing as approximately 3%. So what does 3% mean? Well, those 3% [of patients] led to prognostic categorizations similar to the ones we just heard about, and one of the important things to remember is that the endpoint here is biochemical recurrence.

A recently published study employed a modeling exercise to look at the meaning of biochemical failure. In that analysis, going from radical prostatectomy to developing biochemical failure, what is the likelihood that you’re going to have metastatic disease? This analysis found no significant association, at least in Gleason score 6 disease, for developing metastatic disease. So that 3% becomes a much smaller risk.

Continuing with Dr. Epstein’s work, he and his associates reviewed around 14,000 cases and identified 22 cases that had Gleason score 6 on the radical prostatectomy but showed metastatic disease. Every one of those cases were rereviewed and upgraded using the new classification system that Dr. Epstein outlined. The conclusion of this analysis was that “in contrast to prevailing assumptions, Gleason score 6 tumors do not appear to metastasize to lymph nodes.”

So what about cancer-specific death? In studies from multiple institutions, where they looked at Gleason score 6 cancers and asked what the likelihood was of dying from prostate cancer vs. competing causes, the former had a very low risk of cancer-specific death in patients 60 years and younger.

We performed similar analysis at the Harvard School of Public Health, Boston, a few years ago, looking at the Physicians’ Health Study and the Health Professionals Follow-Up Study and saw that when we re-created the biopsies and radicals, the scores of Gleason 6 and lower went up to Gleason 7 very often. In a blinded analysis, not one of the Gleason score 6 tumors was associated with lethal prostate cancer.

You’re probably thinking about what we know about conservative management in the setting of localized cancer. I would refer you to the work of Dr. Peter C. Albertsen at the Connecticut Tumor Registry, where by looking at similar types of outcomes between cancer-specific deaths and competing causes, it’s shown that there’s very low risk of dying from prostate cancer with Gleason scores 2-6 (statistics are unadjusted for deaths per 1,000 patients).

From the molecular standpoint – we’ve heard a number of times that various cancers have a risk of somatic alterations. Prostate cancer tends to have a very low number of somatic alterations, but copy number alterations are common, going from localized to advanced. We see driver mutation events occurring more in late-stage cancer, and this is provisional data from 333 localized prostate cancer [cases] from many institutions where it’s been organized from the bottom to the top starting with Gleason score 6.

What we can see is an accumulation of molecular alterations, but what I would highlight is that like adenomas, Gleason score 6 has certain characteristic alterations that we often see without driver events.

And going back to the Physicians’ Health study and the Swedish “Watchful Waiting” study, if we look at all lethal prostate cancers, the vast majority were Gleason score 7 and above. The Swedish cohort was pre-PSA, so some of these Gleason score 6 cancers were probably contaminated because of sampling. Even if we include them and look at principle component analysis, we see that the vast majority of the Gleason score 6 cases cluster together; they’re much more homogeneous, molecularly speaking, compared with the Gleason score 8 cancers that are heterogeneous and spread all over.

Another important analysis that will inform next-generation sequencing studies is to look at subclonal alterations. We believe that the subclonal mutations are the ones that are going to merge in as driver mutations, So what you can do is take the Cancer Genome Atlas data, as we’ve done, and go from Gleason score 6 all the way up to the higher-grade tumors. There are more deletions and genomic focus as you go higher, but also you see that the majority of Gleason score 6 cancers are clonal for these alterations. As you move on up to higher-grade tumors, you start seeing some subclonal emergence of driver lesions.

So I would argue that the Gleason pattern 3 or Gleason score 6 cancers have a very, very low risk of disease compared to other cancer grades and is not associated with death following definitive treatment, and is probably dramatically overtreated. It’s genetically homogeneous, and we see little evidence of subclonal driver mutations in Gleason score 6. So my answer to the question “Should Gleason score 6 be called cancer?” is “no.” But I do agree entirely that we need to have categories of risk, and so Gleason score 6 – or whatever we end up calling it – should be recognized as a group of tumors with a very low risk of aggressiveness.

Dr. Mark A. Rubin is the director of the Institute for Precision Medicine at Weill Cornell Medical College, New York. He reported no relevant financial disclosures.

Dr. Epstein and Dr. Rubin made their remarks at the annual meeting of the Society for Urologic Oncology. Reporter Deepak Chitnis covered their presentation.

POINT: Dr. Epstein

The pathologic answer favoring [calling Gleason pattern 3 and Gleason score 6] cancer is that morphologically, it is cancer. There is a loss of basal cells, which is not seen in benign glands. Psychologically and architecturally, it is indistinguishable from higher-grade cancer. You can see perineural invasion, you can see extraprostatic extension – which you don’t see with benign glands – and it merges in with higher-grade cancer. If we look at Gleason score 6 cancer wrapping around a nerve, and if we look at Gleason score 6 invading outside the prostate around the seminal vesicles – this is cancer. Benign glands don’t invade out of the prostate.

Gleason score 6 tumors exist on a molecular continuum with higher-grade cancers; it’s not that they don’t have any molecular features with cancer. If you look at PTEN loss, which is something associated with more aggressive cancer, it’s present in about 5% of Gleason score 6 cancers. Obviously Gleason score 6 has less PTEN loss than higher-grade cancers, but it’s a continuum; it’s not that they don’t have any PTEN loss.

Also, if you look at copy number alterations across the genome, it’s a spectrum across Gleason score 6. Of course, there is an increase [in copy number alterations] among the higher-grade cancers, but it’s not as if there are no copy number alterations among Gleason score 6. That is cancer, it’s just a lower-grade cancer.

Sometimes, in important molecular markers that we look at, Gleason score 6 cancer actually has the same hallmarks as higher-grade cancer: ERG rearrangement is just as common in Gleason score 6 cancer as in Gleason score 7 cancer and above; the relative risk of even Gleason score 8-10 vs. Gleason score 6 for ERG-positive tumors is identical in Gleason score 7 as well. If you look at mutation numbers, Gleason score 6 tumors have mutation numbers similar to those of higher-grade cancers. Again, the emphasis is [that] Gleason score 6 has some of the molecular alterations of cancer, just less so, compared with higher-grade cancer.

Now, let’s take the argument that we’re not going to call it cancer – so what would we call it? One of the terms that has been proposed is “IDLE tumor,” meaning indolent lesion of epithelial origin, or maybe a low malignant potential tumor. Would this make sense if you’re a urologist and you receive a pathology report? An IDLE tumor involving eight cores, 60%-80%, and the patient has a palpable lesion with a PSA [prostate-specific antigen ] above 20? Of course not; you know the patient has cancer, it’s probably an aggressive cancer, and the biopsy just missed the higher-grade lesion.

Also, what happens if you have some cores that have a Gleason score 6 and others of a higher grade? Now, all of a sudden, we don’t call it Gleason score 6 cancer. You’re going to get a pathology report where some of the cores are called an IDLE tumor and some are called Gleason score 7, but we all know that they’re the same tumor. And what happens when we have a tumor that has a mixture of well-formed glands of pattern 3, and poorly formed glands of pattern 4? Is it 3+4 or 4+3? We know it’s all one tumor, and we know that [pattern] 3 has an effect on the tumor, but suddenly we’re saying that if a tumor is all pattern 3, it’s not cancer. If we mix it with pattern 4, then it’s cancer. Again, this is not consistent, and intellectually does not make any sense.

Probably the biggest reason why we want to continue calling Gleason score 6 cancer is the issue of sampling error. If I could have a crystal ball and say that [a] patient has only a Gleason score 6 on the radical prostatectomy, and I’m 100% sure there’s nothing else, I would entertain potentially calling it something other than cancer. But the answer is that about 20% of the time, when we call something Gleason score 6 on a biopsy, it’s Gleason score 7 or higher because of a sampling error. If we don’t call it cancer, and instead use some euphemism for cancer, there will be a significant number of men with Gleason score 6 cancer who won’t be followed as closely, who will drop out of the system, and who will potentially progress to incurable cancer.

The way I look at it, Gleason score 6 cancer is similar to other indolent cancers we have in the body: squamous cell carcinoma, basal cell carcinoma, etc. We call these cancers, but patients have been educated that these are not very aggressive and, for the most part, are not particularly lethal. But they still need to be followed, and patients can deal with this in a rational manner.

So what I think we need is public education. We have to educate patients that most Gleason score 6 cancers can be followed with active surveillance, that they could have a good form of cancer that generally does not cause harm, but that they have to emphasize that there is a risk of having a more aggressive type of cancer that might have been missed, that the cancer could potentially change over time, and that the patient must be followed closely.

I think more and more patients are asking for active surveillance, compared with prior years, and I think urologists need to buy into the concept of “good cancer” to educate the appropriate patients for active surveillance because urologists are the first clinicians that patients typically see following their diagnosis.

One of the problems is that we don’t see Gleason patterns 1 and 2 anymore, so we don’t diagnose Gleason scores 2-5 anymore, for the most part. This makes Gleason score 6 pretty much the lowest cancer we see. The problem is that patients hear they have a Gleason score 6 tumor, they go on the Internet and find out the scale goes from 2-10, and they think their tumor is somewhere in the middle of the range.

Therefore, we are proposing a new grading system. We recently had a meeting in Chicago, which was attended by 85 prostate cancer experts, and this new grading system was accepted to be used, initially, in conjunction with the current Gleason scale. Basically, in the new scale, Gleason scores 2-6 are graded 1 out of 5; Gleason score 3+4=7 would be 2 out of 5; 4+3=7 would be 3 out of 5; Gleason score 8 would be a 4 out of 5; and Gleason scores 9-10 would be a 5 out of 5.

In summary, I don’t think we need to change calling Gleason score 6 cancer. We need to change what patients think when they hear that they have Gleason score 6 cancer. Urologists have to reassure and educate patients, and if you modify the grading system to tell someone that they have a grade 1 tumor out of 5 instead of a 6 out of 10, it will help reassure patients and realign the grading system in prostate cancer so Gleason score 6 tumors are more appropriately considered as indolent, but something that still needs following.

Dr. Jonathan I. Epstein is a professor of pathology, urology and oncology at Johns Hopkins University Hospital, Baltimore. He reported no relevant financial disclosures.

COUNTERPOINT: Dr. Rubin

If we were to name Gleason pattern 3 and Gleason score 6 today, we might go with something different. For me, the term “adenoma” comes to mind because adenomas are neoplastic, but we don’t call them cancer.

It’s very important to remind ourselves that if we look at a spectrum of cancer, ranging from indolent to aggressive, many of the [pertinent] studies that we’ve read or heard about are taken from a very discrete, carefully culled set of cancers in patients who were undergoing radical prostatectomies. One should consider that population-based studies are important for this type of evaluation. We should also remind ourselves that nothing in life is zero risk; even going to the gym and running has some risk associated with it, so the fact that we choose to classify something as cancer or an adenoma will always have some risk associated with it.

In a multi-institutional study that Dr. Epstein published recently, he described the risk of Gleason score 6 cancer progressing as approximately 3%. So what does 3% mean? Well, those 3% [of patients] led to prognostic categorizations similar to the ones we just heard about, and one of the important things to remember is that the endpoint here is biochemical recurrence.

A recently published study employed a modeling exercise to look at the meaning of biochemical failure. In that analysis, going from radical prostatectomy to developing biochemical failure, what is the likelihood that you’re going to have metastatic disease? This analysis found no significant association, at least in Gleason score 6 disease, for developing metastatic disease. So that 3% becomes a much smaller risk.

Continuing with Dr. Epstein’s work, he and his associates reviewed around 14,000 cases and identified 22 cases that had Gleason score 6 on the radical prostatectomy but showed metastatic disease. Every one of those cases were rereviewed and upgraded using the new classification system that Dr. Epstein outlined. The conclusion of this analysis was that “in contrast to prevailing assumptions, Gleason score 6 tumors do not appear to metastasize to lymph nodes.”

So what about cancer-specific death? In studies from multiple institutions, where they looked at Gleason score 6 cancers and asked what the likelihood was of dying from prostate cancer vs. competing causes, the former had a very low risk of cancer-specific death in patients 60 years and younger.

We performed similar analysis at the Harvard School of Public Health, Boston, a few years ago, looking at the Physicians’ Health Study and the Health Professionals Follow-Up Study and saw that when we re-created the biopsies and radicals, the scores of Gleason 6 and lower went up to Gleason 7 very often. In a blinded analysis, not one of the Gleason score 6 tumors was associated with lethal prostate cancer.

You’re probably thinking about what we know about conservative management in the setting of localized cancer. I would refer you to the work of Dr. Peter C. Albertsen at the Connecticut Tumor Registry, where by looking at similar types of outcomes between cancer-specific deaths and competing causes, it’s shown that there’s very low risk of dying from prostate cancer with Gleason scores 2-6 (statistics are unadjusted for deaths per 1,000 patients).

From the molecular standpoint – we’ve heard a number of times that various cancers have a risk of somatic alterations. Prostate cancer tends to have a very low number of somatic alterations, but copy number alterations are common, going from localized to advanced. We see driver mutation events occurring more in late-stage cancer, and this is provisional data from 333 localized prostate cancer [cases] from many institutions where it’s been organized from the bottom to the top starting with Gleason score 6.

What we can see is an accumulation of molecular alterations, but what I would highlight is that like adenomas, Gleason score 6 has certain characteristic alterations that we often see without driver events.

And going back to the Physicians’ Health study and the Swedish “Watchful Waiting” study, if we look at all lethal prostate cancers, the vast majority were Gleason score 7 and above. The Swedish cohort was pre-PSA, so some of these Gleason score 6 cancers were probably contaminated because of sampling. Even if we include them and look at principle component analysis, we see that the vast majority of the Gleason score 6 cases cluster together; they’re much more homogeneous, molecularly speaking, compared with the Gleason score 8 cancers that are heterogeneous and spread all over.

Another important analysis that will inform next-generation sequencing studies is to look at subclonal alterations. We believe that the subclonal mutations are the ones that are going to merge in as driver mutations, So what you can do is take the Cancer Genome Atlas data, as we’ve done, and go from Gleason score 6 all the way up to the higher-grade tumors. There are more deletions and genomic focus as you go higher, but also you see that the majority of Gleason score 6 cancers are clonal for these alterations. As you move on up to higher-grade tumors, you start seeing some subclonal emergence of driver lesions.

So I would argue that the Gleason pattern 3 or Gleason score 6 cancers have a very, very low risk of disease compared to other cancer grades and is not associated with death following definitive treatment, and is probably dramatically overtreated. It’s genetically homogeneous, and we see little evidence of subclonal driver mutations in Gleason score 6. So my answer to the question “Should Gleason score 6 be called cancer?” is “no.” But I do agree entirely that we need to have categories of risk, and so Gleason score 6 – or whatever we end up calling it – should be recognized as a group of tumors with a very low risk of aggressiveness.

Dr. Mark A. Rubin is the director of the Institute for Precision Medicine at Weill Cornell Medical College, New York. He reported no relevant financial disclosures.

Dr. Epstein and Dr. Rubin made their remarks at the annual meeting of the Society for Urologic Oncology. Reporter Deepak Chitnis covered their presentation.

POINT: Dr. Epstein

The pathologic answer favoring [calling Gleason pattern 3 and Gleason score 6] cancer is that morphologically, it is cancer. There is a loss of basal cells, which is not seen in benign glands. Psychologically and architecturally, it is indistinguishable from higher-grade cancer. You can see perineural invasion, you can see extraprostatic extension – which you don’t see with benign glands – and it merges in with higher-grade cancer. If we look at Gleason score 6 cancer wrapping around a nerve, and if we look at Gleason score 6 invading outside the prostate around the seminal vesicles – this is cancer. Benign glands don’t invade out of the prostate.

Gleason score 6 tumors exist on a molecular continuum with higher-grade cancers; it’s not that they don’t have any molecular features with cancer. If you look at PTEN loss, which is something associated with more aggressive cancer, it’s present in about 5% of Gleason score 6 cancers. Obviously Gleason score 6 has less PTEN loss than higher-grade cancers, but it’s a continuum; it’s not that they don’t have any PTEN loss.

Also, if you look at copy number alterations across the genome, it’s a spectrum across Gleason score 6. Of course, there is an increase [in copy number alterations] among the higher-grade cancers, but it’s not as if there are no copy number alterations among Gleason score 6. That is cancer, it’s just a lower-grade cancer.

Sometimes, in important molecular markers that we look at, Gleason score 6 cancer actually has the same hallmarks as higher-grade cancer: ERG rearrangement is just as common in Gleason score 6 cancer as in Gleason score 7 cancer and above; the relative risk of even Gleason score 8-10 vs. Gleason score 6 for ERG-positive tumors is identical in Gleason score 7 as well. If you look at mutation numbers, Gleason score 6 tumors have mutation numbers similar to those of higher-grade cancers. Again, the emphasis is [that] Gleason score 6 has some of the molecular alterations of cancer, just less so, compared with higher-grade cancer.

Now, let’s take the argument that we’re not going to call it cancer – so what would we call it? One of the terms that has been proposed is “IDLE tumor,” meaning indolent lesion of epithelial origin, or maybe a low malignant potential tumor. Would this make sense if you’re a urologist and you receive a pathology report? An IDLE tumor involving eight cores, 60%-80%, and the patient has a palpable lesion with a PSA [prostate-specific antigen ] above 20? Of course not; you know the patient has cancer, it’s probably an aggressive cancer, and the biopsy just missed the higher-grade lesion.

Also, what happens if you have some cores that have a Gleason score 6 and others of a higher grade? Now, all of a sudden, we don’t call it Gleason score 6 cancer. You’re going to get a pathology report where some of the cores are called an IDLE tumor and some are called Gleason score 7, but we all know that they’re the same tumor. And what happens when we have a tumor that has a mixture of well-formed glands of pattern 3, and poorly formed glands of pattern 4? Is it 3+4 or 4+3? We know it’s all one tumor, and we know that [pattern] 3 has an effect on the tumor, but suddenly we’re saying that if a tumor is all pattern 3, it’s not cancer. If we mix it with pattern 4, then it’s cancer. Again, this is not consistent, and intellectually does not make any sense.

Probably the biggest reason why we want to continue calling Gleason score 6 cancer is the issue of sampling error. If I could have a crystal ball and say that [a] patient has only a Gleason score 6 on the radical prostatectomy, and I’m 100% sure there’s nothing else, I would entertain potentially calling it something other than cancer. But the answer is that about 20% of the time, when we call something Gleason score 6 on a biopsy, it’s Gleason score 7 or higher because of a sampling error. If we don’t call it cancer, and instead use some euphemism for cancer, there will be a significant number of men with Gleason score 6 cancer who won’t be followed as closely, who will drop out of the system, and who will potentially progress to incurable cancer.

The way I look at it, Gleason score 6 cancer is similar to other indolent cancers we have in the body: squamous cell carcinoma, basal cell carcinoma, etc. We call these cancers, but patients have been educated that these are not very aggressive and, for the most part, are not particularly lethal. But they still need to be followed, and patients can deal with this in a rational manner.

So what I think we need is public education. We have to educate patients that most Gleason score 6 cancers can be followed with active surveillance, that they could have a good form of cancer that generally does not cause harm, but that they have to emphasize that there is a risk of having a more aggressive type of cancer that might have been missed, that the cancer could potentially change over time, and that the patient must be followed closely.

I think more and more patients are asking for active surveillance, compared with prior years, and I think urologists need to buy into the concept of “good cancer” to educate the appropriate patients for active surveillance because urologists are the first clinicians that patients typically see following their diagnosis.

One of the problems is that we don’t see Gleason patterns 1 and 2 anymore, so we don’t diagnose Gleason scores 2-5 anymore, for the most part. This makes Gleason score 6 pretty much the lowest cancer we see. The problem is that patients hear they have a Gleason score 6 tumor, they go on the Internet and find out the scale goes from 2-10, and they think their tumor is somewhere in the middle of the range.

Therefore, we are proposing a new grading system. We recently had a meeting in Chicago, which was attended by 85 prostate cancer experts, and this new grading system was accepted to be used, initially, in conjunction with the current Gleason scale. Basically, in the new scale, Gleason scores 2-6 are graded 1 out of 5; Gleason score 3+4=7 would be 2 out of 5; 4+3=7 would be 3 out of 5; Gleason score 8 would be a 4 out of 5; and Gleason scores 9-10 would be a 5 out of 5.

In summary, I don’t think we need to change calling Gleason score 6 cancer. We need to change what patients think when they hear that they have Gleason score 6 cancer. Urologists have to reassure and educate patients, and if you modify the grading system to tell someone that they have a grade 1 tumor out of 5 instead of a 6 out of 10, it will help reassure patients and realign the grading system in prostate cancer so Gleason score 6 tumors are more appropriately considered as indolent, but something that still needs following.

Dr. Jonathan I. Epstein is a professor of pathology, urology and oncology at Johns Hopkins University Hospital, Baltimore. He reported no relevant financial disclosures.

COUNTERPOINT: Dr. Rubin

If we were to name Gleason pattern 3 and Gleason score 6 today, we might go with something different. For me, the term “adenoma” comes to mind because adenomas are neoplastic, but we don’t call them cancer.

It’s very important to remind ourselves that if we look at a spectrum of cancer, ranging from indolent to aggressive, many of the [pertinent] studies that we’ve read or heard about are taken from a very discrete, carefully culled set of cancers in patients who were undergoing radical prostatectomies. One should consider that population-based studies are important for this type of evaluation. We should also remind ourselves that nothing in life is zero risk; even going to the gym and running has some risk associated with it, so the fact that we choose to classify something as cancer or an adenoma will always have some risk associated with it.

In a multi-institutional study that Dr. Epstein published recently, he described the risk of Gleason score 6 cancer progressing as approximately 3%. So what does 3% mean? Well, those 3% [of patients] led to prognostic categorizations similar to the ones we just heard about, and one of the important things to remember is that the endpoint here is biochemical recurrence.

A recently published study employed a modeling exercise to look at the meaning of biochemical failure. In that analysis, going from radical prostatectomy to developing biochemical failure, what is the likelihood that you’re going to have metastatic disease? This analysis found no significant association, at least in Gleason score 6 disease, for developing metastatic disease. So that 3% becomes a much smaller risk.

Continuing with Dr. Epstein’s work, he and his associates reviewed around 14,000 cases and identified 22 cases that had Gleason score 6 on the radical prostatectomy but showed metastatic disease. Every one of those cases were rereviewed and upgraded using the new classification system that Dr. Epstein outlined. The conclusion of this analysis was that “in contrast to prevailing assumptions, Gleason score 6 tumors do not appear to metastasize to lymph nodes.”

So what about cancer-specific death? In studies from multiple institutions, where they looked at Gleason score 6 cancers and asked what the likelihood was of dying from prostate cancer vs. competing causes, the former had a very low risk of cancer-specific death in patients 60 years and younger.

We performed similar analysis at the Harvard School of Public Health, Boston, a few years ago, looking at the Physicians’ Health Study and the Health Professionals Follow-Up Study and saw that when we re-created the biopsies and radicals, the scores of Gleason 6 and lower went up to Gleason 7 very often. In a blinded analysis, not one of the Gleason score 6 tumors was associated with lethal prostate cancer.

You’re probably thinking about what we know about conservative management in the setting of localized cancer. I would refer you to the work of Dr. Peter C. Albertsen at the Connecticut Tumor Registry, where by looking at similar types of outcomes between cancer-specific deaths and competing causes, it’s shown that there’s very low risk of dying from prostate cancer with Gleason scores 2-6 (statistics are unadjusted for deaths per 1,000 patients).

From the molecular standpoint – we’ve heard a number of times that various cancers have a risk of somatic alterations. Prostate cancer tends to have a very low number of somatic alterations, but copy number alterations are common, going from localized to advanced. We see driver mutation events occurring more in late-stage cancer, and this is provisional data from 333 localized prostate cancer [cases] from many institutions where it’s been organized from the bottom to the top starting with Gleason score 6.

What we can see is an accumulation of molecular alterations, but what I would highlight is that like adenomas, Gleason score 6 has certain characteristic alterations that we often see without driver events.

And going back to the Physicians’ Health study and the Swedish “Watchful Waiting” study, if we look at all lethal prostate cancers, the vast majority were Gleason score 7 and above. The Swedish cohort was pre-PSA, so some of these Gleason score 6 cancers were probably contaminated because of sampling. Even if we include them and look at principle component analysis, we see that the vast majority of the Gleason score 6 cases cluster together; they’re much more homogeneous, molecularly speaking, compared with the Gleason score 8 cancers that are heterogeneous and spread all over.

Another important analysis that will inform next-generation sequencing studies is to look at subclonal alterations. We believe that the subclonal mutations are the ones that are going to merge in as driver mutations, So what you can do is take the Cancer Genome Atlas data, as we’ve done, and go from Gleason score 6 all the way up to the higher-grade tumors. There are more deletions and genomic focus as you go higher, but also you see that the majority of Gleason score 6 cancers are clonal for these alterations. As you move on up to higher-grade tumors, you start seeing some subclonal emergence of driver lesions.

So I would argue that the Gleason pattern 3 or Gleason score 6 cancers have a very, very low risk of disease compared to other cancer grades and is not associated with death following definitive treatment, and is probably dramatically overtreated. It’s genetically homogeneous, and we see little evidence of subclonal driver mutations in Gleason score 6. So my answer to the question “Should Gleason score 6 be called cancer?” is “no.” But I do agree entirely that we need to have categories of risk, and so Gleason score 6 – or whatever we end up calling it – should be recognized as a group of tumors with a very low risk of aggressiveness.

Dr. Mark A. Rubin is the director of the Institute for Precision Medicine at Weill Cornell Medical College, New York. He reported no relevant financial disclosures.

Dr. Epstein and Dr. Rubin made their remarks at the annual meeting of the Society for Urologic Oncology. Reporter Deepak Chitnis covered their presentation.

A study of hypogonadal men undergoing testosterone therapy has found a lower rate of prostate cancer than previously recorded in screening studies, suggesting the therapy does not increase prostate cancer risk.

Analysis of data from 1,023 hypogonadal men enrolled in three prospective registry studies, who were all being treated with testosterone therapy, found 11 cases of prostate cancer (1.08%), which was significantly lower than the incidence reported in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (7.35%) and the European Randomized Study of Screening for Prostate Cancer (9.6%).

The mean baseline patient age was 58 years in the urology setting, and 41 years in the andrology setting, with patients receiving testosterone undecanoate injections at 12-week intervals and followed up for a median of 5 years.

“Despite the widespread belief regarding the contraindication of T [testosterone] therapy in hypogonadal men with known or suspected PCa [prostate cancer], there is no convincing evidence that the normalization of T levels presents a greater risk for the progression of PCa,” wrote Dr. Ahmad Haider, a urologist in Bremerhaven, Germany, and colleagues (J. Urol. 2014 [doi:10.1016/j.juro.2014.06.071]).

Some authors declared financial interests or relationships with a range of pharmaceutical companies.

A study of hypogonadal men undergoing testosterone therapy has found a lower rate of prostate cancer than previously recorded in screening studies, suggesting the therapy does not increase prostate cancer risk.

Analysis of data from 1,023 hypogonadal men enrolled in three prospective registry studies, who were all being treated with testosterone therapy, found 11 cases of prostate cancer (1.08%), which was significantly lower than the incidence reported in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (7.35%) and the European Randomized Study of Screening for Prostate Cancer (9.6%).

The mean baseline patient age was 58 years in the urology setting, and 41 years in the andrology setting, with patients receiving testosterone undecanoate injections at 12-week intervals and followed up for a median of 5 years.

“Despite the widespread belief regarding the contraindication of T [testosterone] therapy in hypogonadal men with known or suspected PCa [prostate cancer], there is no convincing evidence that the normalization of T levels presents a greater risk for the progression of PCa,” wrote Dr. Ahmad Haider, a urologist in Bremerhaven, Germany, and colleagues (J. Urol. 2014 [doi:10.1016/j.juro.2014.06.071]).

Some authors declared financial interests or relationships with a range of pharmaceutical companies.

A study of hypogonadal men undergoing testosterone therapy has found a lower rate of prostate cancer than previously recorded in screening studies, suggesting the therapy does not increase prostate cancer risk.

Analysis of data from 1,023 hypogonadal men enrolled in three prospective registry studies, who were all being treated with testosterone therapy, found 11 cases of prostate cancer (1.08%), which was significantly lower than the incidence reported in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (7.35%) and the European Randomized Study of Screening for Prostate Cancer (9.6%).

The mean baseline patient age was 58 years in the urology setting, and 41 years in the andrology setting, with patients receiving testosterone undecanoate injections at 12-week intervals and followed up for a median of 5 years.

“Despite the widespread belief regarding the contraindication of T [testosterone] therapy in hypogonadal men with known or suspected PCa [prostate cancer], there is no convincing evidence that the normalization of T levels presents a greater risk for the progression of PCa,” wrote Dr. Ahmad Haider, a urologist in Bremerhaven, Germany, and colleagues (J. Urol. 2014 [doi:10.1016/j.juro.2014.06.071]).

Some authors declared financial interests or relationships with a range of pharmaceutical companies.