Susan London

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

SAN FRANCISCO – New findings on cardiovascular and metabolic risks in men receiving androgen deprivation therapy for nonmetastatic prostate cancer may help individualize decisions about whether to initiate this therapy and how long to continue it.

In a population-based cohort study of more than 3,500 men followed up for 15 years, taking androgen deprivation therapy (ADT) for 2 years or less did not significantly increase the risk of either cardiovascular disease or diabetes, researchers reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Taking it for more than 2 years did increase these risks, but only for men about 75 years of age or older at baseline, first author Dr. Alicia K. Morgans of Vanderbilt University, Nashville, Tennessee, reported in a poster presentation.

As would be expected, comorbidities were also a risk factor for both cardiovascular disease and diabetes.

"There may be a different risk-benefit ratio of ADT in younger men as compared to older men," Dr. Morgans commented in an interview.

"The take-home message is that younger men don’t need to worry so much about the development of diabetes and cardiovascular disease directly related to ADT. Certainly, their other comorbidities may predispose them to developing that complication, but not related to ADT," she elaborated.

"For older men, especially men who have more complicated medical histories with more comorbidities, it is something that they need to consider, and potentially, if they have the ability to choose not to have ADT, if they have a more complicated medical picture and are older, they may want to opt against it," she added.

While acknowledging the potentially heightened risks of these conditions with ADT, guidelines are vague as to monitoring for them, according to Dr. Morgans. "We simply say at this point: watch. Watch for the development of diabetes, watch for the development of cardiovascular disease. And there are no age criteria for that either," she said, so these new data may help in that arena, too.

The investigators analyzed data from the Prostate Cancer Outcomes Study for men aged 39-89 years from six U.S. geographic regions with nonmetastatic prostate cancer diagnosed during 1994-1995 and followed up through 2009-2010.

The presence of cardiovascular disease and diabetes was ascertained from patient surveys at baseline; at 6 months; and at 1, 2, 5, and 15 years, and from death certificates.

Analyses were based on 3,526 men who survived at least 2 years after diagnosis. They had a median age of about 68 years at baseline, and roughly half had at least one comorbidity.

Overall, 23% took ADT for 2 years or less, 9% took ADT for more than 2 years, and the rest did not take any. The median duration of follow-up was about 10 years.

Main results showed that taking ADT for 2 years or less did not significantly increase the risk of developing cardiovascular disease or diabetes, regardless of age at the start of therapy, Dr. Morgans reported.

In contrast, among patients who took ADT for more than 2 years, the risks increased with age at baseline and became significant in the mid-70s. Specifically, men older than 74 years had a significantly elevated risk of cardiovascular disease and men older than 76 years had a significantly elevated risk of diabetes.

Risks also rose with the number of comorbidities, but tumor grade, extent of prostate cancer, and race did not significantly affect these outcomes.

Dr. Morgans disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Almost one-fifth of adult cancer clinical trials fail to reach completion for reasons unrelated to efficacy or adverse effects, according to data being reported at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. Poor accrual is the leading cause.

Trials were more likely to fail completion if they were phase II, single center, funded by industry, or conducted solely in the United States. Trials among patients with genitourinary cancers were no more or less likely to fail than trials among patients with other cancers.

"These findings really underscore the clinical trial accrual problem that we have in the United States. Not only does poor accrual lead to more expensive trials and trials that generate answers much more slowly, but it also prevents many trials from generating answers at all," senior author Dr. Matthew D. Galsky, director of the genitourinary medical oncology program, Icahn School of Medicine at Mount Sinai, New York, said in a press briefing at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

The study is not meant to indict any specific stakeholders, Dr. Galsky stressed. "Rather, what we wanted to do was hold up a mirror to our activities as a cancer clinical trials community and really ask whether the system is optimized to bring better treatments to our patients as efficiently as possible. And clearly there is some work to do.

"Based on this analysis and others, it’s apparent that we need better collaboration and communication within the system and to use novel approaches to increase accrual to cancer clinical trials, which has really been quite steady at 3% to 5% of the adult cancer population for decades."

"This is a really interesting presentation which casts some light on one of the major frustrations that I think ... our whole community shares in designing and implementing clinical trials," said press briefing moderator Dr. Charles J. Ryan, leader of the genitourinary medical oncology program at the University of California, San Francisco. "Hopefully, this may be the beginning of a broader discussion that helps improve some of the efficiencies here."

Dr. Galsky speculated that the explanation for poor accrual is multifactorial. "Clearly, we need to engage patients more in the design of trials. We need to design trials that are more pragmatic; eligibility for trials is often so restrictive that only the patients who are the fittest and represent kind of an extreme of cancer patients can actually enroll," he said.

Other issues likely include financial barriers (such as whether insurers reimburse the costs of care for patients in trials); geographic accessibility; and the time and regulatory burdens of participating, especially as they affect community oncology practices. "Addressing the cancer clinical trials enterprise at large requires making the burden of participation lower because that does address accrual, that does address generalizability, that does address accessibility. It’s a problem that needs to be part of this conversation," Dr. Galsky maintained.

Dr. Ryan, the moderator, cited rapid treatment advances as yet another possible reason for poor accrual. "Some trials may take 2 or 3 years to accrue. During the first year, the standards of care may be one thing, and during the third year, the standards of care may have changed. We are really seeing very rapid evolution in our standards of care, so that could be one issue," he elaborated.

Introducing the study, Dr. Galsky noted that trials that fail to complete (that is, close without enrolling the intended number of patients) represent a major inefficiency of the cancer clinical trials enterprise. "Such trials contribute little knowledge, waste finite resources, and potentially divert patients from participating in other trials," he said.

The Institute of Medicine previously issued a report suggesting that about 40% of trials sponsored by the National Cancer Institute fail to achieve completion. But such trials account for only about 15% of all cancer trials.

The researchers analyzed 7,776 phase II or III interventional adult cancer clinical trials registered on ClinicalTrials.gov that had start dates between 2005 and 2011. They searched for those that had failed to reach completion, meaning that the trial had been stopped and had a "terminated" or "withdrawn" status.

The trials had a total of about 48,000 patients. Overall, 10% were trials in prostate, kidney, bladder, or testicular cancer.

The cumulative incidence of failure to reach completion for reasons unrelated to the efficacy or safety of the intervention was about 20%, according to Dr. Galsky.

Among all noncompleted trials, the largest share, 39%, failed to achieve completion because of poor accrual, topping other reasons such as logistics and efficacy/safety.

Trials were more likely to fail completion if they were funded by industry as compared with the federal government (hazard ratio, 1.97), were phase II as compared with phase III (HR, 1.29), or were single center as compared with multicenter (HR, 1.93).

On the other hand, trials were less likely to fail completion if they were conducted solely outside the United States (HR, 0.65) or both in and outside the United States (HR, 0.67), as compared with solely in the United States.

Dr. Galsky disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Angiotensin system inhibitors prolong survival of patients with metastatic renal cell carcinoma, according to a retrospective study being presented at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Patients taking one of these antihypertensive agents lived on average about 10 months longer than their counterparts not taking them, reported lead author Dr. Rana R. McKay, a clinical oncology fellow at the Dana-Farber Cancer Institute in Boston.

In analyses stratified according to type of cancer treatment, benefit was restricted to patients whose cancer was being treated with agents that target vascular endothelial growth factor (VEGF), which is known to have interactions with the angiotensin system that affect cell proliferation and angiogenesis.

"This is the largest analysis to our knowledge evaluating the role of ASIs [angiotensin system inhibitors] on outcomes not just in metastatic renal cell carcinoma but for all cancers," Dr. McKay commented in a press briefing held before the symposium.

"We demonstrated that ASI users had significantly improved survival when compared to ASI nonusers, even after adjustment for the development of treatment-associated hypertension. ASIs appear to have a synergistic activity in patients on VEGF-targeted therapy," she said.

"Although lab-based and prospective studies are required to explore this relationship further, in patients with metastatic renal cell carcinoma who warrant an antihypertensive agent, ASIs may be the agent of choice for patients without any contraindications for their use," Dr. McKay proposed.

It is noteworthy that nearly half of the patients studied had hypertension at baseline, according to press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the genitourinary medical oncology program.

"There is quite a significant effect here, and it really makes sense given the mechanism of action of VEGF-targeted therapy. I’m sure there will be a lot of interest going forward with this in prospective data," he commented.

There is good rationale for investigating ASIs – a collective term for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) – in renal cell carcinoma, according to Dr. McKay.

"VEGF is an established target in metastatic kidney cancer. Increasing evidence suggests that angiotensin II is an important regulator of vascular homeostasis and modulates VEGF-dependent angiogenesis," she explained.

The investigators reviewed data from a clinical trials database of 4,736 patients with metastatic renal cell carcinoma treated on Pfizer-sponsored phase II and III clinical trials between 2003 and 2013.

The largest share of patients (42%) had intermediate-risk disease according to IMDC (International mRCC Database Consortium) risk classification. In all, 70% had undergone nephrectomy, and 48% had hypertension at baseline.

Overall, 31% of patients in the cohort were using ASIs at baseline or started one in the first 30 days of their trial. Another 17% were using some other type of antihypertensive, and the remaining 52% were not using any.

In the entire study cohort, overall survival was 27 months for ASI users and 17 months for all other patients (hazard ratio, 1.21; P = .0009).

Among patients whose cancer was being treated with VEGF-targeted therapy, overall survival was better for ASI users than for all other patients (HR, 1.36; P less than .0001). But there was no such benefit for patients whose cancers were being treated with mammalian target of rapamycin (mTOR) inhibitors or for patients whose cancer was being treated with interferon-alpha.

In additional findings, among patients taking any kind of antihypertensive and receiving VEGF-targeted therapy, survival was better for ASI users than for users of other types of antihypertensives (31 vs. 22 months; HR, 1.38; P = .0003).

Dr. McKay disclosed no relevant conflicts of interest.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

Adding radiation therapy to lifelong antiandrogen therapy dramatically cuts the long-term risk of death from prostate cancer in men with locally advanced disease, according to updated results of the Scandinavian Prostate Cancer Group’s Study VII.

Compared with antiandrogen therapy alone, the combination more than halved the 10- and 15-year rates of prostate cancer–specific mortality, lead author Dr. Sophie Dorothea Fosså reported in a press briefing preceding the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology. In fact, the benefit increased with the duration of follow-up.

"Given the high mortality reduction and, what is important, only 8% prostate cancer–specific mortality at 10 years, our conclusion is that this combination of radiotherapy and hormones may be considered as a standard curative treatment option in these patients," she commented. "And it is actually ... more or less comparable to a modern prostatectomy series."

Approximately 30%-40% of the patients studied would likely undergo prostatectomy today, estimated Dr. Fosså, who is a professor in the department of oncology at Oslo University Hospital. But it remains unclear whether that treatment is better because other studies testing the combination of radiation therapy and antiandrogens have used much lower doses of radiation, now known to be inadequate.

"Therefore, a randomized trial is absolutely necessary. There is a new trial planned in the Scandinavian Prostate Cancer Group of radiotherapy plus at least 3 years with antiandrogens compared to prostatectomy," she said, noting that shorter durations of hormone treatment are now the norm.

Press briefing moderator Dr. Charles J. Ryan of the division of hematology/oncology at the University of California, San Francisco, and leader of the genitourinary medical oncology program there, said that the study presented is noteworthy for several reasons.

"One is it’s very interesting to see that these results continue to improve over time, which is somewhat different than some other randomized trials where sometimes results actually worsen over time," he elaborated. "Also of note is that this is the use of an antiandrogen as opposed to medical castration lifelong; that’s something that makes this trial somewhat unique."

Men from Norway, Sweden, and Denmark were eligible for the Scandinavian Prostate Cancer Group’s study if they had locally advanced or high-risk prostate cancer and were aged 75 years or younger; 80% had extension of disease beyond the prostatic capsule. Such patients were not considered surgical candidates in 1996, when the trial began, according to Dr. Fosså.

All 875 patients received 3 months of medical castration therapy, consisting of leuprolide injection (Procren Depot) plus oral flutamide (Eulexin). Half then received lifelong antiandrogen therapy alone (oral flutamide), whereas the other half received that therapy plus initial radiation therapy consisting of 75 Gy to the prostate, "which, at that time, was a relatively high dose," she noted.

Initial results, previously reported after a median follow-up of 7.6 years, showed a 12% reduction in prostate cancer–specific mortality in patients with the addition of radiation therapy (Lancet 2009;373:301-8).

Updated results, now after median follow-up of 10.7 years, showed the 10-year cumulative prostate cancer–specific mortality was more than halved by the addition of radiation therapy, from 19% to just 8%, reported to Dr. Fosså, who disclosed no relevant conflicts of interests related to the research.

The trial therefore far exceeded its primary endpoint of a reduction of at least 10% in 10-year prostate cancer–specific mortality from the addition of radiation therapy.

There was also a reduction in overall mortality at this time point, from 35% without radiation therapy to 26% with it.

The 15-year cumulative prostate cancer–specific mortality was also more than halved by the addition of radiation therapy, from 31% to 12%, and overall mortality was reduced by a quarter, from 57% to 43%.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

The androgen receptor–blocker enzalutamide is efficacious and safe in men with metastatic castration-resistant prostate cancer who have not received chemotherapy, according to interim results of the randomized phase III PREVAIL trial.

Patients who received enzalutamide (Xtandi) were 29% less likely to die and 81% less likely to experience radiographic progression than patients who received a placebo, researchers are reporting at the 2014 Genitourinary Cancers Symposium sponsored by the American Society of Clinical Oncology.

Enzalutamide also prolonged the median time to chemotherapy by 17 months and was associated with a nearly 12 times higher rate of response.

Safety results showed that the drug was well tolerated and not associated with an increase in the rate of treatment discontinuation because of adverse events.

"As a result of these observations, it is my view that enzalutamide provides a meaningful clinical benefit to men with metastatic prostate cancer," lead author Dr. Tomasz Beer, professor of medicine and deputy director of the Knight Cancer Institute at Oregon Health and Science University, Portland, commented in a press briefing before the symposium.

The PREVAIL trial’s findings would apply to roughly 50,000 men each year in the United States, he estimated. "For folks who develop metastatic prostate cancer, by and large, all of them at some point or another would be expected to have this metastatic hormone-resistant state that is represented in this study population."

The favorable interim results prompted the investigators to stop the trial early, in October 2013, and offer enzalutamide to patients in the placebo arm. The manufacturer, Medivation, plans to file with the Food and Drug Administration for a new indication for enzalutamide, which is currently approved for the treatment of castration-resistant metastatic prostate cancer in men who have received chemotherapy.

"This is a very important study from the perspective that this applies to patients who have not yet had chemotherapy, which may expand the regulatory approval of enzalutamide. And one key fact for me is that although chemotherapy is sort of held up as the benchmark for this disease, the reality is that our current data suggest that less than 50% of men with castration-resistant prostate cancer actually receive chemotherapy," noted press briefing moderator Dr. Charles J. Ryan, a professor at the University of California, San Francisco, and leader of the Genitourinary Medical Oncology Program.

"So this treatment should change the regulatory status of enzalutamide and would open up this possibility of therapy for a very large group of patients who currently have really only one or two treatment options available to them," Dr. Ryan commented.

Dr. Beer declined to directly compare the efficacy results of PREVAIL with those of Cougar 302, a similar trial of the oral antiandrogen abiraterone (Zytiga) that led to its approval in this patient population.

But he noted that the trials’ populations differed in some respects that may be important; for example, about 12% of patients in PREVAIL had visceral metastases, compared with none in Cougar 302. Also, the former study excluded patients with a history of seizure, whereas the latter excluded those with cardiac risk factors.

Should enzalutamide gain approval for this new indication, the choice between enzalutamide and abiraterone would likely be individualized, taking into account these factors as well as others such as the need to coadminister steroids and follow dietary restrictions with abiraterone, according to Dr. Beer.

"That’s a decision that every clinician and patient will make in the clinic individually ... I don’t think there is a blanket answer to that question for all patients," he said. "We have two active drugs, we are fortunate to have those, and my real hope is that the work we are currently doing on the research front as a part of the [Stand Up to Cancer] West Coast Dream Team and other such efforts will enable us to further define which patient populations benefit the most from which therapeutic approach and be able to answer this question in a scientific manner in the future."

The two drugs may be compared in a head-to-head trial and will likely be tested in sequence, in combination, and in earlier stages of the disease, he added.

In fact, Dr. Ryan, the press briefing moderator, pointed out that just last week, the U.S. cooperative group system launched a trial comparing the combination of enzalutamide and abiraterone with enzalutamide monotherapy.

PREVAIL was sponsored by Medivation and enrolled 1,717 men with metastatic prostate cancer who had experienced progression on androgen deprivation therapy but had not received chemotherapy. They had no or only mild symptoms.

The men were randomized evenly to double-blind treatment with enzalutamide (160 mg/day) or a placebo.

With a median follow-up of about 20 months, enzalutamide was associated with better overall survival (hazard ratio, 0.71; P less than .0001) and better radiographic progression-free survival (HR, 0.19; P less than .0001). In post hoc analyses, the findings were much the same in the small subset of patients who had visceral metastases, according to Dr. Beer.

The response rate was 59% with enzalutamide (20% complete response; 39% partial response), compared with just 5% with placebo (P less than .0001).

Enzalutamide also delayed the median time to receipt of chemotherapy – "a pragmatic measure of real-world treatment effect," he noted – from 11 to 28 months (HR, 0.35; P less than .0001).

The rate of grade 3 or worse adverse events was 43% with enzalutamide and 37% with placebo. The most common toxicities of any grade were fatigue, back pain, constipation, and arthralgia. The rate of treatment discontinuation from adverse events was identical at 6% in each arm.

Two patients (0.1%) – one in each study arm – experienced seizure, which has been a concern with enzalutamide; both were subsequently determined to have a history of seizure unknown to their enrolling physician, which would have excluded them from the trial.

"What that tells us is that with appropriate patient selection, this clinical trial demonstrates that the drug can be administered very safely from the perspective of seizure risk," Dr. Beer said. "In point of fact, in patients who didn’t have a prior history of seizures, there were no seizures at all in this trial."

Dr. Beer disclosed that he receives research funding from Cougar Biotechnology, Janssen Biotech, Astellas Pharma, and Medivation. The trial was sponsored by Medivation.

SAN FRANCISCO – Postoperative complications are prognostic for poor outcomes in patients undergoing resection of gastric cancer, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The team retrospectively analyzed data collected in the U.S. Gastric Cancer Collaborative, a joint effort of seven moderate- to high-volume academic institutions across the United States. Analyses were based on 850 patients who underwent curative resection of gastric or gastroesophageal junction adenocarcinoma by abdominal approach from 2000 to 2012.

Complications occurred within a month of surgery in 40% of the patients, reported coauthor Dr. Ryan C. Fields of Washington University in St. Louis. These patients were 20% less likely to receive adjuvant therapy than were their peers with an uncomplicated postoperative course. And during a median follow-up of almost 3 years, those with postop complications were 60% more likely to die after potential confounding factors were taken into account.

"The particular strength of this data set is the cross-section of real-world treatments and outcomes that it represents," Dr. Fields noted.

Patients who had complications were older, had higher levels of comorbidity and complexity, underwent more extensive surgery, and had more advanced disease. "We could potentially identify preoperatively [these patients] in an attempt to reduce the chance of complications," he said.

Not included in this analysis was "the finding of muscular sarcopenia as measured from the psoas muscle on a preoperative CT scan. There are ongoing studies using this measure to identify patients who may benefit from a short course of intensive physical therapy and nutritional supplementation prior to surgery in an attempt to reduce complications," he added.

The study was limited by its retrospective and nonrandomized design, and factors such as selection bias and missing data may have affected outcomes, Dr. Fields acknowledged. The researchers are therefore conducting further analyses using propensity matching and imputation.

The data set "may not be representative of (patients in) other countries or importantly of the nearly 40% of patients with gastric cancer that are treated at non-university, community-based hospitals in the United States," he added. "I would argue, however, that if we accept the relationship between volume and outcomes that has been shown to be significant in gastrectomy, the effect of complications on outcomes would be expected to be even more significant in these settings."

Groups stratified by Clavien-Dindo score were too small to draw definitive conclusions, but there were trends whereby worse complications had a greater negative impact on outcome, Dr. Fields said.

"One of the problems that we have – as an oncologic community –is there is no real consistent definition of complications in a lot of this literature," he added, which may be generating some of the disparate findings. For example, the severity of a wound infection can range widely, with more severe infections affecting decisions about whether to delay or even withhold adjuvant therapy.

In the study, there were a total of 699 complications in 342 patients, "highlighting the ... observation that often complications can beget further complications," according to Dr. Fields.

More than one-third of the complications (37%) were of Clavien-Dindo grade III or IV, requiring care more invasive than simple treatment at the bedside or with intravenous medications.

The most common were anemia/bleeding (12%), wound infections (8%), pneumonia (6%), and respiratory failure requiring reintubation (6%).

Relative to counterparts without complications, patients who had complications were on average significantly older and had significantly higher American Society of Anesthesiologists scores (reflecting greater preoperative comorbidity and complexity), more extensive and complex surgery, and more advanced cancer.

"Importantly, we did not find neoadjuvant therapy to be associated with an increase in postoperative complications, and this is consistent with literature in other solid tumor types, such as pancreatic cancer and rectal cancer," noted Dr. Fields, who disclosed no conflicts of interest related to the study. Also, the extent of lymphadenectomy was not associated with this outcome.

A minority of patients had a laparoscopic surgery, and the number was too small to say whether this factor influenced complication rate, he said.

"What we can surmise, one, from the literature, and two, is that the specific complications that are oftentimes reduced with laparoscopy and minimally invasive surgery certainly relate to wound infection and wound problems for sure," Dr. Fields commented. "So I think if we can do anything to achieve the same oncologic goals and reduce the morbidity of an operation, and improve the ability of patients to get on adjuvant therapy, that’s going to be critical. And laparoscopy may be a way to do that in gastric cancer. It may be more challenging in some of the bulkier, more advanced tumors to apply it globally, but I think it certainly holds promise for that exact point."

Overall, 60% of patients without complications received adjuvant therapy, compared with 48% of patients with complications (P = .001).

In multivariate analyses conducted after a median follow-up of 35 months, patients who experienced postoperative complications still had shorter median survival (25 vs. 45 months) and were more likely to die (hazard ratio, 1.6; P = .004).

Other significant risk factors were receipt of neoadjuvant therapy, perineural invasion, and stage III or IV disease.

Dr. Fields disclosed no relevant conflicts of interest.

SAN FRANCISCO – Postoperative complications are prognostic for poor outcomes in patients undergoing resection of gastric cancer, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The team retrospectively analyzed data collected in the U.S. Gastric Cancer Collaborative, a joint effort of seven moderate- to high-volume academic institutions across the United States. Analyses were based on 850 patients who underwent curative resection of gastric or gastroesophageal junction adenocarcinoma by abdominal approach from 2000 to 2012.

Complications occurred within a month of surgery in 40% of the patients, reported coauthor Dr. Ryan C. Fields of Washington University in St. Louis. These patients were 20% less likely to receive adjuvant therapy than were their peers with an uncomplicated postoperative course. And during a median follow-up of almost 3 years, those with postop complications were 60% more likely to die after potential confounding factors were taken into account.

"The particular strength of this data set is the cross-section of real-world treatments and outcomes that it represents," Dr. Fields noted.

Patients who had complications were older, had higher levels of comorbidity and complexity, underwent more extensive surgery, and had more advanced disease. "We could potentially identify preoperatively [these patients] in an attempt to reduce the chance of complications," he said.

Not included in this analysis was "the finding of muscular sarcopenia as measured from the psoas muscle on a preoperative CT scan. There are ongoing studies using this measure to identify patients who may benefit from a short course of intensive physical therapy and nutritional supplementation prior to surgery in an attempt to reduce complications," he added.

The study was limited by its retrospective and nonrandomized design, and factors such as selection bias and missing data may have affected outcomes, Dr. Fields acknowledged. The researchers are therefore conducting further analyses using propensity matching and imputation.

The data set "may not be representative of (patients in) other countries or importantly of the nearly 40% of patients with gastric cancer that are treated at non-university, community-based hospitals in the United States," he added. "I would argue, however, that if we accept the relationship between volume and outcomes that has been shown to be significant in gastrectomy, the effect of complications on outcomes would be expected to be even more significant in these settings."

Groups stratified by Clavien-Dindo score were too small to draw definitive conclusions, but there were trends whereby worse complications had a greater negative impact on outcome, Dr. Fields said.

"One of the problems that we have – as an oncologic community –is there is no real consistent definition of complications in a lot of this literature," he added, which may be generating some of the disparate findings. For example, the severity of a wound infection can range widely, with more severe infections affecting decisions about whether to delay or even withhold adjuvant therapy.

In the study, there were a total of 699 complications in 342 patients, "highlighting the ... observation that often complications can beget further complications," according to Dr. Fields.

More than one-third of the complications (37%) were of Clavien-Dindo grade III or IV, requiring care more invasive than simple treatment at the bedside or with intravenous medications.

The most common were anemia/bleeding (12%), wound infections (8%), pneumonia (6%), and respiratory failure requiring reintubation (6%).

Relative to counterparts without complications, patients who had complications were on average significantly older and had significantly higher American Society of Anesthesiologists scores (reflecting greater preoperative comorbidity and complexity), more extensive and complex surgery, and more advanced cancer.

"Importantly, we did not find neoadjuvant therapy to be associated with an increase in postoperative complications, and this is consistent with literature in other solid tumor types, such as pancreatic cancer and rectal cancer," noted Dr. Fields, who disclosed no conflicts of interest related to the study. Also, the extent of lymphadenectomy was not associated with this outcome.

A minority of patients had a laparoscopic surgery, and the number was too small to say whether this factor influenced complication rate, he said.

"What we can surmise, one, from the literature, and two, is that the specific complications that are oftentimes reduced with laparoscopy and minimally invasive surgery certainly relate to wound infection and wound problems for sure," Dr. Fields commented. "So I think if we can do anything to achieve the same oncologic goals and reduce the morbidity of an operation, and improve the ability of patients to get on adjuvant therapy, that’s going to be critical. And laparoscopy may be a way to do that in gastric cancer. It may be more challenging in some of the bulkier, more advanced tumors to apply it globally, but I think it certainly holds promise for that exact point."

Overall, 60% of patients without complications received adjuvant therapy, compared with 48% of patients with complications (P = .001).

In multivariate analyses conducted after a median follow-up of 35 months, patients who experienced postoperative complications still had shorter median survival (25 vs. 45 months) and were more likely to die (hazard ratio, 1.6; P = .004).

Other significant risk factors were receipt of neoadjuvant therapy, perineural invasion, and stage III or IV disease.

Dr. Fields disclosed no relevant conflicts of interest.

SAN FRANCISCO – Postoperative complications are prognostic for poor outcomes in patients undergoing resection of gastric cancer, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

The team retrospectively analyzed data collected in the U.S. Gastric Cancer Collaborative, a joint effort of seven moderate- to high-volume academic institutions across the United States. Analyses were based on 850 patients who underwent curative resection of gastric or gastroesophageal junction adenocarcinoma by abdominal approach from 2000 to 2012.

Complications occurred within a month of surgery in 40% of the patients, reported coauthor Dr. Ryan C. Fields of Washington University in St. Louis. These patients were 20% less likely to receive adjuvant therapy than were their peers with an uncomplicated postoperative course. And during a median follow-up of almost 3 years, those with postop complications were 60% more likely to die after potential confounding factors were taken into account.

"The particular strength of this data set is the cross-section of real-world treatments and outcomes that it represents," Dr. Fields noted.

Patients who had complications were older, had higher levels of comorbidity and complexity, underwent more extensive surgery, and had more advanced disease. "We could potentially identify preoperatively [these patients] in an attempt to reduce the chance of complications," he said.

Not included in this analysis was "the finding of muscular sarcopenia as measured from the psoas muscle on a preoperative CT scan. There are ongoing studies using this measure to identify patients who may benefit from a short course of intensive physical therapy and nutritional supplementation prior to surgery in an attempt to reduce complications," he added.

The study was limited by its retrospective and nonrandomized design, and factors such as selection bias and missing data may have affected outcomes, Dr. Fields acknowledged. The researchers are therefore conducting further analyses using propensity matching and imputation.

The data set "may not be representative of (patients in) other countries or importantly of the nearly 40% of patients with gastric cancer that are treated at non-university, community-based hospitals in the United States," he added. "I would argue, however, that if we accept the relationship between volume and outcomes that has been shown to be significant in gastrectomy, the effect of complications on outcomes would be expected to be even more significant in these settings."

Groups stratified by Clavien-Dindo score were too small to draw definitive conclusions, but there were trends whereby worse complications had a greater negative impact on outcome, Dr. Fields said.

"One of the problems that we have – as an oncologic community –is there is no real consistent definition of complications in a lot of this literature," he added, which may be generating some of the disparate findings. For example, the severity of a wound infection can range widely, with more severe infections affecting decisions about whether to delay or even withhold adjuvant therapy.

In the study, there were a total of 699 complications in 342 patients, "highlighting the ... observation that often complications can beget further complications," according to Dr. Fields.

More than one-third of the complications (37%) were of Clavien-Dindo grade III or IV, requiring care more invasive than simple treatment at the bedside or with intravenous medications.

The most common were anemia/bleeding (12%), wound infections (8%), pneumonia (6%), and respiratory failure requiring reintubation (6%).

Relative to counterparts without complications, patients who had complications were on average significantly older and had significantly higher American Society of Anesthesiologists scores (reflecting greater preoperative comorbidity and complexity), more extensive and complex surgery, and more advanced cancer.

"Importantly, we did not find neoadjuvant therapy to be associated with an increase in postoperative complications, and this is consistent with literature in other solid tumor types, such as pancreatic cancer and rectal cancer," noted Dr. Fields, who disclosed no conflicts of interest related to the study. Also, the extent of lymphadenectomy was not associated with this outcome.

A minority of patients had a laparoscopic surgery, and the number was too small to say whether this factor influenced complication rate, he said.

"What we can surmise, one, from the literature, and two, is that the specific complications that are oftentimes reduced with laparoscopy and minimally invasive surgery certainly relate to wound infection and wound problems for sure," Dr. Fields commented. "So I think if we can do anything to achieve the same oncologic goals and reduce the morbidity of an operation, and improve the ability of patients to get on adjuvant therapy, that’s going to be critical. And laparoscopy may be a way to do that in gastric cancer. It may be more challenging in some of the bulkier, more advanced tumors to apply it globally, but I think it certainly holds promise for that exact point."

Overall, 60% of patients without complications received adjuvant therapy, compared with 48% of patients with complications (P = .001).

In multivariate analyses conducted after a median follow-up of 35 months, patients who experienced postoperative complications still had shorter median survival (25 vs. 45 months) and were more likely to die (hazard ratio, 1.6; P = .004).

Other significant risk factors were receipt of neoadjuvant therapy, perineural invasion, and stage III or IV disease.

Dr. Fields disclosed no relevant conflicts of interest.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – Circulating tumor cells may be useful for ascertaining both the presence and extent of pancreatic cancer, according to the findings of a prospective cohort study reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

A "nano-Velcro" assay to find circulating tumor cells (CTCs) was evaluated prospectively in 61 patients with suspicious pancreatic masses, two-thirds of whom were found to have pancreatic adenocarcinoma.

Finding at least one CTC/2 mL of blood had 71% sensitivity and 95% specificity for the presence of pancreatic cancer, and, among the patients with cancer, finding at least two CTCs/2 mL of blood had 69% sensitivity and 96% specificity for the presence of metastases, reported Dr. Jacob S. Ankeny of the department of surgery, University of California, Los Angeles.

"I think CTCs do have a potential role in aiding in our diagnosis of pancreas cancer and in discriminating which patients are at higher risk of having metastatic disease at the time of their disease presentation," said Dr. Ankeny.

"In our study, circulating tumor cells actually outperformed CA 19-9 [cancer antigen 19-9] for differentiating locoregional vs. metastatic disease, and as a result, I think they show marked promise as a biomarker at the time of disease presentation so that we can perform pretreatment staging and implement more effective initial therapies based on patient stage," he added.

Study limitations included the small sample size and the lack of outcome data, Dr. Ankeny acknowledged. "Additionally, we had minimal inclusion of inflammatory pancreatic conditions and didn’t have any patients with acute pancreatitis. It’s known that some other inflammatory conditions actually lead to false-positive results in some other circulating tumor cell platforms."

A key challenge to using CTCs is their rarity, according to invited discussant Rebecca A. Miksad of Harvard Medical School and the Beth Israel Deaconess Medical Center, both in Boston.

"In the data presented, the difference between cancer and no cancer is one CTC; similarly, the difference between metastatic and locoregional cancer is one CTC. Because CTCs are detected only in whole numbers, these close cutoffs raise questions about the accuracy, reliability, and reproducibility; in other words, will the same result be found in repeated analysis of the same sample and in different samples from the same patient," she commented.

"CTCs in pancreatic cancer are intriguing, although the role remains unclear," Dr. Miksad concluded. "The presented CTC data has a narrow diagnostic predictive window, and we may find with further work that the utility of CTCs as a test to detect the presence of pancreatic cancer may differ from its utility to assist with staging."

The nano-Velcro assay uses antibody-coated silicon nanowires to capture circulating cells with high efficiency, Dr. Ankeny explained. The captured cells are stained immunocytochemically, scanned with fluorescence microscopy, and counted.

In the study, a tumor cell was defined as a cell measuring at least 10 microns that had a DAPI-staining nucleus, was positive for cytokeratin, and was negative for the leukocyte marker CD45.

The investigators tested duplicate 2-mL aliquots from the study patients at the time of their presentation with suspicious pancreatic masses.

The 41 patients determined to have pancreatic adenocarcinoma were roughly equally distributed across tumor stages II, III, and IV. The other 20 patients had more than half a dozen pancreatic conditions, such as intraductal papillary mucinous neoplasms, mucinous cystic neoplasms, and serous cysts.

The assay identified CTCs in 71% of the patients with cancer, reported Dr. Ankeny, who disclosed no conflicts of interest related to the research.

A single patient in the control group was found to have a CTC, meaning a false-positive result. "That was a patient with a nondiagnostic FNA [fine-needle aspiration] of a large cyst containing a large solid component," he explained. "Unfortunately, the patient went elsewhere for surgery and refused surgery, and we don’t have any follow-up pathology. So it’s a theoretical false-positive in our non–adenocarcinoma group."

At an optimal diagnostic cutoff of at least one CTC/2 mL blood, the assay had a sensitivity of 71%, a specificity of 95%, a positive predictive value of 97%, and a negative predictive value of 59% for the presence of pancreatic cancer.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without cancer, Dr. Ankeny said.

Among the patients with cancer, at the optimal cutoff of two or more CTCs/2 mL of blood, the assay had a sensitivity of 69%, a specificity of 96%, and a positive predictive value of 92% for the presence of metastases.

The area under a receiver operating characteristic curve was 0.84 (P less than .001), indicating good discrimination between patients with and without metastases.

A subset of seven patients with presumed stage II disease based on preoperative imaging were found to have liver metastases at the time of surgery. In five of them, preoperative blood samples showed at least two CTCs/2 mL, predicting metastatic disease.

"This indicates that CTCs may be potentially useful in predicting preoperative metastasis and directing patients toward more appropriate therapies while having them avoid potentially morbid surgery," Dr. Ankeny commented.

In a final analysis, CTCs were superior to CA 19-9 for discriminating between locoregional disease and metastatic disease, with an area under the receiver operating characteristic curve of 0.87 (P less than .001) vs. 0.69 (P = .06).

Dr. Ankeny disclosed no relevant conflicts of interest. Dr. Miksad disclosed no relevant conflicts of interest.

SAN FRANCISCO – The incidence of colorectal cancer is rising sharply among younger adults in the United States, a study showed.

Researchers analyzed Surveillance, Epidemiology, and End Results (SEER) data for 383,241 patients in whom colorectal cancer was diagnosed between 1975 and 2010.

The results showed that the age-adjusted incidence rate of colorectal cancer fell steadily among patients aged 50 years and older at diagnosis, lead author Dr. Christina E. Bailey, a surgical oncology fellow at the M.D. Anderson Cancer Center in Houston, reported in a poster session at the annual Gastrointestinal Cancers Symposium. But the rate rose among younger patients.

The annual percentage change in the age-adjusted incidence rate of colorectal cancer during the 35-year period was a significant –0.92 in the cohort overall. In stratified analyses, the annual percentage change fell significantly among patients aged 50-74 at diagnosis (–0.97), and aged 75 years and older at diagnosis (–1.15). But it rose among patients aged 35-49 at diagnosis (0.41) and especially among patients aged 20-34 at diagnosis (1.99).

The findings were similar for colon cancer separately (with strongest results seen for disease that was distant at diagnosis) and for rectal/rectosigmoid cancer separately.

A predictive model suggested that if the observed trends persist between 2010 and 2030, the incidences of colon cancer and of rectal/rectosigmoid cancer will rise by 90% and 124%, respectively, among 20- to 34-year-olds, and by 28% and 46%, respectively, among 35- to 49-year-olds.

Much of the decreasing incidence among older adults "can be attributed to the fact that screening is recommended beginning at the age of 50," Dr. Bailey commented in an interview.

"We saw dramatic rises in the predicted incidences of both colon and rectal cancer in our younger cohort that point out that further studies need to be done to determine why this is happening and what can we do now to prevent this trajectory from occurring in the future," she said at the symposium, sponsored by the American Society of Clinical Oncology.

Likely explanations for this sharp uptick, she suggested, include increasing population levels of obesity and physical inactivity, and consumption of a diet high in fat and red meat – factors implicated as risks for colorectal cancer.

Another possibility is that primary care physicians are now more alert for this cancer in young patients with symptoms such as rectal bleeding, which previously may have been attributed to conditions such as hemorrhoids, delaying diagnosis until an older age.

Recommendations still call for routine colorectal cancer screening only in those patients younger than age 50 who have risk factors such as familial adenomatous polyposis and Lynch syndrome, Dr. Bailey noted. And even though the incidence is rising in the younger age groups, it is still considerably lower than it is among people aged 50 years and older.

Dr. Bailey said she had no relevant financial disclosures.

SAN FRANCISCO – The incidence of colorectal cancer is rising sharply among younger adults in the United States, a study showed.

Researchers analyzed Surveillance, Epidemiology, and End Results (SEER) data for 383,241 patients in whom colorectal cancer was diagnosed between 1975 and 2010.

The results showed that the age-adjusted incidence rate of colorectal cancer fell steadily among patients aged 50 years and older at diagnosis, lead author Dr. Christina E. Bailey, a surgical oncology fellow at the M.D. Anderson Cancer Center in Houston, reported in a poster session at the annual Gastrointestinal Cancers Symposium. But the rate rose among younger patients.

The annual percentage change in the age-adjusted incidence rate of colorectal cancer during the 35-year period was a significant –0.92 in the cohort overall. In stratified analyses, the annual percentage change fell significantly among patients aged 50-74 at diagnosis (–0.97), and aged 75 years and older at diagnosis (–1.15). But it rose among patients aged 35-49 at diagnosis (0.41) and especially among patients aged 20-34 at diagnosis (1.99).

The findings were similar for colon cancer separately (with strongest results seen for disease that was distant at diagnosis) and for rectal/rectosigmoid cancer separately.

A predictive model suggested that if the observed trends persist between 2010 and 2030, the incidences of colon cancer and of rectal/rectosigmoid cancer will rise by 90% and 124%, respectively, among 20- to 34-year-olds, and by 28% and 46%, respectively, among 35- to 49-year-olds.

Much of the decreasing incidence among older adults "can be attributed to the fact that screening is recommended beginning at the age of 50," Dr. Bailey commented in an interview.

"We saw dramatic rises in the predicted incidences of both colon and rectal cancer in our younger cohort that point out that further studies need to be done to determine why this is happening and what can we do now to prevent this trajectory from occurring in the future," she said at the symposium, sponsored by the American Society of Clinical Oncology.

Likely explanations for this sharp uptick, she suggested, include increasing population levels of obesity and physical inactivity, and consumption of a diet high in fat and red meat – factors implicated as risks for colorectal cancer.

Another possibility is that primary care physicians are now more alert for this cancer in young patients with symptoms such as rectal bleeding, which previously may have been attributed to conditions such as hemorrhoids, delaying diagnosis until an older age.

Recommendations still call for routine colorectal cancer screening only in those patients younger than age 50 who have risk factors such as familial adenomatous polyposis and Lynch syndrome, Dr. Bailey noted. And even though the incidence is rising in the younger age groups, it is still considerably lower than it is among people aged 50 years and older.

Dr. Bailey said she had no relevant financial disclosures.

SAN FRANCISCO – The incidence of colorectal cancer is rising sharply among younger adults in the United States, a study showed.

Researchers analyzed Surveillance, Epidemiology, and End Results (SEER) data for 383,241 patients in whom colorectal cancer was diagnosed between 1975 and 2010.

The results showed that the age-adjusted incidence rate of colorectal cancer fell steadily among patients aged 50 years and older at diagnosis, lead author Dr. Christina E. Bailey, a surgical oncology fellow at the M.D. Anderson Cancer Center in Houston, reported in a poster session at the annual Gastrointestinal Cancers Symposium. But the rate rose among younger patients.

The annual percentage change in the age-adjusted incidence rate of colorectal cancer during the 35-year period was a significant –0.92 in the cohort overall. In stratified analyses, the annual percentage change fell significantly among patients aged 50-74 at diagnosis (–0.97), and aged 75 years and older at diagnosis (–1.15). But it rose among patients aged 35-49 at diagnosis (0.41) and especially among patients aged 20-34 at diagnosis (1.99).

The findings were similar for colon cancer separately (with strongest results seen for disease that was distant at diagnosis) and for rectal/rectosigmoid cancer separately.

A predictive model suggested that if the observed trends persist between 2010 and 2030, the incidences of colon cancer and of rectal/rectosigmoid cancer will rise by 90% and 124%, respectively, among 20- to 34-year-olds, and by 28% and 46%, respectively, among 35- to 49-year-olds.

Much of the decreasing incidence among older adults "can be attributed to the fact that screening is recommended beginning at the age of 50," Dr. Bailey commented in an interview.

"We saw dramatic rises in the predicted incidences of both colon and rectal cancer in our younger cohort that point out that further studies need to be done to determine why this is happening and what can we do now to prevent this trajectory from occurring in the future," she said at the symposium, sponsored by the American Society of Clinical Oncology.

Likely explanations for this sharp uptick, she suggested, include increasing population levels of obesity and physical inactivity, and consumption of a diet high in fat and red meat – factors implicated as risks for colorectal cancer.

Another possibility is that primary care physicians are now more alert for this cancer in young patients with symptoms such as rectal bleeding, which previously may have been attributed to conditions such as hemorrhoids, delaying diagnosis until an older age.

Recommendations still call for routine colorectal cancer screening only in those patients younger than age 50 who have risk factors such as familial adenomatous polyposis and Lynch syndrome, Dr. Bailey noted. And even though the incidence is rising in the younger age groups, it is still considerably lower than it is among people aged 50 years and older.

Dr. Bailey said she had no relevant financial disclosures.

SAN FRANCISCO – Regular aspirin use did not improve outcomes among patients with colorectal cancers with mutations of the PIK3CA gene, suggest new data from the largest study yet of aspirin use in this patient population.

Regular aspirin use was reported by 26% of the 185 patients studied, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Users and nonusers were statistically indistinguishable with respect to a variety of recurrence- and survival-related outcomes, according to first author Dr. Nishi Kothari of the H. Lee Moffitt Cancer Center and Research Institute in Tampa.

"Our collaborative study did not validate overall or cancer-specific survival benefits associated with aspirin in PIK3CA-mutant patients across all stages, despite having a larger data set of patients" than earlier studies. "We were also not able to validate the recurrence-free survival benefits associated with aspirin in PIK3CA patients with stages II and III colorectal cancers."

The earlier health professionals study (N. Engl. J. Med. 2012;367:1596-606)and adjuvant VICTOR (Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime) trial (J. Clin. Oncol. 2013;31:4297-305) suggested that PIK3CA mutation, found in about 15% of colorectal cancers, is a biomarker for treatment benefit from aspirin.

Such research has been prompted by the known impact of constitutive PI3K signaling on cyclooxygenase-2 (COX-2) activity and prostaglandin E2 synthesis, blocking tumor cell apoptosis, according to Dr. Kothari. By inhibiting COX-2, aspirin may restore apoptosis.

Factors that may explain the studies’ differing results include differing patient populations, more advanced-stage disease in the new study, a relatively smaller share of right-sided primaries (which are associated with poorer survival) among patients with metastases, inclusion of patients with mutations of PIK3CA in exons 9 and 20 (which have an unclear impact on outcomes), and shorter follow-up.

"At this point, we have positive as well as negative results regarding the predictive value of PIK3CA for aspirin therapy. To help resolve this issue, we will contribute this data to an individual patient meta-analysis" encompassing all three studies, Dr. Kothari said. "To further explore the validity of PIK3CA as a predictive biomarker, a prospective randomized study design should be used."

"As we move into an era of next-generation sequencing, we need to consider which somatic mutations should be studied ... As we identify more mutations in PIK3CA and put together larger patient cohorts, prospective work on aspirin as targeted therapy can begin to evaluate outcomes by mutation," she added.

In the new study, the investigators performed targeted exome sequencing of tumors from patients with stage I to IV colorectal cancer treated at the Moffitt Cancer Center and Royal Melbourne Hospital to identify the cohort with PIK3CA mutations.

The primary colorectal cancer tumor was right sided in 107 patients, left sided in 77 patients, and of unknown location in 1 patient.

With a median follow-up of 46 months, aspirin users and nonusers had statistically indistinguishable overall survival and cancer-specific survival, reported Dr. Kothari. The findings remained the same in a multivariate analysis that included potential confounders.

Furthermore, there was no benefit in terms of recurrence-free survival among patients with stage II and III disease.

There was a trend toward better overall survival for aspirin users among patients with stage IV disease in univariate analysis (hazard ratio, 0.40; P = .06) but not in multivariate analysis.

"Of note, we did find a statistically significant worsened survival with right-sided cancers in this stage IV population," Dr. Kothari pointed out (HR for left vs. right, 0.43; P = .037). "The improved survival with aspirin use seen initially in our stage IV univariate analysis might thus be due to a decrease in incidence of right-sided cancers."

Dr. Kothari disclosed no relevant conflicts of interest.

SAN FRANCISCO – Regular aspirin use did not improve outcomes among patients with colorectal cancers with mutations of the PIK3CA gene, suggest new data from the largest study yet of aspirin use in this patient population.

Regular aspirin use was reported by 26% of the 185 patients studied, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Users and nonusers were statistically indistinguishable with respect to a variety of recurrence- and survival-related outcomes, according to first author Dr. Nishi Kothari of the H. Lee Moffitt Cancer Center and Research Institute in Tampa.

"Our collaborative study did not validate overall or cancer-specific survival benefits associated with aspirin in PIK3CA-mutant patients across all stages, despite having a larger data set of patients" than earlier studies. "We were also not able to validate the recurrence-free survival benefits associated with aspirin in PIK3CA patients with stages II and III colorectal cancers."

The earlier health professionals study (N. Engl. J. Med. 2012;367:1596-606)and adjuvant VICTOR (Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime) trial (J. Clin. Oncol. 2013;31:4297-305) suggested that PIK3CA mutation, found in about 15% of colorectal cancers, is a biomarker for treatment benefit from aspirin.

Such research has been prompted by the known impact of constitutive PI3K signaling on cyclooxygenase-2 (COX-2) activity and prostaglandin E2 synthesis, blocking tumor cell apoptosis, according to Dr. Kothari. By inhibiting COX-2, aspirin may restore apoptosis.

Factors that may explain the studies’ differing results include differing patient populations, more advanced-stage disease in the new study, a relatively smaller share of right-sided primaries (which are associated with poorer survival) among patients with metastases, inclusion of patients with mutations of PIK3CA in exons 9 and 20 (which have an unclear impact on outcomes), and shorter follow-up.

"At this point, we have positive as well as negative results regarding the predictive value of PIK3CA for aspirin therapy. To help resolve this issue, we will contribute this data to an individual patient meta-analysis" encompassing all three studies, Dr. Kothari said. "To further explore the validity of PIK3CA as a predictive biomarker, a prospective randomized study design should be used."

"As we move into an era of next-generation sequencing, we need to consider which somatic mutations should be studied ... As we identify more mutations in PIK3CA and put together larger patient cohorts, prospective work on aspirin as targeted therapy can begin to evaluate outcomes by mutation," she added.

In the new study, the investigators performed targeted exome sequencing of tumors from patients with stage I to IV colorectal cancer treated at the Moffitt Cancer Center and Royal Melbourne Hospital to identify the cohort with PIK3CA mutations.

The primary colorectal cancer tumor was right sided in 107 patients, left sided in 77 patients, and of unknown location in 1 patient.

With a median follow-up of 46 months, aspirin users and nonusers had statistically indistinguishable overall survival and cancer-specific survival, reported Dr. Kothari. The findings remained the same in a multivariate analysis that included potential confounders.

Furthermore, there was no benefit in terms of recurrence-free survival among patients with stage II and III disease.

There was a trend toward better overall survival for aspirin users among patients with stage IV disease in univariate analysis (hazard ratio, 0.40; P = .06) but not in multivariate analysis.

"Of note, we did find a statistically significant worsened survival with right-sided cancers in this stage IV population," Dr. Kothari pointed out (HR for left vs. right, 0.43; P = .037). "The improved survival with aspirin use seen initially in our stage IV univariate analysis might thus be due to a decrease in incidence of right-sided cancers."

Dr. Kothari disclosed no relevant conflicts of interest.

SAN FRANCISCO – Regular aspirin use did not improve outcomes among patients with colorectal cancers with mutations of the PIK3CA gene, suggest new data from the largest study yet of aspirin use in this patient population.

Regular aspirin use was reported by 26% of the 185 patients studied, researchers reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

Users and nonusers were statistically indistinguishable with respect to a variety of recurrence- and survival-related outcomes, according to first author Dr. Nishi Kothari of the H. Lee Moffitt Cancer Center and Research Institute in Tampa.

"Our collaborative study did not validate overall or cancer-specific survival benefits associated with aspirin in PIK3CA-mutant patients across all stages, despite having a larger data set of patients" than earlier studies. "We were also not able to validate the recurrence-free survival benefits associated with aspirin in PIK3CA patients with stages II and III colorectal cancers."

The earlier health professionals study (N. Engl. J. Med. 2012;367:1596-606)and adjuvant VICTOR (Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime) trial (J. Clin. Oncol. 2013;31:4297-305) suggested that PIK3CA mutation, found in about 15% of colorectal cancers, is a biomarker for treatment benefit from aspirin.

Such research has been prompted by the known impact of constitutive PI3K signaling on cyclooxygenase-2 (COX-2) activity and prostaglandin E2 synthesis, blocking tumor cell apoptosis, according to Dr. Kothari. By inhibiting COX-2, aspirin may restore apoptosis.

Factors that may explain the studies’ differing results include differing patient populations, more advanced-stage disease in the new study, a relatively smaller share of right-sided primaries (which are associated with poorer survival) among patients with metastases, inclusion of patients with mutations of PIK3CA in exons 9 and 20 (which have an unclear impact on outcomes), and shorter follow-up.

"At this point, we have positive as well as negative results regarding the predictive value of PIK3CA for aspirin therapy. To help resolve this issue, we will contribute this data to an individual patient meta-analysis" encompassing all three studies, Dr. Kothari said. "To further explore the validity of PIK3CA as a predictive biomarker, a prospective randomized study design should be used."

"As we move into an era of next-generation sequencing, we need to consider which somatic mutations should be studied ... As we identify more mutations in PIK3CA and put together larger patient cohorts, prospective work on aspirin as targeted therapy can begin to evaluate outcomes by mutation," she added.

In the new study, the investigators performed targeted exome sequencing of tumors from patients with stage I to IV colorectal cancer treated at the Moffitt Cancer Center and Royal Melbourne Hospital to identify the cohort with PIK3CA mutations.

The primary colorectal cancer tumor was right sided in 107 patients, left sided in 77 patients, and of unknown location in 1 patient.

With a median follow-up of 46 months, aspirin users and nonusers had statistically indistinguishable overall survival and cancer-specific survival, reported Dr. Kothari. The findings remained the same in a multivariate analysis that included potential confounders.

Furthermore, there was no benefit in terms of recurrence-free survival among patients with stage II and III disease.

There was a trend toward better overall survival for aspirin users among patients with stage IV disease in univariate analysis (hazard ratio, 0.40; P = .06) but not in multivariate analysis.

"Of note, we did find a statistically significant worsened survival with right-sided cancers in this stage IV population," Dr. Kothari pointed out (HR for left vs. right, 0.43; P = .037). "The improved survival with aspirin use seen initially in our stage IV univariate analysis might thus be due to a decrease in incidence of right-sided cancers."

Dr. Kothari disclosed no relevant conflicts of interest.

SAN FRANCISCO – Oral capecitabine is as effective as infused 5-fluorouracil when given as part of neoadjuvant therapy for rectal cancer, new data show. Adding oxaliplatin to either regimen increases toxicity and does not improve efficacy.

These were among the mature results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-04 trial, being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

In the trial, 1,608 patients with resectable stage II or III rectal cancer received neoadjuvant chemoradiotherapy consisting of radiation plus either capecitabine or fluorouracil, each with or without oxaliplatin.

The 3-year rate of locoregional control was high overall, at almost 90%, and statistically indistinguishable between patients who received capecitabine and patients who received 5-fluorouracil (5-FU), lead study author Dr. Carmen Joseph Allegra, a professor of medicine at the University of Florida in Gainesville reported in a press briefing.

"Capecitabine with preop radiation therapy achieved rates similar to continuous infusion 5-FU for the primary endpoint of locoregional failure, as well as for pathologic complete response rate and longer-term outcomes such as disease-free survival and overall survival," Dr. Allegra commented. "This study establishes capecitabine as a standard of care in the preop rectal setting."

"Oxaliplatin did not improve outcomes but added significant toxicity, primarily in the form of diarrhea, and is therefore not indicated in combination with radiation therapy in the preop rectal therapy setting," he added.

Capecitabine has advantages over 5-FU in terms of convenience and avoidance of the need to place central venous catheters and use infusion pumps. Although capecitabine is more expensive in terms of simple drug cost, 5-FU carries the additional costs of ports and infusions.

"This study in over 1,600 patients definitively demonstrates that patients can be treated with oral capecitabine instead of continuous infusion 5-FU, giving our patients a more convenient treatment option. The study also adds to data from prior trials concluding that oxaliplatin does not improve tumor response in this setting," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland.

For the R-04 trial, patients were randomly assigned to receive 5 weeks of radiation therapy. They also received either 5-FU alone; 5-FU with oxaliplatin; capecitabine alone; or capecitabine with oxaliplatin. About a month later, they underwent surgery.

Capecitabine (Xeloda) is approved by the Food and Drug Administration for the treatment of breast and colorectal cancers. Fluorouracil (Adrucil) is approved for the treatment of colorectal and multiple other cancers. Oxaliplatin (Eloxatin) is approved for the treatment of colorectal cancer.

Main results showed that the trial arms were statistically indistinguishable with respect to rates of locoregional control, which required that the patient undergo surgery, have an R0 (complete) resection, and not have any recurrence.

The 3-year values ranged from 87.9% to 88.8%, with no significant difference between the capecitabine and 5-FU groups, or between the oxaliplatin and no-oxaliplatin groups.

The rate of locoregional recurrence was about 4% overall, with values essentially the same across groups, reported Dr. Allegra, who disclosed no relevant conflicts of interest.

In the entire trial population, the 5-year rate of disease-free survival was about 65%, and the 5-year rate of overall survival was about 80%, also with statistically indistinguishable rates by group.

There was no evidence of a significant interaction between capecitabine/5-FU treatment and oxaliplatin treatment in any of the efficacy analyses.

Capecitabine and 5-FU were similar with respect to the rate of overall grade 3 or worse toxicity (30% and 27%) and grade 3 or 4 diarrhea (7% for each).

However, adding oxaliplatin to either regimen increased to 40%-42% the rate of overall grade 3 or worse toxicity and to 16% the rate of grade 3 or 4 diarrhea.

SAN FRANCISCO – Oral capecitabine is as effective as infused 5-fluorouracil when given as part of neoadjuvant therapy for rectal cancer, new data show. Adding oxaliplatin to either regimen increases toxicity and does not improve efficacy.

These were among the mature results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-04 trial, being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

In the trial, 1,608 patients with resectable stage II or III rectal cancer received neoadjuvant chemoradiotherapy consisting of radiation plus either capecitabine or fluorouracil, each with or without oxaliplatin.

The 3-year rate of locoregional control was high overall, at almost 90%, and statistically indistinguishable between patients who received capecitabine and patients who received 5-fluorouracil (5-FU), lead study author Dr. Carmen Joseph Allegra, a professor of medicine at the University of Florida in Gainesville reported in a press briefing.

"Capecitabine with preop radiation therapy achieved rates similar to continuous infusion 5-FU for the primary endpoint of locoregional failure, as well as for pathologic complete response rate and longer-term outcomes such as disease-free survival and overall survival," Dr. Allegra commented. "This study establishes capecitabine as a standard of care in the preop rectal setting."

"Oxaliplatin did not improve outcomes but added significant toxicity, primarily in the form of diarrhea, and is therefore not indicated in combination with radiation therapy in the preop rectal therapy setting," he added.

Capecitabine has advantages over 5-FU in terms of convenience and avoidance of the need to place central venous catheters and use infusion pumps. Although capecitabine is more expensive in terms of simple drug cost, 5-FU carries the additional costs of ports and infusions.

"This study in over 1,600 patients definitively demonstrates that patients can be treated with oral capecitabine instead of continuous infusion 5-FU, giving our patients a more convenient treatment option. The study also adds to data from prior trials concluding that oxaliplatin does not improve tumor response in this setting," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland.

For the R-04 trial, patients were randomly assigned to receive 5 weeks of radiation therapy. They also received either 5-FU alone; 5-FU with oxaliplatin; capecitabine alone; or capecitabine with oxaliplatin. About a month later, they underwent surgery.

Capecitabine (Xeloda) is approved by the Food and Drug Administration for the treatment of breast and colorectal cancers. Fluorouracil (Adrucil) is approved for the treatment of colorectal and multiple other cancers. Oxaliplatin (Eloxatin) is approved for the treatment of colorectal cancer.

Main results showed that the trial arms were statistically indistinguishable with respect to rates of locoregional control, which required that the patient undergo surgery, have an R0 (complete) resection, and not have any recurrence.

The 3-year values ranged from 87.9% to 88.8%, with no significant difference between the capecitabine and 5-FU groups, or between the oxaliplatin and no-oxaliplatin groups.

The rate of locoregional recurrence was about 4% overall, with values essentially the same across groups, reported Dr. Allegra, who disclosed no relevant conflicts of interest.

In the entire trial population, the 5-year rate of disease-free survival was about 65%, and the 5-year rate of overall survival was about 80%, also with statistically indistinguishable rates by group.

There was no evidence of a significant interaction between capecitabine/5-FU treatment and oxaliplatin treatment in any of the efficacy analyses.

Capecitabine and 5-FU were similar with respect to the rate of overall grade 3 or worse toxicity (30% and 27%) and grade 3 or 4 diarrhea (7% for each).

However, adding oxaliplatin to either regimen increased to 40%-42% the rate of overall grade 3 or worse toxicity and to 16% the rate of grade 3 or 4 diarrhea.

SAN FRANCISCO – Oral capecitabine is as effective as infused 5-fluorouracil when given as part of neoadjuvant therapy for rectal cancer, new data show. Adding oxaliplatin to either regimen increases toxicity and does not improve efficacy.

These were among the mature results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol R-04 trial, being reported at the annual Gastrointestinal Cancers Symposium sponsored by the American Society of Clinical Oncology.

In the trial, 1,608 patients with resectable stage II or III rectal cancer received neoadjuvant chemoradiotherapy consisting of radiation plus either capecitabine or fluorouracil, each with or without oxaliplatin.

The 3-year rate of locoregional control was high overall, at almost 90%, and statistically indistinguishable between patients who received capecitabine and patients who received 5-fluorouracil (5-FU), lead study author Dr. Carmen Joseph Allegra, a professor of medicine at the University of Florida in Gainesville reported in a press briefing.

"Capecitabine with preop radiation therapy achieved rates similar to continuous infusion 5-FU for the primary endpoint of locoregional failure, as well as for pathologic complete response rate and longer-term outcomes such as disease-free survival and overall survival," Dr. Allegra commented. "This study establishes capecitabine as a standard of care in the preop rectal setting."

"Oxaliplatin did not improve outcomes but added significant toxicity, primarily in the form of diarrhea, and is therefore not indicated in combination with radiation therapy in the preop rectal therapy setting," he added.

Capecitabine has advantages over 5-FU in terms of convenience and avoidance of the need to place central venous catheters and use infusion pumps. Although capecitabine is more expensive in terms of simple drug cost, 5-FU carries the additional costs of ports and infusions.

"This study in over 1,600 patients definitively demonstrates that patients can be treated with oral capecitabine instead of continuous infusion 5-FU, giving our patients a more convenient treatment option. The study also adds to data from prior trials concluding that oxaliplatin does not improve tumor response in this setting," commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland.

For the R-04 trial, patients were randomly assigned to receive 5 weeks of radiation therapy. They also received either 5-FU alone; 5-FU with oxaliplatin; capecitabine alone; or capecitabine with oxaliplatin. About a month later, they underwent surgery.

Capecitabine (Xeloda) is approved by the Food and Drug Administration for the treatment of breast and colorectal cancers. Fluorouracil (Adrucil) is approved for the treatment of colorectal and multiple other cancers. Oxaliplatin (Eloxatin) is approved for the treatment of colorectal cancer.

Main results showed that the trial arms were statistically indistinguishable with respect to rates of locoregional control, which required that the patient undergo surgery, have an R0 (complete) resection, and not have any recurrence.

The 3-year values ranged from 87.9% to 88.8%, with no significant difference between the capecitabine and 5-FU groups, or between the oxaliplatin and no-oxaliplatin groups.

The rate of locoregional recurrence was about 4% overall, with values essentially the same across groups, reported Dr. Allegra, who disclosed no relevant conflicts of interest.

In the entire trial population, the 5-year rate of disease-free survival was about 65%, and the 5-year rate of overall survival was about 80%, also with statistically indistinguishable rates by group.

There was no evidence of a significant interaction between capecitabine/5-FU treatment and oxaliplatin treatment in any of the efficacy analyses.

Capecitabine and 5-FU were similar with respect to the rate of overall grade 3 or worse toxicity (30% and 27%) and grade 3 or 4 diarrhea (7% for each).

However, adding oxaliplatin to either regimen increased to 40%-42% the rate of overall grade 3 or worse toxicity and to 16% the rate of grade 3 or 4 diarrhea.