ASCO: Genitourinary Cancers Symposium 2012

A fundamental problem with contemporary prostate cancer treatment in the United States is that our system for reimbursement rewards technology rather than outcomes, with the result that economic incentives drive treatment decisions that should instead be based on clinical risk and patient-centered outcomes.

Proton beam therapy is perhaps the most extreme example of perverse incentives. There has never been a single published study that has shown any clinical benefit in terms of oncologic outcomes or quality of life for proton therapy over contemporary photon-based radiation – or over surgery, for that matter – for prostate cancer. In fact, not only is proton therapy no better than intensity-modulated radiation therapy (IMRT), a recent large-scale study suggested it has greater rectal toxicity (ASCO GU, Abstract 3).

Yet Medicare and other payers reimburse for proton beam therapy extraordinarily generously – far more than for any other treatment. Researchers have argued that even if proton therapy allowed dose-escalation up to 90 Gy, it would still not be cost-effective (J. Clin. Oncol. 2007;25:3603-8).

Fortunately, proton beam therapy for prostate cancer is still relatively rare, though this may change as new facilities are constructed across the county. IMRT, on the other hand, the next most expensive treatment, is used very commonly for low-risk disease, again despite absence of any evidence of advantage over – or even equivalence to – brachytherapy, a much more economical option. IMRT generally requires that patients attend treatment sessions daily for up to 8 weeks. Another abstract at the ASCO GU symposium suggested that this required number of treatment sessions could safely be reduced to as few as five total. But as long as payers continue to reimburse radiation on a per-fraction basis, this strategy seems unlikely to gain traction among providers, no matter what the convenience benefit may be to the patient.

Though not discussed directly at the ASCO GU session, robot-assisted prostatectomy has been another example of rapid dissemination of a novel technology in advance of clinical data demonstrating superiority. As with the competing radiation modalities, large-scale studies so far have not demonstrated improved outcomes for robot-assisted over open surgery in broad community practice. However, in the case of surgery there is substantial literature showing improved outcomes in centers with very high surgical volumes. A fundamental difference, too, between the spread of IMRT and that of robot-assisted surgery is that the latter has been driven in part by hospitals competing for market share – but not by reimbursement incentives. In most cases, robot-assisted prostatectomy is paid no differently than open surgery, and the additional costs of the surgery are assumed by the hospitals rather than payers. Neither surgical modality approaches IMRT, to say nothing of proton-beam therapy – in terms of cost.

The evolution of practice patterns for prostate cancer is in a sense emblematic of the failings of the U.S. health care system as a whole. Treatment is frequently supply sensitive: driven by availability of technology and system capacity rather than clinical need; this situation is reinforced by economic incentives that reward maximal rather than efficient care, and that do not emphasize achievement – or even assessment – of high-quality outcomes. Responsibility for this situation is shared among payers, providers, hospitals, manufacturers of equipment, and patients. The public tends to misplace faith in new technology, assuming that if it’s newer and more expensive, it must be better. Marketing has of course played a major role as well, and there are unquestionably instances of misleading and even false advertising of these new technologies.

We need more high-quality comparative effectiveness research (CER) of prostate cancer treatments. Indeed, prostate cancer has been identified as one of the highest-priority areas for comparative effectiveness research by the Agency for Healthcare Research and Quality, the National Institutes of Health, and the Institute of Medicine. Despite saber-rattling by some members of Congress, CER will someday by necessity inform at least some insurance coverage decisions.

But the research has to be done well. There is no denying that prostate cancer studies are difficult; they are long and they are expensive if done properly. They require collecting patient-reported data with validated quality of life instruments prospectively, regularly, and consistently across all centers and treatment modalities. Relying on administrative coding data or on physician-reported toxicities to assess complications is not sufficient – patients must report their own outcomes. And metastasis and mortality outcomes – the only end points useful for comparing surgery and radiation – take years to reach and must be associated with rich clinical detail for adequate risk adjustment.

Ultimately, the lively debates over surgery vs. radiation or IMRT vs. proton-beam therapy obscure the fact that for most low-risk prostate cancers, the best treatment is no treatment; most low-risk patients should be on active surveillance. But again, reimbursement incentives are aligned against doing the right thing: We need a CPT code for surveillance of malignancy, if we want to fix the critical problem of overtreatment. Prostate cancer is not unique in this need: Oncology is now beset with new epidemiologic and public health problems arising from overdiagnosis in an era of widespread imaging and advanced diagnostics. The health care system needs incentive structures that recognize the nuances of diagnosis and risk stratification, and that do not drive maximal – and maximally expensive – therapy for all patients at all times.

Strident advocates for particular technologies run the risk of winning pyrrhic victories over other modalities but ultimately helping lose the broader war on prostate cancer. Whether or not the U.S. Preventive Services Task Force’s draft statement against prostate cancer screening becomes its final recommendation, the writing is on the wall that the broader medical community’s tolerance for overtreatment is, appropriately, dissipating quickly. If the treating community – urologists, radiation oncologists, and medical oncologists – does not tackle overtreatment more aggressively, and target treatments to individual patients’ tumor characteristics and comorbidities, there is a real risk that primary care providers will stop screening altogether, and much of the progress realized in recent years in prostate cancer mortality rates will be lost.

Conversely, for men with high-risk prostate cancer, arguments among modalities should yield to a paradigm recognizing these tumors as aggressive and potentially lethal, best treated with a combination of surgery, radiation, and systemic therapy – just like rectal, breast, and other malignancies.

Hopefully, one result of the many ongoing comparative effectiveness research efforts will eventually be a system that rewards outcomes rather than technology, although clearly more than research will be required to effect the needed reforms.

In the meantime, for treating clinicians to retain (or regain) leadership in setting the terms of the debate over prostate cancer, we need to demonstrate that we can routinely assess and report the long-term outcomes that matter most, engage patients fully in shared decision-making, target intensity of treatment to individual patients’ cancer risk and comorbidities, and prescribe interventions that are proved to be both effective and cost-effective.

Dr. Matthew R. Cooperberg is assistant professor of urology at the University of California, San Francisco. He disclosed having no relevant conflicts of interest.

A fundamental problem with contemporary prostate cancer treatment in the United States is that our system for reimbursement rewards technology rather than outcomes, with the result that economic incentives drive treatment decisions that should instead be based on clinical risk and patient-centered outcomes.

Proton beam therapy is perhaps the most extreme example of perverse incentives. There has never been a single published study that has shown any clinical benefit in terms of oncologic outcomes or quality of life for proton therapy over contemporary photon-based radiation – or over surgery, for that matter – for prostate cancer. In fact, not only is proton therapy no better than intensity-modulated radiation therapy (IMRT), a recent large-scale study suggested it has greater rectal toxicity (ASCO GU, Abstract 3).

Yet Medicare and other payers reimburse for proton beam therapy extraordinarily generously – far more than for any other treatment. Researchers have argued that even if proton therapy allowed dose-escalation up to 90 Gy, it would still not be cost-effective (J. Clin. Oncol. 2007;25:3603-8).

Fortunately, proton beam therapy for prostate cancer is still relatively rare, though this may change as new facilities are constructed across the county. IMRT, on the other hand, the next most expensive treatment, is used very commonly for low-risk disease, again despite absence of any evidence of advantage over – or even equivalence to – brachytherapy, a much more economical option. IMRT generally requires that patients attend treatment sessions daily for up to 8 weeks. Another abstract at the ASCO GU symposium suggested that this required number of treatment sessions could safely be reduced to as few as five total. But as long as payers continue to reimburse radiation on a per-fraction basis, this strategy seems unlikely to gain traction among providers, no matter what the convenience benefit may be to the patient.

Though not discussed directly at the ASCO GU session, robot-assisted prostatectomy has been another example of rapid dissemination of a novel technology in advance of clinical data demonstrating superiority. As with the competing radiation modalities, large-scale studies so far have not demonstrated improved outcomes for robot-assisted over open surgery in broad community practice. However, in the case of surgery there is substantial literature showing improved outcomes in centers with very high surgical volumes. A fundamental difference, too, between the spread of IMRT and that of robot-assisted surgery is that the latter has been driven in part by hospitals competing for market share – but not by reimbursement incentives. In most cases, robot-assisted prostatectomy is paid no differently than open surgery, and the additional costs of the surgery are assumed by the hospitals rather than payers. Neither surgical modality approaches IMRT, to say nothing of proton-beam therapy – in terms of cost.

The evolution of practice patterns for prostate cancer is in a sense emblematic of the failings of the U.S. health care system as a whole. Treatment is frequently supply sensitive: driven by availability of technology and system capacity rather than clinical need; this situation is reinforced by economic incentives that reward maximal rather than efficient care, and that do not emphasize achievement – or even assessment – of high-quality outcomes. Responsibility for this situation is shared among payers, providers, hospitals, manufacturers of equipment, and patients. The public tends to misplace faith in new technology, assuming that if it’s newer and more expensive, it must be better. Marketing has of course played a major role as well, and there are unquestionably instances of misleading and even false advertising of these new technologies.

We need more high-quality comparative effectiveness research (CER) of prostate cancer treatments. Indeed, prostate cancer has been identified as one of the highest-priority areas for comparative effectiveness research by the Agency for Healthcare Research and Quality, the National Institutes of Health, and the Institute of Medicine. Despite saber-rattling by some members of Congress, CER will someday by necessity inform at least some insurance coverage decisions.

But the research has to be done well. There is no denying that prostate cancer studies are difficult; they are long and they are expensive if done properly. They require collecting patient-reported data with validated quality of life instruments prospectively, regularly, and consistently across all centers and treatment modalities. Relying on administrative coding data or on physician-reported toxicities to assess complications is not sufficient – patients must report their own outcomes. And metastasis and mortality outcomes – the only end points useful for comparing surgery and radiation – take years to reach and must be associated with rich clinical detail for adequate risk adjustment.

Ultimately, the lively debates over surgery vs. radiation or IMRT vs. proton-beam therapy obscure the fact that for most low-risk prostate cancers, the best treatment is no treatment; most low-risk patients should be on active surveillance. But again, reimbursement incentives are aligned against doing the right thing: We need a CPT code for surveillance of malignancy, if we want to fix the critical problem of overtreatment. Prostate cancer is not unique in this need: Oncology is now beset with new epidemiologic and public health problems arising from overdiagnosis in an era of widespread imaging and advanced diagnostics. The health care system needs incentive structures that recognize the nuances of diagnosis and risk stratification, and that do not drive maximal – and maximally expensive – therapy for all patients at all times.

Strident advocates for particular technologies run the risk of winning pyrrhic victories over other modalities but ultimately helping lose the broader war on prostate cancer. Whether or not the U.S. Preventive Services Task Force’s draft statement against prostate cancer screening becomes its final recommendation, the writing is on the wall that the broader medical community’s tolerance for overtreatment is, appropriately, dissipating quickly. If the treating community – urologists, radiation oncologists, and medical oncologists – does not tackle overtreatment more aggressively, and target treatments to individual patients’ tumor characteristics and comorbidities, there is a real risk that primary care providers will stop screening altogether, and much of the progress realized in recent years in prostate cancer mortality rates will be lost.

Conversely, for men with high-risk prostate cancer, arguments among modalities should yield to a paradigm recognizing these tumors as aggressive and potentially lethal, best treated with a combination of surgery, radiation, and systemic therapy – just like rectal, breast, and other malignancies.

Hopefully, one result of the many ongoing comparative effectiveness research efforts will eventually be a system that rewards outcomes rather than technology, although clearly more than research will be required to effect the needed reforms.

In the meantime, for treating clinicians to retain (or regain) leadership in setting the terms of the debate over prostate cancer, we need to demonstrate that we can routinely assess and report the long-term outcomes that matter most, engage patients fully in shared decision-making, target intensity of treatment to individual patients’ cancer risk and comorbidities, and prescribe interventions that are proved to be both effective and cost-effective.

Dr. Matthew R. Cooperberg is assistant professor of urology at the University of California, San Francisco. He disclosed having no relevant conflicts of interest.

A fundamental problem with contemporary prostate cancer treatment in the United States is that our system for reimbursement rewards technology rather than outcomes, with the result that economic incentives drive treatment decisions that should instead be based on clinical risk and patient-centered outcomes.

Proton beam therapy is perhaps the most extreme example of perverse incentives. There has never been a single published study that has shown any clinical benefit in terms of oncologic outcomes or quality of life for proton therapy over contemporary photon-based radiation – or over surgery, for that matter – for prostate cancer. In fact, not only is proton therapy no better than intensity-modulated radiation therapy (IMRT), a recent large-scale study suggested it has greater rectal toxicity (ASCO GU, Abstract 3).

Yet Medicare and other payers reimburse for proton beam therapy extraordinarily generously – far more than for any other treatment. Researchers have argued that even if proton therapy allowed dose-escalation up to 90 Gy, it would still not be cost-effective (J. Clin. Oncol. 2007;25:3603-8).

Fortunately, proton beam therapy for prostate cancer is still relatively rare, though this may change as new facilities are constructed across the county. IMRT, on the other hand, the next most expensive treatment, is used very commonly for low-risk disease, again despite absence of any evidence of advantage over – or even equivalence to – brachytherapy, a much more economical option. IMRT generally requires that patients attend treatment sessions daily for up to 8 weeks. Another abstract at the ASCO GU symposium suggested that this required number of treatment sessions could safely be reduced to as few as five total. But as long as payers continue to reimburse radiation on a per-fraction basis, this strategy seems unlikely to gain traction among providers, no matter what the convenience benefit may be to the patient.

Though not discussed directly at the ASCO GU session, robot-assisted prostatectomy has been another example of rapid dissemination of a novel technology in advance of clinical data demonstrating superiority. As with the competing radiation modalities, large-scale studies so far have not demonstrated improved outcomes for robot-assisted over open surgery in broad community practice. However, in the case of surgery there is substantial literature showing improved outcomes in centers with very high surgical volumes. A fundamental difference, too, between the spread of IMRT and that of robot-assisted surgery is that the latter has been driven in part by hospitals competing for market share – but not by reimbursement incentives. In most cases, robot-assisted prostatectomy is paid no differently than open surgery, and the additional costs of the surgery are assumed by the hospitals rather than payers. Neither surgical modality approaches IMRT, to say nothing of proton-beam therapy – in terms of cost.

The evolution of practice patterns for prostate cancer is in a sense emblematic of the failings of the U.S. health care system as a whole. Treatment is frequently supply sensitive: driven by availability of technology and system capacity rather than clinical need; this situation is reinforced by economic incentives that reward maximal rather than efficient care, and that do not emphasize achievement – or even assessment – of high-quality outcomes. Responsibility for this situation is shared among payers, providers, hospitals, manufacturers of equipment, and patients. The public tends to misplace faith in new technology, assuming that if it’s newer and more expensive, it must be better. Marketing has of course played a major role as well, and there are unquestionably instances of misleading and even false advertising of these new technologies.

We need more high-quality comparative effectiveness research (CER) of prostate cancer treatments. Indeed, prostate cancer has been identified as one of the highest-priority areas for comparative effectiveness research by the Agency for Healthcare Research and Quality, the National Institutes of Health, and the Institute of Medicine. Despite saber-rattling by some members of Congress, CER will someday by necessity inform at least some insurance coverage decisions.

But the research has to be done well. There is no denying that prostate cancer studies are difficult; they are long and they are expensive if done properly. They require collecting patient-reported data with validated quality of life instruments prospectively, regularly, and consistently across all centers and treatment modalities. Relying on administrative coding data or on physician-reported toxicities to assess complications is not sufficient – patients must report their own outcomes. And metastasis and mortality outcomes – the only end points useful for comparing surgery and radiation – take years to reach and must be associated with rich clinical detail for adequate risk adjustment.

Ultimately, the lively debates over surgery vs. radiation or IMRT vs. proton-beam therapy obscure the fact that for most low-risk prostate cancers, the best treatment is no treatment; most low-risk patients should be on active surveillance. But again, reimbursement incentives are aligned against doing the right thing: We need a CPT code for surveillance of malignancy, if we want to fix the critical problem of overtreatment. Prostate cancer is not unique in this need: Oncology is now beset with new epidemiologic and public health problems arising from overdiagnosis in an era of widespread imaging and advanced diagnostics. The health care system needs incentive structures that recognize the nuances of diagnosis and risk stratification, and that do not drive maximal – and maximally expensive – therapy for all patients at all times.

Strident advocates for particular technologies run the risk of winning pyrrhic victories over other modalities but ultimately helping lose the broader war on prostate cancer. Whether or not the U.S. Preventive Services Task Force’s draft statement against prostate cancer screening becomes its final recommendation, the writing is on the wall that the broader medical community’s tolerance for overtreatment is, appropriately, dissipating quickly. If the treating community – urologists, radiation oncologists, and medical oncologists – does not tackle overtreatment more aggressively, and target treatments to individual patients’ tumor characteristics and comorbidities, there is a real risk that primary care providers will stop screening altogether, and much of the progress realized in recent years in prostate cancer mortality rates will be lost.

Conversely, for men with high-risk prostate cancer, arguments among modalities should yield to a paradigm recognizing these tumors as aggressive and potentially lethal, best treated with a combination of surgery, radiation, and systemic therapy – just like rectal, breast, and other malignancies.

Hopefully, one result of the many ongoing comparative effectiveness research efforts will eventually be a system that rewards outcomes rather than technology, although clearly more than research will be required to effect the needed reforms.

In the meantime, for treating clinicians to retain (or regain) leadership in setting the terms of the debate over prostate cancer, we need to demonstrate that we can routinely assess and report the long-term outcomes that matter most, engage patients fully in shared decision-making, target intensity of treatment to individual patients’ cancer risk and comorbidities, and prescribe interventions that are proved to be both effective and cost-effective.

Dr. Matthew R. Cooperberg is assistant professor of urology at the University of California, San Francisco. He disclosed having no relevant conflicts of interest.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Tyrosine kinase inhibitors that target the vascular endothelial growth factor receptor increase the risk of a fatal adverse event in cancer patients, but the absolute rate is still low, investigators concluded from a meta-analysis of 10 randomized trials with a total of 4,679 patients.

Trial participants given sorafenib (Nexavar), sunitinib (Sutent), or pazopanib (Votrient) were more than twice as likely to die from an adverse event as were peers given control treatment, said lead investigator Dr. Christopher J. Richards of the Beth Israel Deaconess Medical Center in Boston. Yet, the rate was still less than 2%.

"Our analysis may underestimate the true incidence of fatal adverse events, as study patients may be healthier than the general population exposed to these drugs," he noted at the Genitourinary Cancers Symposium. But that said, "all three of the study drugs have been shown in various randomized controlled trials to improve clinical outcomes compared to traditional therapies."

Discussant Dr. Thomas E. Hutson of the Baylor Sammons Cancer Center in Dallas commented, "I feel confident that everyone or almost everyone in the room today would agree with me that our current therapy benefit outweighs the risk associated with the treatment."

Moreover, even among the new targeted agents, the 1.5% rate seen with the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in the meta-analysis "compares very favorably" with the rate of 2.9% seen previously with bevacizumab (Avastin), another VEGF-targeted therapy, in a similar analysis (JAMA 2011;305:487-94).

"Targeted therapies have real toxicities, and these toxicities include a low risk of death – a risk of death not much different than other therapies used for kidney and other cancer types," Dr. Hutson asserted. "If anything, this meta-analysis shows us that close monitoring is going to be essential for optimal use of these agents."

In the study, Dr. Richards and his colleagues identified 10 randomized controlled phase II or III trials in which patients received any of three VEGFR TKIs approved by the Food and Drug Administration for cancer treatment as of February 2011: sorafenib, sunitinib, or pazopanib. The control groups were usually treated with a placebo, but in some cases with chemotherapy or immunotherapy.

The enrolled patients had a variety of malignancies: renal cell carcinoma, hepatocellular carcinoma, melanoma, non–small cell lung cancer, breast cancer, and pancreatic neuroendocrine tumor. "All patients included in the studies had good performance status and had adequate baseline cardiac, hematologic, and renal function at the time of study entry," Dr. Richards pointed out.

In a pooled analysis, relative to control treatment, VEGFR TKI treatment was associated with a 2.23-fold increased risk of fatal adverse events (P = .02). But even so, the absolute rate of such events was just 1.5%, compared with 0.7% with the control treatment.

In stratified analyses, there was no significant difference in the relative risks across the three agents or the relative risks for renal cell carcinoma vs. other types of cancer.

The most common fatal adverse events in the trials overall (considering both control and VEGFR TKI arms) were hemorrhage (48% of the total), myocardial infarction (15%), and hepatic failure (10%). These events "occurred in both the placebo and control groups as well as study groups," Dr. Richards noted.

He acknowledged that limitations of the study included the fact that the analysis used study-level instead of patient-level data, which may have resulted in confounding, and that it did not have adequate power to detect differences between the three VEGFR TKIs, although they all have a similar mechanism of action.

The symposium was sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Richards disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Healthy middle-aged and older men who take vitamin E supplements have an increased risk of prostate cancer, although the risk takes some time to emerge, suggests an update of the randomized SELECT prevention trial.

At a median follow-up of 7 years – or 1.5 years after the trial had been closed early for futility and men had been told to stop taking supplements – those who had taken vitamin E had a significant 17% greater risk of prostate cancer than those who had taken a placebo. The risk had been increased, although not significantly so, at the time of trial closure.

Photo credit: Juanmonino/iStockphoto

In absolute terms, the elevated risk from taking vitamin E translated to 11 more cancers for every 1,000 men over a 7-year period, Dr. Eric A. Klein said at the Genitourinary Cancers Symposium.

The findings serve as a cautionary tale, he said. "Nutritional supplements are biologically active and may in fact be harmful, and importantly, the effect may continue after the intervention stops," Dr. Klein commented.

More than half of U.S. men over age 60 take vitamin E, with about one-quarter taking at least 400 IU daily (Ann. Intern. Med. 2005;143:116-20), the dose used in the trial. "Consumers should be skeptical about health claims for unregulated over-the-counter products in the absence of strong evidence of benefit from clinical trials," said Dr. Klein at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

In other updated results, men who took selenium with vitamin E and men who took selenium alone did not have any significant increase in the risk of prostate cancer. And baseline plasma levels of various tocopherols (forms of vitamin E) modified prostate cancer risk: Within the vitamin E group, for example, higher levels of alpha-tocopherol were protective, whereas higher levels of gamma-tocopherol were deleterious.

The obvious question now is, how does vitamin E increase prostate cancer risk? said Dr. Klein, who is chairman of the Glickman Urological and Kidney Institute at the Cleveland Clinic. Theories that have been advanced include the possibility that antioxidants become carcinogenic pro-oxidants at high doses; there may be interplay between the different types of tocopherols; high doses of vitamin E may inhibit absorption of other, protective fat-soluble vitamins; and genetic susceptibility may affect the actions of antioxidants. A related, as yet unanswered question is why adding selenium to vitamin E abolishes the excess risk.

"We need to sort all of this out," Dr. Klein said, pointing to the SELECT (Selenium and Vitamin E Cancer Prevention Trial) Biorepository, which contains a wealth of information about the men studied and is being offered as a resource. "I invite anybody in the scientific community to float a hypothesis. If it passes scientific muster, we will give you access to the Biorepository to help us answer [these questions]." More than a half dozen studies have already been approved, he said.

In SELECT, 35,533 healthy North American men aged 50 years or older if black or 55 years or older if of other races/ethnicities who had an average risk of prostate cancer were randomized to four groups: vitamin E (400 IU/day, all rac-alpha-tocopherol acetate), selenium (200 mcg/day from l-selenomethionine), the combination, or a placebo.

"It was recommended, but not required in this trial, unlike in the PCPT [Prostate Cancer Prevention Trial], that men be screened yearly with PSA and digital rectal exam," Dr. Klein noted. "One of the strengths of the trial is that the screening interval and the trigger for biopsy were not prescribed by the trial; they were left to local community standards at these 400-plus sites."

At the time that the trial was halted early, men in the vitamin E group had a marginally increased risk of prostate cancer compared with men in the placebo group (hazard ratio, 1.13; P = .06) (JAMA 2009;301:39-51). But with the additional follow-up, despite cessation of supplement use, the trend continued and became significant (hazard ratio, 1.17; P = .008) (JAMA 2011;306:1549-56).

"There was no difference in tumor aggressiveness across the four arms as assessed by tumor stage and grade," Dr. Klein reported. "And the increased risk of being diagnosed with prostate cancer in the vitamin E arm was not accounted for by more intense screening or an increasing rate of biopsy."

In the vitamin E group, the risk of prostate cancer generally decreased with each additional quintile of alpha-tocopherol at baseline. In contrast, within the selenium and combination groups, the risk increased with quintile, and within the placebo group, risk was unaffected.

The results were "somewhat opposite" for plasma gamma-tocopherol levels at baseline. In the vitamin E group, the risk generally increased with quintile. In contrast, within all the other groups, the risk decreased with quintile.

The findings have noteworthy implications for the design of clinical trials, said Dr. Klein.

"There were interactions between selenium and vitamin E with respect to risk, and a factorial design would not have captured that. So it’s important that these be powered to allow for these interactions to be tested for," he explained. "And maybe most importantly, for agents whose biology we don’t really understand and don’t really understand what the time line of the effect is, that postintervention follow-up is critical: If we had not continued to follow these men beyond the 5.5 years that they took the supplements, we would not have discovered [the elevated risk with vitamin E]".

Dr. Klein disclosed that he had no relevant conflicts of interest.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Two new U.S. studies involving more than 150,000 older men with prostate cancer are likely to add to the intense debate about the optimal treatment for early disease, especially the various radiation therapy options.

One study suggests that the newer intensity-modulated radiation therapy (IMRT) is more effective and less toxic than the older conformal radiation therapy. But it found that proton therapy, which is even newer, not only wasn’t more effective than IMRT but also had higher bowel toxicity.

The second study suggests that external beam radiation therapy (EBRT) is more toxic than both prostatectomy and brachytherapy. Also, EBRT was at least twice as expensive.

Both studies used linked SEER (Surveillance, Epidemiology, and End Results) and Medicare data.

"We all love new technology, regardless of how much it costs," said Dr. Paul L. Nguyen in a discussion of both presentations at the Genitourinary Cancers Symposium. But third-party payers are increasingly seeking comparative effectiveness data to show that the benefits of newer therapies justify their higher expense.

"Whether you agree with the findings or not, these two provocative studies provide data that are going to shape the public’s thinking about the relative value of our treatments," added Dr. Nguyen of the Dana-Farber Cancer Institute in Boston.

"More work is needed from us as a field to generate the data [to prove] that our treatments are cost effective. And if we do not generate [these data], then third parties are going to increasingly dictate the treatments that we can and cannot offer."

IMRT Tops External RT Options

In the first study, Dr. Nathan C. Sheets and colleagues at the University of North Carolina at Chapel Hill analyzed data for 12,976 men who had localized prostate cancer and were diagnosed in 2002-2006. "We observed a rapid and nearly complete adoption of IMRT as the radiation treatment of choice for localized prostate cancer between 2002 and 2008," he noted.

Results using propensity adjustment (to try to compensate for factors that might have influenced treatment choice) showed that with a median follow-up of 4.5 years, IMRT was superior to conformal radiation therapy in terms of a lower rate of additional cancer treatment, which is a proxy for effectiveness (2.5 vs. 3.1 events per 100 person-years; P less than .001), and which he proposed might be related to the ability to increase the radiation dose given with IMRT.

Billing claims data indicated that IMRT also had lower rates of bowel toxicity (13.4 vs. 14.7 events; P less than .001) and hip fracture (0.8 vs. 1.0 events; P = .006), but a higher rate of erectile dysfunction (5.9 vs. 5.3 events; P = .006).

Proton Therapy Adds Cost, Toxicity

In an additional analysis of 1,638 men that compared proton therapy vs. IMRT – the largest series of proton therapy to date – the former was no more effective, as assessed from receipt of additional cancer treatments. Furthermore, it had a higher rate of bowel toxicity (17.8 vs. 12.2 events per 100 person-years; P less than .001), Dr. Sheets reported.

"This study supports the use of IMRT as the current standard radiation technique for prostate cancer. ... There is currently no clear evidence that proton therapy is better than IMRT," he concluded, adding that because of limitations of the data, the result for proton therapy is "hypothesis generating, but it is not in any way definitive."

The favorable findings for IMRT vs. conformal radiation therapy add to results of other studies to "support the use of IMRT despite its higher cost," according to Dr. Nguyen, the discussant. However, "this study raises doubts that protons are better than IMRT for prostate cancer."

"If you are a proponent of proton therapy, you should consider participating in the randomized trial of protons vs. IMRT that’s going to hopefully be opening later this year, ... or otherwise, commit to enrolling patients on the national prospective registry so that we can try to collect prospectively some of the data and make some of the adjustments, so we can see a little bit better what’s causing these differences," he recommended.

"In 2012, absent any data which has ever shown any clinical benefit for proton beam therapy over photon therapy, while the randomized trials are going on, how can we continue to pay what we pay for proton therapy?" Dr. Matthew R. Cooperberg of the University of California, San Francisco, asked during the comments period.

"Protons have a lot of promise, and there is a model now, maybe, of paying for this kind of therapy while we investigate it. So we want to pay for protons, but we want to learn something from every patient that is going to get proton therapy," Dr. Nguyen replied. "So I think that if we have that model where we try to enroll patients on trials, it’s worth it."

Dr. William U. Shipley, chair of the genitourinary oncology unit at the Massachusetts General Hospital in Boston, one of two institutions spearheading the randomized trial of protons vs. IMRT, noted the apparent reluctance of proton centers to participate.

"We are opening that trial, and we will be joined, surprisingly, by as many as 5 of the 25 centers in the United States. For some reason, the other 20 feel that they don’t want to test the protons," he commented. "But we are, and I assure you that it will give you whatever information we have."

Surgery and Brachytherapy Top EBRT

In the second study, Dr. Jay P. Ciezki of the Cleveland Clinic and colleagues, analyzed data for 137,427 men with prostate cancer of various stages diagnosed in 1991-2007 who received single-modality therapy.

The lengthy study period is important because patients are unlikely to die of prostate cancer, whereas morbidity may become problematic with time, he said. "It’s really of great interest to all of us who treat prostate cancer what happens after that 5-year mark."

With a median duration of follow-up of 5.9 years, the overall rate of toxicity requiring intervention, as determined from billing codes, was higher for men treated with EBRT (8.8%) than for their counterparts treated with prostatectomy (6.9%) or brachytherapy (3.7%). The most common gastrointestinal toxicity by far was rectal bleeding that required cauterization, whereas the most common genitourinary toxicity was urinary stricture requiring dilation.

The cumulative incidence of gastrointestinal and genitourinary toxicity with EBRT continued to rise over the 17-year period, whereas it generally plateaued for the other two modalities after the first 5 years. When the external beam group was stratified by radiation technique, the late rise in genitourinary toxicity seemed to be largely driven by IMRT.

EBRT was also the most expensive of the three modalities, Dr. Ciezki reported. When both the initial treatment and the treatment of any toxicity were considered, the mean total cost per patient per year was $6,412 – twice that for open prostatectomy, at $3,206, and more than twice that for brachytherapy, at $2,557 (P less than .0001).

Based on these data, "the long-term toxicity and cost per patient-year of the major prostate cancer treatment modalities [differ], with the external beam being the most toxic and the most costly," he commented.

Dr. Nguyen noted that it is unclear from the study whether EBRT should be abandoned for patients with low-risk disease, given factors such as potential confounding and the big improvement in the targeting of EBRT during the study period, so that the results might not reflect what is done today.

"Further prospective or randomized trials are needed to try to separate the effects of the treatment from the effects of patient selection," he concluded. "But if this study is confirmed in other large studies, this could provide a societal and clinical rationale to favor brachytherapy over external beam in men who qualify for both."

The symposium was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Sheets and Dr. Ciezki disclosed that they had no relevant conflicts of interest. Dr. Nguyen disclosed that he receives research funding from Varian.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Everolimus is efficacious and safe for shrinking renal angiomyolipomas and reducing the formation of new ones in patients having the genetic disorder tuberous sclerosis complex or sporadic lymphangiomyomatosis, new data suggest.

More than 40% of the 118 patients enrolled in a randomized, phase III trial met criteria for tumor response when given everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), researchers reported at the Genitourinary Cancers Symposium. In sharp contrast, none of those given a matching placebo did.

Everolimus could potentially provide the first effective pharmacologic option for treating angiomyolipomas, the surgical management of which is often frustrating, according to lead investigator Dr. John J. Bissler, a nephrologist at the Cincinnati Children’s Hospital Medical Center.

"These lesions can be multiple and bilateral, so surgical approaches can be problematic for this genetic disease. The lesions continue to pop up. You can remove a lesion ... and then you come back and have a lesion growing there that you thought you just took out. Maybe you did take the whole lesion out, but now you have incited another to begin to grow," he explained in an interview.

"So at the end of the day, having a drug therapy is just incredibly exciting," he commented.

The trial is also important in that it adds more evidence of benefit of this class of agents in tumors having dysregulated mTOR signaling, such as subependymal giant cell astrocytomas (SEGAs), for which everolimus is already an approved treatment, Dr. Bissler said at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

The drug was well tolerated, too, with adverse effects that were largely expected based on prior experience. "The only thing that we saw that was a little bit different and [that] we haven’t seen in other populations as much was ... a very small increase in amenorrhea," he said. "But we know that mTOR inhibition has effects on different sex hormones, so it’s not unexpected that you would see that, and we just need to keep track of that."

Angiomyolipomas are the most common renal manifestation of tuberous sclerosis complex. They are also seen in patients having lymphangiomyomatosis, a pulmonary condition occurring both in association with tuberous sclerosis complex and sporadically.

Of relevance to targeted therapy, mutations in the tuberous sclerosis complex genes TSC1 and TSC2 in these diseases lead to constitutive up-regulation of mTOR complex 1, resulting in excessive cell growth and proliferation.

The current trial, called EXIST-2, enrolled patients at least 18 years of age who had angiomyolipomas, and randomized them 2:1 to receive oral everolimus (Afinitor) at 10 mg once daily or placebo until tumor progression or unacceptable toxicity. Those in the latter group were allowed to cross over to everolimus if their disease progressed.

The investigators used central radiology review of serial kidney CT and MRI images to assess angiomyolipoma response, which required at least a one-half reduction in the sum of the volumes of all angiomyolipomas, no new tumors measuring 1 cm or larger, no increase in kidney volume of more than 20%, and no serious angiomyolipoma-related bleeding.

Patients were enrolled at 24 centers in 11 countries. Participants were about 32 years old on average, and two-thirds were female. Nearly all had tuberous sclerosis complex. A sizable proportion (39%) had previously had surgery or an invasive procedure, such as renal embolization, for their angiomyolipomas.

Trial results, reported in a poster session at the meeting, showed that with a median follow-up of 9.5 months, the angiomyolipoma response rate was 41.8% with everolimus and 0% with placebo (P less than .0001). Benefit was similar across patient subgroups stratified by sex, age, race, and use of enzyme-inducing antiepileptic drugs.

Additionally, patients in the everolimus group had a longer median time to angiomyolipoma progression (not reached vs. 11.4 months; hazard ratio, 0.08; P less than .0001) and were more likely to have a response of skin lesions as well (26% vs. 0%; P = .0002).

Everolimus was associated with higher (although still low) rates of grade 3 or 4 stomatitis/oral mucositis and cytopenia. Amenorrhea occurred in 14% of women in the everolimus group vs. 4% of their counterparts in the placebo group.

There was a single death in the study population, occurring in the everolimus arm and resulting from status epilepticus that was thought to be unrelated to the drug.

Dr. Bissler disclosed that he is a consultant to Gambro and receives honoraria and research funding from Novartis. The trial was sponsored by Novartis.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Chronic kidney disease, even on the milder end of the spectrum, is an independent risk factor for urinary cancers and may therefore be useful for targeting screening, the results of a large observational study suggest.

In the study of nearly 1.2 million adults in the Kaiser Permanente Renal Registry, none of whom were on dialysis, the risks of urinary cancers increased in stepwise fashion with decreasing estimated glomerular filtration rate (GFR), Dr. William T. Lowrance reported at the Genitourinary Cancers Symposium.

After adjustments, patients having the lowest estimated GFRs had a more than 100% increase in the risk of renal cell cancer and a 35% increase in the risk of urothelial cancer. The risks of other types of cancers – breast, lung, prostate, and colorectal – and of cancer overall increased with decreasing estimated GFR in univariate analyses but not in multivariate analyses.

"We found an independent, graded increased risk of renal and urothelial cancer as you went to a lower estimated GFR, and this was especially true when your estimated GFR was less than 45 mL/min per 1.73 m2, in this large diverse population-based cohort," said Dr. Lowrance of the Huntsman Cancer Institute at the University of Utah, Salt Lake City.

"Estimated GFRs may play a role in identifying patients at higher risk for renal and urothelial malignancies," he added. "Certainly, prospective studies are needed to further assess any net clinical benefit of targeted cancer screening in these patients with CKD. And we also need to try and elucidate the etiology of this mechanism: Is there some underlying biological process that explains this association?"

"As far as I could determine on a literature search, this is the largest number of patients in a study to date," commented Thomas E. Hutson, D.O., Pharm.D., of the Baylor Sammons Cancer Center in Dallas, who was invited to discuss the study.

"We are used to screening patients with end-stage renal disease already, using renal ultrasounds, looking for renal tumors," he noted. This new study suggests that "GFR may play a role in identifying patients at higher risk, and therefore we may want to use that as a potential screening mechanism," a practice that should be studied prospectively, he agreed.

End-stage renal disease is a known risk factor for cancer, according to Dr. Lowrance. And previous studies have implicated CKD generally in cancer risk, "but they are somewhat limited by their size and their ability to control for important factors that may confound the association between CKD and cancer," he maintained.

The investigators studied adults aged 40 years or older who were in the Kaiser Permanente Renal Registry and had at least one outpatient, non–emergency department measurement of serum creatinine level between 2000 and 2008. Those who had cancer or a history of dialysis or renal transplantation were excluded.

Estimated GFR values within 3 months of cancer diagnosis and incident cancers in the first 2 years of follow-up were excluded from analysis to minimize the possibility of cancer affecting kidney function.

Results were based on 1.2 million patients with a median age of 55 years. A total of 76,809 cancers were diagnosed during a median follow-up of 5.3 years.

Univariate analyses showed increasing rates of various types of common cancers and of cancer overall with decreasing GFR, which was estimated with the CKD-Epi equation.

Multivariate analysis – adjusted for numerous potential confounders, such as proteinuria, comorbidities (including diabetes), smoking status, prescription medications taken, and health care use – showed that patients having an estimated GFR of 59 mL/min per 1.73 m² or lower had a significantly increased risk of renal cell cancer, and patients having an estimated GFR of 44 mL/min per 1.73 m² or lower had a significantly increased risk of urothelial cancer – both compared with their counterparts having an estimated GFR of 60 to 89 mL/min per 1.73 m².

Those with the poorest renal function – an estimated GFR of less than 30 mL/min per 1.73 m² – had a significant 2.09-fold increased risk of renal cell cancer and a significant 1.35-fold increased risk of urothelial cancer.

"A big concern [in such a study] is potential detection bias, meaning subjects with worse renal function may be followed more closely than those with normal renal function, and as a result, we are likely to diagnose more cancers in those patients," Dr. Lowrance acknowledged. However, analyses took into account numbers of outpatient visits and hospitalizations (although not specifically hematuria tests or imaging tests), reducing this possible source of bias.

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Dr. Lowrance disclosed that he had no relevant conflicts of interest. Dr. Hutson disclosed that he is a consultant to and receives honoraria from Bayer, Genentech, GlaxoSmithKline, Novartis, Onyx, Pfizer, and Wyeth, and that he receives research funding from GlaxoSmithKline, Pfizer, and Wyeth.

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.

SAN FRANCISCO – Some patients with metastatic renal cell carcinoma may need a higher-than-standard dose of the newly approved antiangiogenic agent axitinib to achieve optimal benefit, according to a secondary analysis of data from the phase III AXIS trial.

Progression-free survival and adverse event rates were essentially the same for patients who continued on the standard dose of 5 mg twice daily of axitinib or less when compared with patients who tolerated the standard dose well enough to advance to a higher one – up to twice as high – lead investigator Dr. Brian I. Rini reported at the Genitourinary Cancers Symposium here.

These findings are consistent with pharmacokinetic data from the phase II trial leading up to AXIS, which suggested that some patients simply need a higher dose of axitinib – an inhibitor of signaling in the vascular endothelial growth factor receptor (VEGFR) pathway – to achieve the same blood level of the drug, according to Dr. Rini, a urologic oncologist at the Cleveland Clinic Taussig Cancer Institute.

"Clearly, there is interpatient variability in the pharmacokinetics of axitinib, and therefore, dose increases to greater than 5 mg twice daily are likely required to optimize both exposure and clinical efficacy in this setting," he said.

An ongoing front-line trial is looking more closely at the issue by testing safety-based dose escalation in a randomized way, he added; results are likely to be reported at the main American Society of Clinical Oncology meeting later this year.

The analysis also found that a response to prior sunitinib (Sutent) did not affect progression-free survival with axitinib, but it did with sorafenib (Nexavar), the trial’s comparator drug, which also inhibits VEGFR signaling, as well as signaling in other pathways. Yet, for both trial drugs, longer progression-free survival on prior sunitinib portended longer progression-free survival with the trial drug.

Discussant Dr. Daniel Cho of Beth Israel Deaconess Medical Center in Boston noted that some might wonder whether axitinib’s superiority in the AXIS trial was due in part to lack of dose escalation of sorafenib, but data on the feasibility of dose escalating that agent are mixed. "It could very well be that the kind of more focused toxicity of the more novel TKIs [tyrosine kinase inhibitors], which allows them to be dose escalated, is a major advantage for these drugs," he commented.

The finding of longer progression-free survival with both trial drugs in patients faring better on prior sunitinib raises an important question relevant to treatment decisions, according to Dr. Cho: "Can a longer progression-free survival on your first VEGF TKI be helpful in determining the next line of therapy?"

"On one hand, you could hypothesize that patients who are on the VEGF TKI longer in the first-line setting represent a group that is more VEGF sensitive and should receive a VEGF TKI as the second-line treatment instead of an mTOR [mammalian target of rapamycin] inhibitor; on the other hand, this group could just sort of represent a group of people whose tumors are growing slower," he explained.

"Other efforts to correlate the response to first-line treatment with response to second-line treatment have largely been negative. ... This remains a critical issue, and a lot of work needs to be done on this subject."

Patients were eligible for the AXIS trial if they had metastatic clear-cell renal cell carcinoma and had experienced a failure of certain first-line therapies; in slightly more than half of patients, that first-line therapy was sunitinib.

The 723 patients were randomized evenly to axitinib (starting at 5 mg twice daily with optional, stepwise dose escalation up to 10 mg twice daily, safety measures permitting) or sorafenib (400 mg twice daily). Axitinib (Inlyta, manufactured by Pfizer) had not yet been approved by the Food and Drug Administration as a second-line treatment for advanced renal cell carcinoma; sorafenib (Nexavar, manufactured by Bayer) had already been approved for treating advanced disease.

Main results of AXIS, previously reported, showed significantly longer progression-free survival with axitinib than with sorafenib in the trial population as a whole (Lancet 2011;376:1931-9).

The new analysis showed that 37% of patients in the axitinib arm had dose escalation of the drug above the starting dose of 5 mg twice daily.

Progression-free survival was essentially the same for patients who did and did not have an axitinib dose escalation – and in both cases, higher than that with sorafenib. Additionally, rates of grade 3 or worse adverse events and serious adverse events were similar between the axitinib groups that did and did not have dose escalation.

These findings are in keeping with the phase II data, which showed first that dose escalation reduced the proportion of patients having subtherapeutic axitinib blood levels, and second that patients achieving therapeutic blood levels had progression-free survival about twice as long as that in their counterparts who did not achieve these levels.

"Dose titration with axitinib serves to normalize plasma exposure. ... We’re not increasing their drug levels above what patients at 5 mg get, but rather their drug levels are catching up to what some patients are able to achieve without titration," Dr. Rini explained.

Thus, in AXIS, "as you would expect from the pharmacokinetic data in which there is normalization of axitinib drug levels for both of these groups, they have roughly equivalent clinical outcomes, both of which were superior to sorafenib in the second-line setting."

The new analysis also showed that with axitinib, progression-free survival was essentially the same for prior sunitinib responders and nonresponders; in contrast, with sorafenib, it tended to be longer for prior sunitinib responders.

For both trial drugs, progression-free survival on prior sunitinib appeared to influence progression-free survival on the trial drug. For example, in the axitinib group, it was 40% longer for patients whose duration of prior sunitinib response was at least 9 months vs. shorter than that (6.3 vs. 4.5 months).

The Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Pfizer sponsored the AXIS trial. Dr. Rini disclosed that he is a consultant to and receives research funding from Pfizer. Dr. Cho disclosed that he has no relevant conflicts of interest.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.

SAN FRANCISCO – Radium-223 chloride, the first alpha particle–emitting bone-targeted agent, is efficacious and safe for treating men with bone metastases of castration-resistant prostate cancer, according to a randomized, phase-III trial reported at the Genitourinary Cancers Symposium.

The 809 men in the ALSYMPCA trial had a 30% reduction in the risk of death and a nearly 40% reduction in the risk of a first clinical skeletal-related event if treated with radium-223 chloride, compared with placebo. The agent had a good safety profile as well, with low rates of myelosuppression and, thus far, no cases of secondary cancers.

Trial results were reported in a poster session by Dr. A. Oliver Sartor, Laborde Professor of Cancer Research at Tulane University, New Orleans, and medical director of the Tulane Cancer Center, and in an oral presentation by Dr. Chris Parker of the Royal Marsden NHS Foundation Trust in Sutton, England.

"We believe that this novel alpha pharmaceutical – the very first one to be tested in phase III in all of medicine – may provide a new standard of care for the treatment of patients with bone metastasis in advanced prostate cancer," Dr. Sartor said in a press briefing.

There is every reason to believe that radium-223 "will be very well received by the regulatory agencies, not only in the U.S. but also abroad," he predicted. In fact, it has been submitted for approval in the United States, where the Food and Drug Administration has agreed to fast-track status.

In the question-and-answer period following the oral presentation, Dr. Anthony V. D’Amico of the Dana-Farber Cancer Institute, Boston, said that the trial’s findings were "quite striking," but he questioned radium-223’s long-term safety, especially should the drug be eyed for treatment of less advanced cancer.

"Oftentimes, when we see a result like this, it then gets transferred back into earlier stages of disease. The one thing you can’t assess here are late effects, particularly leukemias and second cancers, like bone sarcomas, because patients die very quickly," he noted. "So caution would have to be thought of before one would administer such a drug even in a clinical trial in earlier settings when people have long life expectancies."

Another attendee asked about the ability to administer chemotherapy after a patient has been treated with radium-223, given that the agent might compromise bone marrow reserve; this in turn would influence decisions about the sequencing of treatment.

"Although we have seen that radium-223 has little effect on the full blood count, I don’t think that we can assume that the bone marrow reserve will be normal," Dr. Parker replied. "So it’s very important that we do collect data going forward on the safety and tolerability of chemotherapy after radium." To that end, data on patients in ALSYMPCA (A Double-Blind, Randomised, Multiple Dose, Phase III, Multicentre Study of Alpharadin in the Treatment of Patients With Symptomatic Hormone Refractory Prostate Cancer With Skeletal Metastases) subsequently given chemotherapy will be reported later this year.

Radiopharmaceuticals have not historically been widely used in metastatic prostate cancer, but radium-223 "is a different beast because of the survival benefit," Dr. Sartor noted in an interview during the poster session.

Additionally, because it was given in the trial along with best standard of care, it should be easy to combine with several commonly used therapies in this patient population. "Things like abiraterone and prednisone, I personally believe, will be incorporated very easily into this treatment schema," he commented. Data for various combinations will also be reported later this spring.

"Another issue with which I’m personally a little bit enamored is that when you utilize radiation, you actually enhance the epitopes that are important in some immunological therapies," Dr. Sartor added. "I believe that [radium-223] ... may play very well with immunotherapies. Now that’s a hypothesis, not a fact. But nevertheless, I want to see it tested."

Men were eligible for ALSYMPCA if they had symptomatic castration-resistant prostate cancer, had received docetaxel or were ineligible for or declined this chemotherapy, and had at least two bone metastases but no visceral metastases.

The docetaxel-naive population "perhaps constitutes about 40% of all men with castration-refractory disease. At the moment, there are no drugs approved in that setting that improve overall survival," Dr. Parker noted in his presentation. "So it’s a real unmet need present in that group of patients."

The men were assigned 2:1 to intravenous radium-223 or placebo given every 4 weeks, for a total of six treatments, each along with best standard of care, which could include secondary hormonal treatments, external beam radiation therapy, and steroids. (Treatments could not include chemotherapy, other experimental therapy, hemibody radiation, or other radiopharmaceuticals.)

Radium-223 chloride (Alpharadin, manufactured by Algeta in partnership with Bayer) mimics calcium and therefore targets new bone growth in and around bone metastases. Because of the short distance alpha particles travel, the agent results in highly localized tumor cell killing with minimal damage to nearby normal tissue.

"What you’re doing here is very different from all the other bone-targeted agents: You are actually killing cancer cells," Dr. Sartor commented. "The other bone-targeted agents – samarium, strontium, denosumab, and zoledronic acid are the four FDA-approved ones – none of them kill cancer cells like this one does. This is mechanistically distinct."

The men in the trial were 70 years old on average. More than 80% had at least six bone metastases, and more than 50% had bone pain requiring opioid analgesia. About half had received docetaxel.

In main results, radium-223 was associated with longer overall survival (14.0 vs. 11.2 months; hazard ratio [HR], 0.70; P = .002), the trial’s primary end point, a benefit that Dr. Sartor attributed to a reduction of disease burden in this population, whose only known disease was in bone. This finding in an interim analysis prompted early trial closure.

Radium-223 also prolonged the time to first skeletal-related events (13.5 vs. 8.4 months; HR, 0.61; P = .0005). Importantly, and in contrast to trials of zoledronic acid and denosumab, the events included were only clinical ones that came to attention because of signs or symptoms, as the trial did not use routine skeletal surveys, Dr. Parker noted. In addition, fractures were included only if they were pathologic.

Subgroup analyses showed perhaps the greatest reduction in these events among men receiving bisphosphonates (HR, 0.46). "Whilst one must interpret subgroup analyses with great caution, it’s interesting that radium-223 appears to be, if anything, more effective in the presence of bisphosphonates," he commented. "And there is a biologic rationale for that: If you are on a bisphosphonate, you have reduced osteoclast activity, and you could imagine that the radium-223 would be bound for longer. It also, of course, makes the point that radium-223 provides added value over and above bisphosphonates in terms of skeletal-related event prevention."

There also was significant improvement in rates of three of the four assessed skeletal-related events individually: pathologic bone fracture (HR, 0.45), spinal cord compression (HR, 0.44), and external beam radiation to bone (HR, 0.65).

The overall rate of grade 3 or 4 adverse events was lower with radium-223 than with placebo (51% vs. 59%). "You don’t often see phase-III trials with more adverse events in the control arm," Dr. Parker commented at the meeting, which was sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

Rates of hematologic and nonhematologic adverse events of interest were generally similar in the two groups. Grade 3 or 4 neutropenia and thrombocytopenia were more common with radium-223 but still rare (2% and 4%). Also, there was a lower rate of grade 3 or 4 bone pain with the drug vs. placebo (18% vs. 23%).

Dr. Sartor disclosed that he is a consultant to Algeta ASA. Dr. Parker disclosed that he is a consultant to Algeta ASA and receives honoraria from Bayer.