ASTRO Annual Meeting 2012

BOSTON – Cosmetic results were significantly worse after 3 years for women who had accelerated partial-breast irradiation than for women treated with whole-breast irradiation in a randomized clinical trial, investigators found.

Nearly a third (32%) of women who underwent accelerated partial breast irradiation (APBI) with a 3-D conformal technique had cosmetic results rated as fair or poor by a nurse, compared with 19% of women who had undergone whole-breast irradiation (WBI), Dr. Timothy J. Whelan reported at the annual meeting of the American Society for Radiation Oncology.

APBI was also associated with more grade 1 and 2 toxicities than WBI, but there were few grade 3 toxicities with either technique and no grade 4 toxicities, said Dr. Whelan, a radiation oncologist at the Juravinski Cancer Centre in Hamilton, Ont.

"This increase in toxicity may have resulted from limited conformality of the 3-D conformal approach, the short time between the fractions – radiation with APBI was given twice a day with 6 hours between the fractions, which may not have been adequate – and maybe due to the asymmetric nature of partial breast irradiation itself, given that it’s only given to part of the breast," he said at a press briefing.

Trading Convenience for Toxicity?

APBI – in which a large dose per fraction of external beam radiation is given only to the surgical cavity with an additional safety margin – allows radiation therapy to be delivered in 1 week or less, making it an attractive alternative to multifraction therapy that can stretch over many weeks.

But it is still not clear whether APBI trades poorer outcomes for convenience, Dr. Whelan said. He and colleagues in Canada, Australia, and New Zealand conducted the RAPID trial (Randomized Trial of Accelerated Partial-Breast Irradiation Using 3-D Conformal External Beam Radiation Therapy) to find out. The study compared the efficacy and safety of the two modalities in women over 40 years of age with invasive or noninvasive breast cancers smaller than 3 cm.

Investigators enrolled 2,135 patients and randomized them to receive either WBI (1,065 patients) at 50 Gy in 25 fractions or 42.5 Gy in 16 fractions given once daily with or without boost irradiation or 3-D conformal APBI at 38.5 Gy in 10 fractions twice daily (1,070 patients). Cosmetic results were rated by a trained nurse on a global assessment using the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System for Breast Cancer, and for toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Radiologists blinded to treatment type also rated results on digital photographs.

Immediately after radiation, cosmetic results were similar between the groups, with nurse-assessed appearance rated as fair or poor in 17% of women who had WBI, and 19% who had APBI (P = .35). However, an interim toxicity analysis among 850 evaluable patients, showed that at 3 years (2.3 years median follow-up) 13% more of the patients who had undergone APBI had fair or poor cosmesis.

The Jury Is Out

Dr. Whelan noted that the between-group differences were about the same at 5 years, but did not provide data.

"The evidence for partial-breast irradiation is still not very clear. We don’t have very robust evidence about its efficacy, and we just now have recent evidence about its potential toxicities, he said.

Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey in New Brunswick, commented that "the results from the RAPID trial shed further light on the use of accelerated partial-breast irradiation, and emphasize the need to further investigate these fractionation schemes and sort out whether in fact the toxicity from partial-breast irradiation may be slightly worse than with whole-breast irradiation."

Dr. Haffty moderated a briefing where the data were presented, but was not involved in the RAPID trial.

The RAPID trial is supported by the Canadian Institutes of Health Research and Canadian Breast Cancer Research Alliance. Dr. Whelan has received honoraria from AstraZeneca and Novartis. Dr. Haffty reported no relevant disclosures.

BOSTON – Cosmetic results were significantly worse after 3 years for women who had accelerated partial-breast irradiation than for women treated with whole-breast irradiation in a randomized clinical trial, investigators found.

Nearly a third (32%) of women who underwent accelerated partial breast irradiation (APBI) with a 3-D conformal technique had cosmetic results rated as fair or poor by a nurse, compared with 19% of women who had undergone whole-breast irradiation (WBI), Dr. Timothy J. Whelan reported at the annual meeting of the American Society for Radiation Oncology.

APBI was also associated with more grade 1 and 2 toxicities than WBI, but there were few grade 3 toxicities with either technique and no grade 4 toxicities, said Dr. Whelan, a radiation oncologist at the Juravinski Cancer Centre in Hamilton, Ont.

"This increase in toxicity may have resulted from limited conformality of the 3-D conformal approach, the short time between the fractions – radiation with APBI was given twice a day with 6 hours between the fractions, which may not have been adequate – and maybe due to the asymmetric nature of partial breast irradiation itself, given that it’s only given to part of the breast," he said at a press briefing.

Trading Convenience for Toxicity?

APBI – in which a large dose per fraction of external beam radiation is given only to the surgical cavity with an additional safety margin – allows radiation therapy to be delivered in 1 week or less, making it an attractive alternative to multifraction therapy that can stretch over many weeks.

But it is still not clear whether APBI trades poorer outcomes for convenience, Dr. Whelan said. He and colleagues in Canada, Australia, and New Zealand conducted the RAPID trial (Randomized Trial of Accelerated Partial-Breast Irradiation Using 3-D Conformal External Beam Radiation Therapy) to find out. The study compared the efficacy and safety of the two modalities in women over 40 years of age with invasive or noninvasive breast cancers smaller than 3 cm.

Investigators enrolled 2,135 patients and randomized them to receive either WBI (1,065 patients) at 50 Gy in 25 fractions or 42.5 Gy in 16 fractions given once daily with or without boost irradiation or 3-D conformal APBI at 38.5 Gy in 10 fractions twice daily (1,070 patients). Cosmetic results were rated by a trained nurse on a global assessment using the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System for Breast Cancer, and for toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Radiologists blinded to treatment type also rated results on digital photographs.

Immediately after radiation, cosmetic results were similar between the groups, with nurse-assessed appearance rated as fair or poor in 17% of women who had WBI, and 19% who had APBI (P = .35). However, an interim toxicity analysis among 850 evaluable patients, showed that at 3 years (2.3 years median follow-up) 13% more of the patients who had undergone APBI had fair or poor cosmesis.

The Jury Is Out

Dr. Whelan noted that the between-group differences were about the same at 5 years, but did not provide data.

"The evidence for partial-breast irradiation is still not very clear. We don’t have very robust evidence about its efficacy, and we just now have recent evidence about its potential toxicities, he said.

Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey in New Brunswick, commented that "the results from the RAPID trial shed further light on the use of accelerated partial-breast irradiation, and emphasize the need to further investigate these fractionation schemes and sort out whether in fact the toxicity from partial-breast irradiation may be slightly worse than with whole-breast irradiation."

Dr. Haffty moderated a briefing where the data were presented, but was not involved in the RAPID trial.

The RAPID trial is supported by the Canadian Institutes of Health Research and Canadian Breast Cancer Research Alliance. Dr. Whelan has received honoraria from AstraZeneca and Novartis. Dr. Haffty reported no relevant disclosures.

BOSTON – Cosmetic results were significantly worse after 3 years for women who had accelerated partial-breast irradiation than for women treated with whole-breast irradiation in a randomized clinical trial, investigators found.

Nearly a third (32%) of women who underwent accelerated partial breast irradiation (APBI) with a 3-D conformal technique had cosmetic results rated as fair or poor by a nurse, compared with 19% of women who had undergone whole-breast irradiation (WBI), Dr. Timothy J. Whelan reported at the annual meeting of the American Society for Radiation Oncology.

APBI was also associated with more grade 1 and 2 toxicities than WBI, but there were few grade 3 toxicities with either technique and no grade 4 toxicities, said Dr. Whelan, a radiation oncologist at the Juravinski Cancer Centre in Hamilton, Ont.

"This increase in toxicity may have resulted from limited conformality of the 3-D conformal approach, the short time between the fractions – radiation with APBI was given twice a day with 6 hours between the fractions, which may not have been adequate – and maybe due to the asymmetric nature of partial breast irradiation itself, given that it’s only given to part of the breast," he said at a press briefing.

Trading Convenience for Toxicity?

APBI – in which a large dose per fraction of external beam radiation is given only to the surgical cavity with an additional safety margin – allows radiation therapy to be delivered in 1 week or less, making it an attractive alternative to multifraction therapy that can stretch over many weeks.

But it is still not clear whether APBI trades poorer outcomes for convenience, Dr. Whelan said. He and colleagues in Canada, Australia, and New Zealand conducted the RAPID trial (Randomized Trial of Accelerated Partial-Breast Irradiation Using 3-D Conformal External Beam Radiation Therapy) to find out. The study compared the efficacy and safety of the two modalities in women over 40 years of age with invasive or noninvasive breast cancers smaller than 3 cm.

Investigators enrolled 2,135 patients and randomized them to receive either WBI (1,065 patients) at 50 Gy in 25 fractions or 42.5 Gy in 16 fractions given once daily with or without boost irradiation or 3-D conformal APBI at 38.5 Gy in 10 fractions twice daily (1,070 patients). Cosmetic results were rated by a trained nurse on a global assessment using the European Organisation for Research and Treatment of Cancer (EORTC) Cosmetic Rating System for Breast Cancer, and for toxicity using the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0. Radiologists blinded to treatment type also rated results on digital photographs.

Immediately after radiation, cosmetic results were similar between the groups, with nurse-assessed appearance rated as fair or poor in 17% of women who had WBI, and 19% who had APBI (P = .35). However, an interim toxicity analysis among 850 evaluable patients, showed that at 3 years (2.3 years median follow-up) 13% more of the patients who had undergone APBI had fair or poor cosmesis.

The Jury Is Out

Dr. Whelan noted that the between-group differences were about the same at 5 years, but did not provide data.

"The evidence for partial-breast irradiation is still not very clear. We don’t have very robust evidence about its efficacy, and we just now have recent evidence about its potential toxicities, he said.

Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey in New Brunswick, commented that "the results from the RAPID trial shed further light on the use of accelerated partial-breast irradiation, and emphasize the need to further investigate these fractionation schemes and sort out whether in fact the toxicity from partial-breast irradiation may be slightly worse than with whole-breast irradiation."

Dr. Haffty moderated a briefing where the data were presented, but was not involved in the RAPID trial.

The RAPID trial is supported by the Canadian Institutes of Health Research and Canadian Breast Cancer Research Alliance. Dr. Whelan has received honoraria from AstraZeneca and Novartis. Dr. Haffty reported no relevant disclosures.

BOSTON – The drugs that have revitalized the love lives of millions of aging men may also help preserve sexual function in men undergoing radiation therapy for prostate cancer, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Men who took sildenafil citrate (Viagra) before, during, and for 6 months after radiotherapy for prostate cancer had better sexual function and reported better overall satisfaction than did men who took placebo in a randomized double-blind trial, said Dr. Michael J. Zelefsky, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York City.

Men who were also treated with androgen deprivation, however, did not appear to experience a benefit from sildenafil and were excluded from the analysis.

"We believe our study is a very important one, for it demonstrates proof of principle that penile rehabilitation is important in the population of radiotherapy patients treated for prostate cancer, and demonstrates a significant benefit for improved sexual function outcomes," Dr. Zelefsky said at a plenary session.

Studies in animal models have suggested that phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, vardenafil (Levitra), and tadalafil (Cialis) could help to preserve or rehabilitate penile function by protecting the vascular endothelium of the corpus cavernosum of the penis and smooth muscle tissue involved in erections.

Dr. Zelefsky pointed to a European randomized trial showing that patients who had undergone bilateral nerve-sparing prostatectomy and were randomized to vardenafil had improved spontaneous erections compared with placebo-taking controls (Eur. Urol. 2008;54:924-31).

Pretreatment Potency Assessed

The current study enrolled 295 men who had excellent sexual function (defined as a score of 17 or greater on the International Index of Erectile Function 5 [IIEF-5]) and were scheduled to undergo radiotherapy to the prostate with either external-beam radiation (EBRT) or brachytherapy. They were randomly assigned on a 2:1 basis to sildenafil or placebo, respectively.

Sildenafil was given in a 50-mg dose starting 3 days before therapy and continuing out to 6 months. Patients were followed with the patient-derived IIEF-5 (including domains of erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction), International Prostate Symptom Score (IPSS), and a quality of life questionnaire every 3 months for the first year, and then every 6 months up to 2 years.

"Thirty one patients were treated with androgen-deprivation therapy, and when we looked at erectile function scores over time, there were no significant differences or improvements noted with the use of daily sildenafil compared to the placebo group, suggesting that there was no apparent benefit among this cohort of patients. For this reason, we excluded this cohort and turned our attention to a group of patients who did not receive androgen deprivation therapy, leaving us with an evaluable cohort of 142 patients," Dr. Zelefsky said. The analysis included patients who completed surveys before treatment and at least one additional time period.

There were no significant between-group differences at baseline in factors that might affect erectile function, such as smoking history, diabetes, or hypertension.

Overall total IEFF-5 scores were significantly higher among patients in the sildenafil arm at 6 (P = .006), 12 (P=.02) and 24 months (P = .04) after therapy. However, at 24 months, there were significant differences in favor of sildenafil only in the IEFF-5 domains of sexual desire (P = .001) and overall satisfaction (P = .04).

The investigators also noted that the differences between the treatment groups became less apparent beyond 12 months.

Does This Set a New Standard?

The study had a few minor limitations, including variations in treatment, once-daily rather than more frequent dosing, and the lack of information on a relationship or partner effect, but these do not detract from the conclusion, said invited discussant Dr. Thomas M. Pisansky, professor of radiation oncology at Mayo Clinic, Rochester, Minn.

"Nonetheless, this does serve as an additional test of proof of principle of early PDE5 inhibitor use. Does this represent a new standard? I believe that for the time being it certainly does, but additional study is warranted, and that is ongoing," he said.

Dr. Pisansky added that it is incumbent upon radiation oncologists, when evaluating patients for radiotherapy to the prostate, to incorporate a validated instrument of sexual function such as the IIEF-5.

Dr. Zelefsky and a coauthor disclosed receiving grants from Pfizer, maker of Viagra. Dr. Pisansky reported no conflicts of interest.

BOSTON – The drugs that have revitalized the love lives of millions of aging men may also help preserve sexual function in men undergoing radiation therapy for prostate cancer, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Men who took sildenafil citrate (Viagra) before, during, and for 6 months after radiotherapy for prostate cancer had better sexual function and reported better overall satisfaction than did men who took placebo in a randomized double-blind trial, said Dr. Michael J. Zelefsky, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York City.

Men who were also treated with androgen deprivation, however, did not appear to experience a benefit from sildenafil and were excluded from the analysis.

"We believe our study is a very important one, for it demonstrates proof of principle that penile rehabilitation is important in the population of radiotherapy patients treated for prostate cancer, and demonstrates a significant benefit for improved sexual function outcomes," Dr. Zelefsky said at a plenary session.

Studies in animal models have suggested that phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, vardenafil (Levitra), and tadalafil (Cialis) could help to preserve or rehabilitate penile function by protecting the vascular endothelium of the corpus cavernosum of the penis and smooth muscle tissue involved in erections.

Dr. Zelefsky pointed to a European randomized trial showing that patients who had undergone bilateral nerve-sparing prostatectomy and were randomized to vardenafil had improved spontaneous erections compared with placebo-taking controls (Eur. Urol. 2008;54:924-31).

Pretreatment Potency Assessed

The current study enrolled 295 men who had excellent sexual function (defined as a score of 17 or greater on the International Index of Erectile Function 5 [IIEF-5]) and were scheduled to undergo radiotherapy to the prostate with either external-beam radiation (EBRT) or brachytherapy. They were randomly assigned on a 2:1 basis to sildenafil or placebo, respectively.

Sildenafil was given in a 50-mg dose starting 3 days before therapy and continuing out to 6 months. Patients were followed with the patient-derived IIEF-5 (including domains of erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction), International Prostate Symptom Score (IPSS), and a quality of life questionnaire every 3 months for the first year, and then every 6 months up to 2 years.

"Thirty one patients were treated with androgen-deprivation therapy, and when we looked at erectile function scores over time, there were no significant differences or improvements noted with the use of daily sildenafil compared to the placebo group, suggesting that there was no apparent benefit among this cohort of patients. For this reason, we excluded this cohort and turned our attention to a group of patients who did not receive androgen deprivation therapy, leaving us with an evaluable cohort of 142 patients," Dr. Zelefsky said. The analysis included patients who completed surveys before treatment and at least one additional time period.

There were no significant between-group differences at baseline in factors that might affect erectile function, such as smoking history, diabetes, or hypertension.

Overall total IEFF-5 scores were significantly higher among patients in the sildenafil arm at 6 (P = .006), 12 (P=.02) and 24 months (P = .04) after therapy. However, at 24 months, there were significant differences in favor of sildenafil only in the IEFF-5 domains of sexual desire (P = .001) and overall satisfaction (P = .04).

The investigators also noted that the differences between the treatment groups became less apparent beyond 12 months.

Does This Set a New Standard?

The study had a few minor limitations, including variations in treatment, once-daily rather than more frequent dosing, and the lack of information on a relationship or partner effect, but these do not detract from the conclusion, said invited discussant Dr. Thomas M. Pisansky, professor of radiation oncology at Mayo Clinic, Rochester, Minn.

"Nonetheless, this does serve as an additional test of proof of principle of early PDE5 inhibitor use. Does this represent a new standard? I believe that for the time being it certainly does, but additional study is warranted, and that is ongoing," he said.

Dr. Pisansky added that it is incumbent upon radiation oncologists, when evaluating patients for radiotherapy to the prostate, to incorporate a validated instrument of sexual function such as the IIEF-5.

Dr. Zelefsky and a coauthor disclosed receiving grants from Pfizer, maker of Viagra. Dr. Pisansky reported no conflicts of interest.

BOSTON – The drugs that have revitalized the love lives of millions of aging men may also help preserve sexual function in men undergoing radiation therapy for prostate cancer, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Men who took sildenafil citrate (Viagra) before, during, and for 6 months after radiotherapy for prostate cancer had better sexual function and reported better overall satisfaction than did men who took placebo in a randomized double-blind trial, said Dr. Michael J. Zelefsky, a radiation oncologist at Memorial Sloan-Kettering Cancer Center in New York City.

Men who were also treated with androgen deprivation, however, did not appear to experience a benefit from sildenafil and were excluded from the analysis.

"We believe our study is a very important one, for it demonstrates proof of principle that penile rehabilitation is important in the population of radiotherapy patients treated for prostate cancer, and demonstrates a significant benefit for improved sexual function outcomes," Dr. Zelefsky said at a plenary session.

Studies in animal models have suggested that phosphodiesterase-5 (PDE5) inhibitors such as sildenafil, vardenafil (Levitra), and tadalafil (Cialis) could help to preserve or rehabilitate penile function by protecting the vascular endothelium of the corpus cavernosum of the penis and smooth muscle tissue involved in erections.

Dr. Zelefsky pointed to a European randomized trial showing that patients who had undergone bilateral nerve-sparing prostatectomy and were randomized to vardenafil had improved spontaneous erections compared with placebo-taking controls (Eur. Urol. 2008;54:924-31).

Pretreatment Potency Assessed

The current study enrolled 295 men who had excellent sexual function (defined as a score of 17 or greater on the International Index of Erectile Function 5 [IIEF-5]) and were scheduled to undergo radiotherapy to the prostate with either external-beam radiation (EBRT) or brachytherapy. They were randomly assigned on a 2:1 basis to sildenafil or placebo, respectively.

Sildenafil was given in a 50-mg dose starting 3 days before therapy and continuing out to 6 months. Patients were followed with the patient-derived IIEF-5 (including domains of erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction), International Prostate Symptom Score (IPSS), and a quality of life questionnaire every 3 months for the first year, and then every 6 months up to 2 years.

"Thirty one patients were treated with androgen-deprivation therapy, and when we looked at erectile function scores over time, there were no significant differences or improvements noted with the use of daily sildenafil compared to the placebo group, suggesting that there was no apparent benefit among this cohort of patients. For this reason, we excluded this cohort and turned our attention to a group of patients who did not receive androgen deprivation therapy, leaving us with an evaluable cohort of 142 patients," Dr. Zelefsky said. The analysis included patients who completed surveys before treatment and at least one additional time period.

There were no significant between-group differences at baseline in factors that might affect erectile function, such as smoking history, diabetes, or hypertension.

Overall total IEFF-5 scores were significantly higher among patients in the sildenafil arm at 6 (P = .006), 12 (P=.02) and 24 months (P = .04) after therapy. However, at 24 months, there were significant differences in favor of sildenafil only in the IEFF-5 domains of sexual desire (P = .001) and overall satisfaction (P = .04).

The investigators also noted that the differences between the treatment groups became less apparent beyond 12 months.

Does This Set a New Standard?

The study had a few minor limitations, including variations in treatment, once-daily rather than more frequent dosing, and the lack of information on a relationship or partner effect, but these do not detract from the conclusion, said invited discussant Dr. Thomas M. Pisansky, professor of radiation oncology at Mayo Clinic, Rochester, Minn.

"Nonetheless, this does serve as an additional test of proof of principle of early PDE5 inhibitor use. Does this represent a new standard? I believe that for the time being it certainly does, but additional study is warranted, and that is ongoing," he said.

Dr. Pisansky added that it is incumbent upon radiation oncologists, when evaluating patients for radiotherapy to the prostate, to incorporate a validated instrument of sexual function such as the IIEF-5.

Dr. Zelefsky and a coauthor disclosed receiving grants from Pfizer, maker of Viagra. Dr. Pisansky reported no conflicts of interest.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.

BOSTON – An oral rinse solution of the antidepressant doxepin provided modest relief of pain from cancer treatment–induced oral mucositis in a randomized phase III trial.

Patients with head and neck cancer had a mean reduction of about two points on a 0-10 pain scale 30 minutes after using a doxepin rinse, compared with an approximate one-point reduction for patients who rinsed with a placebo (P = .0003), investigators reported at the annual meeting of the American Society for Radiation Oncology (ASTRO).

All patients in the trial had been treated with radiation with or without chemotherapy.

"Doxepin was used solely for pain relief. We did not expect it to reduce or prevent mucositis, but merely [to] treat the patients’ pain symptoms," said Dr. Robert C. Miller, a radiation oncologist at the Mayo Clinic in Rochester, Minn.

He added that "the efficacy of doxepin in treating oral mucositis pain caused by chemotherapy alone, by stem cell transplantation, or benign conditions such as aphthous ulcers warrants further study."

Conclusion Called Premature

Dr. Paul M. Harari, professor and chairman of human oncology at the University of Wisconsin, Madison, the invited discussant, agreed that oral mucositis "is a very real entity, one that impacts both patients and health care providers."

He applauded the trial’s multicenter, randomized design but noted that the overall reduction in mucositis pain with doxepin was modest, only one point better than placebo, and that mucositis pain is only one element of a host of acute and late toxicities of radiation and chemotherapy for patients with head and neck cancer.

He also said that the authors’ conclusion that "this study provides a new standard of treatment of radiotherapy-induced oral mucositis" is premature and warrants closer scrutiny.

"I would just caution for careful thought and further study before we introduce a new class of agents into the context of agents that head and neck cancer patients receive," he said. "Is this the most effective way to lower the pain score by one point in a transient measure?"

Antidepressant and Antihistamine

Doxepin is a tricyclic antidepressant with antihistaminic properties, approved in the United States for treatment of depression and anxiety as well as moderate pruritus. Preliminary data from a 2007 study suggested that doxepin could reduce mucositis pain in cancer patients (J. Pain Symptom Manage. 2007;33:111-4).

In the current study, patients with radiation to the head and neck, with or without chemotherapy and oral mucositis pain of four or greater on a 10-point pain assessment scale were enrolled. Patients received definitive radiotherapy with doses of at least 50 Gy involving more than 30% of the oral cavity.

The patients were randomized on day 1 in a double-blinded fashion to use either a single dose of either placebo or doxepin 25 mg in a 5-mL rinse and gargle, which they spat out after 1 minute. The trial had a crossover phase on day 2, with optional continuation of the active agent at the end of the study.

Participants filled out pain assessment questionnaires at baseline, four times in the first hour after rinse (in clinic), and then at 2 and 4 hours at home. Those who opted to continue doxepin filled out weekly questionnaires. Patients also were allowed to take analgesics 1 hour before or after doxepin.

A total of 140 patients (69 in the doxepin group, 71 on placebo) were available for the primary end point, total pain reduction as calculated by average mouth and throat pain area-under-the-curve (AUC) reduction over time. The AUC reduction was –9.1 among patients on doxepin, compared with –4.7 for those on placebo (P = .0003), Dr. Miller reported.

However, in 129 patients available for secondary end point analysis, doxepin, which has a known sedative effect, was associated with significantly more mean drowsiness over time (P = .03). Patients on doxepin also reported temporary unpleasant taste in the mouth, burning, and stinging, he said.

Asked whether they would continue doxepin after the randomized phase, 64% said yes and 36% declined (P = .002).

In a crossover analysis comparing the effects of doxepin and placebo in each patient, doxepin was seen to generate a benefit whether it was given before or after placebo (P less than .0001), he noted.

The study was conducted through the Alliance for Clinical Trials in Oncology and supported by a grant from the North Central Cancer Treatment Group and Mayo Clinic. Dr. Miller disclosed serving on the scientific advisory board of Tekcapital Ltd. Dr. Harari disclosed receiving research grants from the National Cancer Institute, Genentech, and Symphogen.

BOSTON – A concurrent combination of the targeted agent sorafenib and stereotactic body radiotherapy showed promising efficacy against advanced liver cancer in a phase I clinical trial, but investigators found toxicity was unacceptable for clinical use.

Only 3 of 16 patients completed the study evaluating the safety of concurrent sorafenib (Nexavar) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC), Dr. Anthony Brade reported at the annual meeting of the American Society for Radiation Oncology.

"We found delivery concurrently of sorafenib and radiotherapy was challenging and likely limited by the volume of tumor and liver that’s irradiated, as well as drug dose," Dr. Brade, a radiation oncologist at the University of Toronto, said at a news briefing.

"Despite the advanced tumor burden and toxicity, the response rates we observed were encouraging," he added. "Sorafenib alone has a response rate under 2%, so to see response rates in the 36%-50% range was very encouraging."

Two of four patients with small tumors involving less than 40% of the liver had a partial response to the combined therapy, and the other two had stable disease over 8-12 weeks of follow-up. Among 11 patients with tumors involving 40%-60% of the liver, four had a partial response and 7 had stable disease. One patient died of tumor rupture before receiving radiation.

The investigators reported a 50% response rate for the smaller-tumor group and 36% for the larger-tumor group.

Promise and Peril

Sorafenib, a tyrosine kinase inhibitor, is standard of care for locally advanced HCC. In a 2008 study it was shown to improve overall survival and time to radiologic progression in patients with advanced HCC who were ineligible for local therapies but had good liver function (Child-Pugh Class A), Dr. Brade noted (N. Engl. J. Med. 2008;359:378-90). Preclinical data also suggest that the combination of sorafenib and radiotherapy may improve outcomes, he said.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal three-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as four to six fractions delivered over 2-2.5 weeks, compared with 8-9 weeks of daily fractions for other techniques.

The current phase I study enrolled patients with good performance status, good liver function (Child-Pugh Class A), more than 800 cc of liver without tumor involvement, adequate hematologic parameters and liver and kidney function, and minimal extrahepatic disease.

The participants had a median age of 61.5 years, and 10 patients each had the significant adverse prognostic features of tumor thrombus and multiple lesions, Dr. Brade noted.

Patients with smaller tumors (stratum 1) were assigned to receive low effective liver volume irradiation at less than 30% of volume, with doses ranges from 39-54 Gy in six fractions over 2 weeks.

Patients with larger tumors had high effective volume (30%-60%) irradiation, with doses ranging from 39-54 Gy, also in six fractions. The maximum permitted doses to the gastrointestinal lumen was 31-34 Gy.

Patients received sorafenib 1 week prior to, during, and 4 weeks post SBRT, at which point escalation to full-dose sorafenib was allowed. Although the protocol called for escalating from an initial dose of 200 mg b.i.d. (400 mg daily) to 600 mg daily delivered in a 400-mg morning and a 200-mg evening dose and finally to 800 mg (400 mg b.i.d.), the study was closed before the maximum was reached in stratum 1. In stratum 1 patients, the 200 mg b.i.d. dose appeared to be tolerable, Dr. Brade said.

Four patients discontinued the drug at less than 4 weeks either because of tumor progression (2) or toxicity (2). There were three dose-limiting toxicities in the larger tumor cohort: a grade-4 small bowel obstruction, a grade-3 lower gastrointestinal tract bleed, and a death from an upper gastrointestinal bleed and tumor rupture. These toxicities led to dose reductions to 200 mg sorafenib daily (compared with a standard oral dose of 400 mg b.i.d.).

"We do not recommend concurrent sorafenib and SBRT outside the context of clinical trials," Dr. Brade said.

Sequential Trial Being Planned

He noted that the outcomes of this trial have influenced the design of the Radiation Therapy Oncology Group (RTOG) 1112 phase III trial, which will compare sorafenib with sorafenib following stereotactic radiotherapy. The trial is still in its planning stages and the protocol has not been made public.

"The use of biologic targeting for radiosensitization in the context of SBRT is both a novel and promising approach," commented Dr. Catherine Park, a radiation oncologist at the University of California, San Francisco.

"The phase I study combining sorafenib with SBRT shown today highlights the exciting promise of greater efficacy, but with caution due to potential toxicity," she said. "It also reflects the challenging research necessary to optimize such novel approaches for clinical use."

Dr. Park was comoderator at a briefing where the data were presented but was not involved in the study.

Dr. Brade disclosed a research grant from Bayer. Dr. Park disclosed having an investment interest in Oncosynergy, a biotechnology company.

BOSTON – A concurrent combination of the targeted agent sorafenib and stereotactic body radiotherapy showed promising efficacy against advanced liver cancer in a phase I clinical trial, but investigators found toxicity was unacceptable for clinical use.

Only 3 of 16 patients completed the study evaluating the safety of concurrent sorafenib (Nexavar) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC), Dr. Anthony Brade reported at the annual meeting of the American Society for Radiation Oncology.

"We found delivery concurrently of sorafenib and radiotherapy was challenging and likely limited by the volume of tumor and liver that’s irradiated, as well as drug dose," Dr. Brade, a radiation oncologist at the University of Toronto, said at a news briefing.

"Despite the advanced tumor burden and toxicity, the response rates we observed were encouraging," he added. "Sorafenib alone has a response rate under 2%, so to see response rates in the 36%-50% range was very encouraging."

Two of four patients with small tumors involving less than 40% of the liver had a partial response to the combined therapy, and the other two had stable disease over 8-12 weeks of follow-up. Among 11 patients with tumors involving 40%-60% of the liver, four had a partial response and 7 had stable disease. One patient died of tumor rupture before receiving radiation.

The investigators reported a 50% response rate for the smaller-tumor group and 36% for the larger-tumor group.

Promise and Peril

Sorafenib, a tyrosine kinase inhibitor, is standard of care for locally advanced HCC. In a 2008 study it was shown to improve overall survival and time to radiologic progression in patients with advanced HCC who were ineligible for local therapies but had good liver function (Child-Pugh Class A), Dr. Brade noted (N. Engl. J. Med. 2008;359:378-90). Preclinical data also suggest that the combination of sorafenib and radiotherapy may improve outcomes, he said.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal three-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as four to six fractions delivered over 2-2.5 weeks, compared with 8-9 weeks of daily fractions for other techniques.

The current phase I study enrolled patients with good performance status, good liver function (Child-Pugh Class A), more than 800 cc of liver without tumor involvement, adequate hematologic parameters and liver and kidney function, and minimal extrahepatic disease.

The participants had a median age of 61.5 years, and 10 patients each had the significant adverse prognostic features of tumor thrombus and multiple lesions, Dr. Brade noted.

Patients with smaller tumors (stratum 1) were assigned to receive low effective liver volume irradiation at less than 30% of volume, with doses ranges from 39-54 Gy in six fractions over 2 weeks.

Patients with larger tumors had high effective volume (30%-60%) irradiation, with doses ranging from 39-54 Gy, also in six fractions. The maximum permitted doses to the gastrointestinal lumen was 31-34 Gy.

Patients received sorafenib 1 week prior to, during, and 4 weeks post SBRT, at which point escalation to full-dose sorafenib was allowed. Although the protocol called for escalating from an initial dose of 200 mg b.i.d. (400 mg daily) to 600 mg daily delivered in a 400-mg morning and a 200-mg evening dose and finally to 800 mg (400 mg b.i.d.), the study was closed before the maximum was reached in stratum 1. In stratum 1 patients, the 200 mg b.i.d. dose appeared to be tolerable, Dr. Brade said.

Four patients discontinued the drug at less than 4 weeks either because of tumor progression (2) or toxicity (2). There were three dose-limiting toxicities in the larger tumor cohort: a grade-4 small bowel obstruction, a grade-3 lower gastrointestinal tract bleed, and a death from an upper gastrointestinal bleed and tumor rupture. These toxicities led to dose reductions to 200 mg sorafenib daily (compared with a standard oral dose of 400 mg b.i.d.).

"We do not recommend concurrent sorafenib and SBRT outside the context of clinical trials," Dr. Brade said.

Sequential Trial Being Planned

He noted that the outcomes of this trial have influenced the design of the Radiation Therapy Oncology Group (RTOG) 1112 phase III trial, which will compare sorafenib with sorafenib following stereotactic radiotherapy. The trial is still in its planning stages and the protocol has not been made public.

"The use of biologic targeting for radiosensitization in the context of SBRT is both a novel and promising approach," commented Dr. Catherine Park, a radiation oncologist at the University of California, San Francisco.

"The phase I study combining sorafenib with SBRT shown today highlights the exciting promise of greater efficacy, but with caution due to potential toxicity," she said. "It also reflects the challenging research necessary to optimize such novel approaches for clinical use."

Dr. Park was comoderator at a briefing where the data were presented but was not involved in the study.

Dr. Brade disclosed a research grant from Bayer. Dr. Park disclosed having an investment interest in Oncosynergy, a biotechnology company.

BOSTON – A concurrent combination of the targeted agent sorafenib and stereotactic body radiotherapy showed promising efficacy against advanced liver cancer in a phase I clinical trial, but investigators found toxicity was unacceptable for clinical use.

Only 3 of 16 patients completed the study evaluating the safety of concurrent sorafenib (Nexavar) and stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC), Dr. Anthony Brade reported at the annual meeting of the American Society for Radiation Oncology.

"We found delivery concurrently of sorafenib and radiotherapy was challenging and likely limited by the volume of tumor and liver that’s irradiated, as well as drug dose," Dr. Brade, a radiation oncologist at the University of Toronto, said at a news briefing.

"Despite the advanced tumor burden and toxicity, the response rates we observed were encouraging," he added. "Sorafenib alone has a response rate under 2%, so to see response rates in the 36%-50% range was very encouraging."

Two of four patients with small tumors involving less than 40% of the liver had a partial response to the combined therapy, and the other two had stable disease over 8-12 weeks of follow-up. Among 11 patients with tumors involving 40%-60% of the liver, four had a partial response and 7 had stable disease. One patient died of tumor rupture before receiving radiation.

The investigators reported a 50% response rate for the smaller-tumor group and 36% for the larger-tumor group.

Promise and Peril

Sorafenib, a tyrosine kinase inhibitor, is standard of care for locally advanced HCC. In a 2008 study it was shown to improve overall survival and time to radiologic progression in patients with advanced HCC who were ineligible for local therapies but had good liver function (Child-Pugh Class A), Dr. Brade noted (N. Engl. J. Med. 2008;359:378-90). Preclinical data also suggest that the combination of sorafenib and radiotherapy may improve outcomes, he said.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal three-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as four to six fractions delivered over 2-2.5 weeks, compared with 8-9 weeks of daily fractions for other techniques.

The current phase I study enrolled patients with good performance status, good liver function (Child-Pugh Class A), more than 800 cc of liver without tumor involvement, adequate hematologic parameters and liver and kidney function, and minimal extrahepatic disease.

The participants had a median age of 61.5 years, and 10 patients each had the significant adverse prognostic features of tumor thrombus and multiple lesions, Dr. Brade noted.

Patients with smaller tumors (stratum 1) were assigned to receive low effective liver volume irradiation at less than 30% of volume, with doses ranges from 39-54 Gy in six fractions over 2 weeks.

Patients with larger tumors had high effective volume (30%-60%) irradiation, with doses ranging from 39-54 Gy, also in six fractions. The maximum permitted doses to the gastrointestinal lumen was 31-34 Gy.

Patients received sorafenib 1 week prior to, during, and 4 weeks post SBRT, at which point escalation to full-dose sorafenib was allowed. Although the protocol called for escalating from an initial dose of 200 mg b.i.d. (400 mg daily) to 600 mg daily delivered in a 400-mg morning and a 200-mg evening dose and finally to 800 mg (400 mg b.i.d.), the study was closed before the maximum was reached in stratum 1. In stratum 1 patients, the 200 mg b.i.d. dose appeared to be tolerable, Dr. Brade said.

Four patients discontinued the drug at less than 4 weeks either because of tumor progression (2) or toxicity (2). There were three dose-limiting toxicities in the larger tumor cohort: a grade-4 small bowel obstruction, a grade-3 lower gastrointestinal tract bleed, and a death from an upper gastrointestinal bleed and tumor rupture. These toxicities led to dose reductions to 200 mg sorafenib daily (compared with a standard oral dose of 400 mg b.i.d.).

"We do not recommend concurrent sorafenib and SBRT outside the context of clinical trials," Dr. Brade said.

Sequential Trial Being Planned

He noted that the outcomes of this trial have influenced the design of the Radiation Therapy Oncology Group (RTOG) 1112 phase III trial, which will compare sorafenib with sorafenib following stereotactic radiotherapy. The trial is still in its planning stages and the protocol has not been made public.

"The use of biologic targeting for radiosensitization in the context of SBRT is both a novel and promising approach," commented Dr. Catherine Park, a radiation oncologist at the University of California, San Francisco.

"The phase I study combining sorafenib with SBRT shown today highlights the exciting promise of greater efficacy, but with caution due to potential toxicity," she said. "It also reflects the challenging research necessary to optimize such novel approaches for clinical use."

Dr. Park was comoderator at a briefing where the data were presented but was not involved in the study.

Dr. Brade disclosed a research grant from Bayer. Dr. Park disclosed having an investment interest in Oncosynergy, a biotechnology company.

BOSTON – Delivering stereotactic body radiation for early-stage, inoperable non–small cell lung cancer doubled overall survival rates achieved in historical series with conventional radiation, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 3-year overall survival rate reached 59.9% for 100 patients whose stage IA non–small cell lung cancer (NSCLC) was treated with stereotactic body radiation therapy (SBRT), said Dr. Yasushi Nagata. He compared results of the nonrandomized phase II trial with 31%-39% in historical series with conventional radiation.

The 5-year overall survival rate was 40.8%, compared with 13%-22.2% historically, added Dr. Nagata from Hiroshima University, Japan.

He described SBRT as well tolerated with only mild toxicities, making it a suitable alternative to other therapies, particularly in older patients. "Patients with early inoperable lung cancer should consider this treatment," Dr. Nagata advised in a briefing.

The investigators concluded that the treatment should be the new standard, replacing conventional radiotherapy in this population.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal 3-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as 4-6 fractions delivered over 2 to 2.5 weeks, compared with 8 to 9 weeks of daily fractions for other techniques.

The phase II Japanese Clinical Oncology Group trial, JCOG-0403, is said to be the first to evaluate SBRT in both operable and nonoperable NSCLC. At the 2010 ASTRO annual meeting, the investigators reported 3-year survival rates for 64 patients with surgically resectable NSCLC: overall survival was 76%; progression-free survival, 54.5%; local progression-free survival, 68.5%; and event-free survival, 51.4%.

In the current study, 77 men and 27 women with a median age of 78 years (range 59-90 years) were enrolled; four patients were later excluded from the study, three because they developed a second primary cancer within 5 years of registration, and one was "unexpectedly" treated with SBRT and chemotherapy.

The median tumor size was 21 mm (range 9-30 mm). Fifty patients had adenocarcinomas, 40 had squamous cell carcinomas, and 14 had other tumor histologies. All patients had histologically or cytologically proven NSCLC, clinical T1N0M0 disease, and were determined by thoracic surgeons to be inoperable.

All patients completed the treatment protocol, consisting of a dose of 48 Gy at the isocenter divided into 4 fractions over 4-8 days.

The progression-free survival rate at 3 years was 49.8%; the local progression-free survival rate was 52.8%, and event-free survival, 46.8%.

Grade 3 adverse events include dyspnea in 10 patients, hypoxia in 8, pneumonitis in 7, chest pain in 2 and cough in 1. There was one case each of grade 4 dyspnea and hypoxia, but no treatment-related deaths.

The study results indicate that "SBRT, a highly effective targeted approach for selected nonoperable cancers, is a modality with acceptable toxicity to consider for lung cancer patients," commented Dr. Eric Lin Chang, a professor of radiation oncology at the University of Southern California, Los Angeles. Dr. Chang was co-moderator of a briefing at which the data were presented, but was not involved in the study.

The study was supported by Japan’s Ministry of Health. Dr. Nagata and Dr. Chang disclosed no relevant conflicts of interest.

BOSTON – Delivering stereotactic body radiation for early-stage, inoperable non–small cell lung cancer doubled overall survival rates achieved in historical series with conventional radiation, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 3-year overall survival rate reached 59.9% for 100 patients whose stage IA non–small cell lung cancer (NSCLC) was treated with stereotactic body radiation therapy (SBRT), said Dr. Yasushi Nagata. He compared results of the nonrandomized phase II trial with 31%-39% in historical series with conventional radiation.

The 5-year overall survival rate was 40.8%, compared with 13%-22.2% historically, added Dr. Nagata from Hiroshima University, Japan.

He described SBRT as well tolerated with only mild toxicities, making it a suitable alternative to other therapies, particularly in older patients. "Patients with early inoperable lung cancer should consider this treatment," Dr. Nagata advised in a briefing.

The investigators concluded that the treatment should be the new standard, replacing conventional radiotherapy in this population.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal 3-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as 4-6 fractions delivered over 2 to 2.5 weeks, compared with 8 to 9 weeks of daily fractions for other techniques.

The phase II Japanese Clinical Oncology Group trial, JCOG-0403, is said to be the first to evaluate SBRT in both operable and nonoperable NSCLC. At the 2010 ASTRO annual meeting, the investigators reported 3-year survival rates for 64 patients with surgically resectable NSCLC: overall survival was 76%; progression-free survival, 54.5%; local progression-free survival, 68.5%; and event-free survival, 51.4%.

In the current study, 77 men and 27 women with a median age of 78 years (range 59-90 years) were enrolled; four patients were later excluded from the study, three because they developed a second primary cancer within 5 years of registration, and one was "unexpectedly" treated with SBRT and chemotherapy.

The median tumor size was 21 mm (range 9-30 mm). Fifty patients had adenocarcinomas, 40 had squamous cell carcinomas, and 14 had other tumor histologies. All patients had histologically or cytologically proven NSCLC, clinical T1N0M0 disease, and were determined by thoracic surgeons to be inoperable.

All patients completed the treatment protocol, consisting of a dose of 48 Gy at the isocenter divided into 4 fractions over 4-8 days.

The progression-free survival rate at 3 years was 49.8%; the local progression-free survival rate was 52.8%, and event-free survival, 46.8%.

Grade 3 adverse events include dyspnea in 10 patients, hypoxia in 8, pneumonitis in 7, chest pain in 2 and cough in 1. There was one case each of grade 4 dyspnea and hypoxia, but no treatment-related deaths.

The study results indicate that "SBRT, a highly effective targeted approach for selected nonoperable cancers, is a modality with acceptable toxicity to consider for lung cancer patients," commented Dr. Eric Lin Chang, a professor of radiation oncology at the University of Southern California, Los Angeles. Dr. Chang was co-moderator of a briefing at which the data were presented, but was not involved in the study.

The study was supported by Japan’s Ministry of Health. Dr. Nagata and Dr. Chang disclosed no relevant conflicts of interest.

BOSTON – Delivering stereotactic body radiation for early-stage, inoperable non–small cell lung cancer doubled overall survival rates achieved in historical series with conventional radiation, investigators reported at the annual meeting of the American Society for Radiation Oncology.

The 3-year overall survival rate reached 59.9% for 100 patients whose stage IA non–small cell lung cancer (NSCLC) was treated with stereotactic body radiation therapy (SBRT), said Dr. Yasushi Nagata. He compared results of the nonrandomized phase II trial with 31%-39% in historical series with conventional radiation.

The 5-year overall survival rate was 40.8%, compared with 13%-22.2% historically, added Dr. Nagata from Hiroshima University, Japan.

He described SBRT as well tolerated with only mild toxicities, making it a suitable alternative to other therapies, particularly in older patients. "Patients with early inoperable lung cancer should consider this treatment," Dr. Nagata advised in a briefing.

The investigators concluded that the treatment should be the new standard, replacing conventional radiotherapy in this population.

Similar in concept to stereotactic radiosurgery with a cyberknife, SBRT is a technique for precise high-dose targeting of tissues from multiple angles and planes, allowing delivery of much larger doses by fraction than conformal 3-dimensional or intensity-modulated radiation therapy. With SBRT, radiation therapy sessions can often be compressed into as little as 4-6 fractions delivered over 2 to 2.5 weeks, compared with 8 to 9 weeks of daily fractions for other techniques.

The phase II Japanese Clinical Oncology Group trial, JCOG-0403, is said to be the first to evaluate SBRT in both operable and nonoperable NSCLC. At the 2010 ASTRO annual meeting, the investigators reported 3-year survival rates for 64 patients with surgically resectable NSCLC: overall survival was 76%; progression-free survival, 54.5%; local progression-free survival, 68.5%; and event-free survival, 51.4%.

In the current study, 77 men and 27 women with a median age of 78 years (range 59-90 years) were enrolled; four patients were later excluded from the study, three because they developed a second primary cancer within 5 years of registration, and one was "unexpectedly" treated with SBRT and chemotherapy.

The median tumor size was 21 mm (range 9-30 mm). Fifty patients had adenocarcinomas, 40 had squamous cell carcinomas, and 14 had other tumor histologies. All patients had histologically or cytologically proven NSCLC, clinical T1N0M0 disease, and were determined by thoracic surgeons to be inoperable.

All patients completed the treatment protocol, consisting of a dose of 48 Gy at the isocenter divided into 4 fractions over 4-8 days.

The progression-free survival rate at 3 years was 49.8%; the local progression-free survival rate was 52.8%, and event-free survival, 46.8%.

Grade 3 adverse events include dyspnea in 10 patients, hypoxia in 8, pneumonitis in 7, chest pain in 2 and cough in 1. There was one case each of grade 4 dyspnea and hypoxia, but no treatment-related deaths.

The study results indicate that "SBRT, a highly effective targeted approach for selected nonoperable cancers, is a modality with acceptable toxicity to consider for lung cancer patients," commented Dr. Eric Lin Chang, a professor of radiation oncology at the University of Southern California, Los Angeles. Dr. Chang was co-moderator of a briefing at which the data were presented, but was not involved in the study.

The study was supported by Japan’s Ministry of Health. Dr. Nagata and Dr. Chang disclosed no relevant conflicts of interest.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

BOSTON – Here’s heartening news that physicians can convey to breast cancer survivors: Modern breast irradiation did not appear to cause late-term cardiac toxicity in a study that examined women a quarter of a century after they were treated.

Investigators found no significant differences in Framingham Heart Study risk scores, hemodynamic parameters, pericardial thickening, or heart failure among 50 women who had been randomized in the 1970s and 1980s to either mastectomy or breast-conserving surgery (BCS) and radiation, Dr. Charles B. Simone II reported at the annual meeting of the American Society for Radiation Oncology.

Neil Osterweil/IMNG Medical Media

Although the survival rate was slightly lower among patients treated with breast-conserving therapy, the difference does not appear to be related to radiation dose to the heart, said Dr. Simone of the Hospital of the University of Pennsylvania in Philadelphia. There were no differences in survival among women treated with BCS and radiation to left- or right-sided tumors.

"Based on this study, in the era of 3D planning, patients with early-stage breast cancer treated with radiotherapy do not have a higher risk of long-term cardiac morbidity compared with patients having mastectomy," he said.

The patients studied included 50 of 102 survivors from an original cohort of 237 women who had participated in the National Cancer Institute’s Breast Conservation Trial (79-C-0111), with randomization from 1979 to 1986. In that trial, women with stage I or II breast cancer received modified radical mastectomy with axillary node dissection or they underwent lumpectomy plus node dissection and a radiation dose of 45-50.4 Gy to the whole breast; the latter came with or without treatment of regional nodes, followed by a boost of 15-20 Gy with either iridium 192 brachytherapy or electrons.

All node-positive patients underwent 6-11 cycles of chemotherapy with doxorubicin and cyclophosphamide, and beginning in 1985 postmenopausal women with positive nodes were given tamoxifen.

The trial was unique at the time in that it used CT simulations for treatment planning and dose inhomogeneity corrections, Dr. Simone noted.

Diverging Survival Curves

At a median of 25.7 years after randomization, 43.8% of mastectomy patients were still alive, compared with 37.9% of BCS patients. Although the difference was not significant, it appeared to represent a divergence of survival curves that had been virtually identical for the first 25 years.

The trend could not be accounted for by secondary malignancies, changes in distant metastasis, or any other breast cancer–related causes, leading the investigators to question whether it might be due to radiation toxicity to the heart, as some studies have suggested.

In all, 26 patients who had had BCS and 24 who underwent mastectomy agreed to come back for the cardiac toxicity study.

The investigators took a detailed cardiac history, and subjected the women to exams, cardiac labs, cardiac MRI with a 3 Tesla magnet to look for anatomic and functional abnormalities, and CT angiogram to look for stenotic coronary disease and determine coronary arterial calcium score (CAC) of atherosclerotic burden.

They also looked at radiation technique parameters such as central lung distance, field size, dose, and boost dose.

On cardiac MRI, they only saw two significant between-group differences. Time to peak filling rate was shorter for BCS patients (487 milliseconds vs. 647 ms for mastectomy patients; P = .02), but there was no difference in the peak filling rate itself. Left ventricular mass was smaller for BCS patients (mean 90.5 gm vs. 111 gm for mastectomy patients), but this difference was no longer significant after adjustment for systolic blood pressure, Dr. Simone noted.

"Interestingly, we didn’t see any evidence of myocardial fibrosis in any patient assessed, and only one patient in each arm had any degree of pericardial thickening," he said.

Reassuring Data

Additionally, investigators saw no significant differences on CT angiography in the presence of visible plaque or significant or severe vascular stenosis. There were also no differences in plaque or stenosis in the left anterior descending arteries of women treated with radiation for tumors on the left or the right side of the body.

"For each and every vessel we looked at, there was no difference in the degree of stenosis," Dr. Simone said.

Median CAC scores were low and in the normal range, but patients who had received chemotherapy had a trend toward increased atherosclerosis and plaque formation, Dr. Simone noted.

The study "gives some reassurance to our patients that, after 25 years of follow-up, using modern radiation techniques the delivery of radiation to the left does not cause cardiac toxicity," Dr. Bruce Haffty, chair of radiation oncology at the Cancer Institute of New Jersey, New Brunswick, said at a briefing.

The study was supported by the National Cancer Institute. Dr. Simone and Dr. Haffty reported no relevant disclosures.

BOSTON – A review of data on nearly 30,000 women suggests older age by itself should not be a barrier to radiotherapy after lumpectomy for early-stage breast cancer.

Older patients treated with both modalities had higher rates of overall and breast cancer–specific survival at 5 and 10 years compared with women who underwent lumpectomy alone, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy American Society for Radiation Oncology

"The improvement in cause-specific survival with the addition or radiation suggests that in healthy, elderly women, adjuvant radiation should be strongly considered as part of their breast cancer treatment," said Dr. Randi J. Cohen, a radiation oncologist at the University of Maryland in Baltimore.

The review examined Surveillance, Epidemiology, and End Results (SEER) database records on 29,949 women, who were aged 70-84 years at diagnosis with clinical stage I, estrogen receptor–positive breast cancer and survived at least 1 year. About three-fourths underwent radiation after lumpectomy.

Women treated with lumpectomy and radiation had an overall survival rate of 88.6% at 5 years vs. 73.1% among those with no radiation (P less than .0001), Dr. Cohen reported. Overall survival rates at 10 years were 65.0% and 41.7%, respectively.

Cause-specific survival rates at 5 years were 98.3% for patients in the radiation plus surgery group and 97.4% for those with no radiation. At 10 years, the respective rates were 95.5% and 93.3% (P less than .0001 for both comparisons).

The median length of survival also was greater with the addition of radiotherapy – 13.1 years vs. 11.1 years with lumpectomy alone.

Radiation Was Independent Predictor

In multivariate analysis that controlled for age, tumor size, race, ductal histology, lymph nodes and marital status, hazard ratios also showed significantly worse outcomes without radiation – 1.56 in the overall survival analysis and 1.41 in the cause-specific survival analysis.

The results are similar to those in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), said Dr. Cohen. That study showed an absolute benefit for adding radiation of 3% at 10 years, compared with 2.2% at 10 years in the current study.

Dr. Cohen said the review was prompted by questions raised in a 2004 study from the Cancer and Leukemia Group B (CALGB). In that trial, investigators looked at whether adding radiation to lumpectomy plus tamoxifen would have an effect on overall or breast cancer–specific survival in 630 women 70 years and older with early-stage disease. They found that at a median follow-up of 10.5 years, there was an absolute reduction of 6% in same-breast tumor recurrence with radiation, but no difference overall of disease-free survival.

In the much larger EBTCG study and the current study, however, the disease-specific survival advantages with the addition of radiation were likely related to greater locoregional control. Dr. Cohen said that the overall survival advantage in her study was probably due to selection of healthier patients with longer predicted life expectancy for radiotherapy.

She noted, however, that the study was limited by a lack of data on recurrence rates or hormonal therapy.

Strength of Benefit Questioned

"It’s highly unlikely that the magnitude of the benefits of cause-specific survival can be attributed to just radiation alone," said Dr. Meema Moran, the invited discussant. She noted that in EBCTCG study, there was only about a 3% benefit at 15 years in a seemingly low-risk population with shorter follow-up. The favorable survival in the meta-analysis may therefore be partly attributable to treatment selections bias, said Dr. Moran, a radiation oncologist at Yale University in New Haven, Conn.

She also noted that because local recurrence data are not collected in SEER, mastectomy-free survival is used as a surrogate for relapse, but mastectomy rates may vary due to differences in management of ipsilateral recurrence, such as mastectomy or repeat breast-conserving surgery.

The funding source for Dr. Cohen’s study was not disclosed. She reported no conflicts of interest. Dr. Moran reported serving on the Genomic Health Advisory Board.

BOSTON – A review of data on nearly 30,000 women suggests older age by itself should not be a barrier to radiotherapy after lumpectomy for early-stage breast cancer.

Older patients treated with both modalities had higher rates of overall and breast cancer–specific survival at 5 and 10 years compared with women who underwent lumpectomy alone, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy American Society for Radiation Oncology

"The improvement in cause-specific survival with the addition or radiation suggests that in healthy, elderly women, adjuvant radiation should be strongly considered as part of their breast cancer treatment," said Dr. Randi J. Cohen, a radiation oncologist at the University of Maryland in Baltimore.

The review examined Surveillance, Epidemiology, and End Results (SEER) database records on 29,949 women, who were aged 70-84 years at diagnosis with clinical stage I, estrogen receptor–positive breast cancer and survived at least 1 year. About three-fourths underwent radiation after lumpectomy.

Women treated with lumpectomy and radiation had an overall survival rate of 88.6% at 5 years vs. 73.1% among those with no radiation (P less than .0001), Dr. Cohen reported. Overall survival rates at 10 years were 65.0% and 41.7%, respectively.

Cause-specific survival rates at 5 years were 98.3% for patients in the radiation plus surgery group and 97.4% for those with no radiation. At 10 years, the respective rates were 95.5% and 93.3% (P less than .0001 for both comparisons).

The median length of survival also was greater with the addition of radiotherapy – 13.1 years vs. 11.1 years with lumpectomy alone.

Radiation Was Independent Predictor

In multivariate analysis that controlled for age, tumor size, race, ductal histology, lymph nodes and marital status, hazard ratios also showed significantly worse outcomes without radiation – 1.56 in the overall survival analysis and 1.41 in the cause-specific survival analysis.

The results are similar to those in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), said Dr. Cohen. That study showed an absolute benefit for adding radiation of 3% at 10 years, compared with 2.2% at 10 years in the current study.

Dr. Cohen said the review was prompted by questions raised in a 2004 study from the Cancer and Leukemia Group B (CALGB). In that trial, investigators looked at whether adding radiation to lumpectomy plus tamoxifen would have an effect on overall or breast cancer–specific survival in 630 women 70 years and older with early-stage disease. They found that at a median follow-up of 10.5 years, there was an absolute reduction of 6% in same-breast tumor recurrence with radiation, but no difference overall of disease-free survival.

In the much larger EBTCG study and the current study, however, the disease-specific survival advantages with the addition of radiation were likely related to greater locoregional control. Dr. Cohen said that the overall survival advantage in her study was probably due to selection of healthier patients with longer predicted life expectancy for radiotherapy.

She noted, however, that the study was limited by a lack of data on recurrence rates or hormonal therapy.

Strength of Benefit Questioned

"It’s highly unlikely that the magnitude of the benefits of cause-specific survival can be attributed to just radiation alone," said Dr. Meema Moran, the invited discussant. She noted that in EBCTCG study, there was only about a 3% benefit at 15 years in a seemingly low-risk population with shorter follow-up. The favorable survival in the meta-analysis may therefore be partly attributable to treatment selections bias, said Dr. Moran, a radiation oncologist at Yale University in New Haven, Conn.

She also noted that because local recurrence data are not collected in SEER, mastectomy-free survival is used as a surrogate for relapse, but mastectomy rates may vary due to differences in management of ipsilateral recurrence, such as mastectomy or repeat breast-conserving surgery.

The funding source for Dr. Cohen’s study was not disclosed. She reported no conflicts of interest. Dr. Moran reported serving on the Genomic Health Advisory Board.

BOSTON – A review of data on nearly 30,000 women suggests older age by itself should not be a barrier to radiotherapy after lumpectomy for early-stage breast cancer.

Older patients treated with both modalities had higher rates of overall and breast cancer–specific survival at 5 and 10 years compared with women who underwent lumpectomy alone, investigators reported at the annual meeting of the American Society for Radiation Oncology.

Courtesy American Society for Radiation Oncology

"The improvement in cause-specific survival with the addition or radiation suggests that in healthy, elderly women, adjuvant radiation should be strongly considered as part of their breast cancer treatment," said Dr. Randi J. Cohen, a radiation oncologist at the University of Maryland in Baltimore.

The review examined Surveillance, Epidemiology, and End Results (SEER) database records on 29,949 women, who were aged 70-84 years at diagnosis with clinical stage I, estrogen receptor–positive breast cancer and survived at least 1 year. About three-fourths underwent radiation after lumpectomy.

Women treated with lumpectomy and radiation had an overall survival rate of 88.6% at 5 years vs. 73.1% among those with no radiation (P less than .0001), Dr. Cohen reported. Overall survival rates at 10 years were 65.0% and 41.7%, respectively.

Cause-specific survival rates at 5 years were 98.3% for patients in the radiation plus surgery group and 97.4% for those with no radiation. At 10 years, the respective rates were 95.5% and 93.3% (P less than .0001 for both comparisons).

The median length of survival also was greater with the addition of radiotherapy – 13.1 years vs. 11.1 years with lumpectomy alone.

Radiation Was Independent Predictor

In multivariate analysis that controlled for age, tumor size, race, ductal histology, lymph nodes and marital status, hazard ratios also showed significantly worse outcomes without radiation – 1.56 in the overall survival analysis and 1.41 in the cause-specific survival analysis.

The results are similar to those in a meta-analysis from the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), said Dr. Cohen. That study showed an absolute benefit for adding radiation of 3% at 10 years, compared with 2.2% at 10 years in the current study.

Dr. Cohen said the review was prompted by questions raised in a 2004 study from the Cancer and Leukemia Group B (CALGB). In that trial, investigators looked at whether adding radiation to lumpectomy plus tamoxifen would have an effect on overall or breast cancer–specific survival in 630 women 70 years and older with early-stage disease. They found that at a median follow-up of 10.5 years, there was an absolute reduction of 6% in same-breast tumor recurrence with radiation, but no difference overall of disease-free survival.

In the much larger EBTCG study and the current study, however, the disease-specific survival advantages with the addition of radiation were likely related to greater locoregional control. Dr. Cohen said that the overall survival advantage in her study was probably due to selection of healthier patients with longer predicted life expectancy for radiotherapy.

She noted, however, that the study was limited by a lack of data on recurrence rates or hormonal therapy.

Strength of Benefit Questioned

"It’s highly unlikely that the magnitude of the benefits of cause-specific survival can be attributed to just radiation alone," said Dr. Meema Moran, the invited discussant. She noted that in EBCTCG study, there was only about a 3% benefit at 15 years in a seemingly low-risk population with shorter follow-up. The favorable survival in the meta-analysis may therefore be partly attributable to treatment selections bias, said Dr. Moran, a radiation oncologist at Yale University in New Haven, Conn.

She also noted that because local recurrence data are not collected in SEER, mastectomy-free survival is used as a surrogate for relapse, but mastectomy rates may vary due to differences in management of ipsilateral recurrence, such as mastectomy or repeat breast-conserving surgery.

The funding source for Dr. Cohen’s study was not disclosed. She reported no conflicts of interest. Dr. Moran reported serving on the Genomic Health Advisory Board.

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

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

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

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

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

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

The Final Word

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

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

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

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

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

Treatment Well Tolerated

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

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

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

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

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

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

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

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

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

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

The Final Word

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

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

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

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

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

Treatment Well Tolerated

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

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

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

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

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

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

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

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

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

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

The Final Word

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

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

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

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

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

Treatment Well Tolerated

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

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

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

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