Fine-tuning the Use of Radiation Therapy: Research Roundup

When and how to optimize the use of radiation therapy continues to be controversial, and studies reported at this year's ASTRO Annual Meeting illustrated the importance of practicing the art as well as the science of medicine. One study expected to likely change practice showed that radiation added to anti-androgen therapy for prostate cancer resulted in a 10% absolute reduction in mortality compared with patients not receiving both treatments. ASTRO Highlights: Fine-tuning the Use of RadiationFigureBOSTON—When and how to optimize the use of radiation therapy continues to be controversial, and studies presented here at this year's American Society for Therapeutic Radiology and Oncology Annual Meeting, the organization's 50th, illustrate that doctors must still practice the art as well as the science of medicine in determining what form of radiation is best for their patients. One report that is likely to change practice patterns would be the addition of radiation therapy to hormone treatment for prostate cancer, doctors said. Researchers from Sweden and other Scandinavian and northern European reported a 10% absolute reduction in mortality among patients who were treated with both hormone therapy and radiation for prostate cancer. “Our findings show that 18 percent of patients who underwent hormone therapy alone died of prostate cancer versus 8.5 percent of those who had both hormone and radiation treatment,” said Anders Widmark, MD, Professor of Radiation Oncology at Umea University in Sweden. “I would encourage men with locally advanced prostate cancer to talk to their doctor to see if they would be a good candidate for radiation therapy in addition to hormone treatment.” The study enrolled 875 patients, randomly assigned to receive anti-androgen medication or the same hormone therapy plus radiation. More than three-fourths of the patients had been diagnosed with Stage T3 tumors. In more than 20% of the cases seminal vesicle involvement was seen. After 10 years of follow-up, 79 patients who were treated with anti-androgen therapy alone either died of prostate cancer or it was determined that prostate cancer contributed to the death, compared with 37 patients who were treated with both conformal external-beam radiation and hormone therapy. Dr. Widmark said that the trial also scrutinized the impact of radiation treatment on patients' quality of life, and after four years, there were no significant differences between the groups in overall health, erectile dysfunction, or fatigue. Prostate specific antigen (PSA) recurrence occurred in about 75% of patients treated with hormones alone vs only 26% of those who had combination therapy. After 10 years, the overall mortality was 39% in patients who received hormone therapy only vs 30% in those receiving combination therapy. “There is nothing more controversial in oncology than prostate cancer and the management of prostate cancer,” noted Anthony Zietman, MD, the Jenot W. and William U. Shipley Professor of Radiation Oncology at Massachusetts General Hospital and Harvard Medical School. “For locally advanced hormone cancer we have had a fatalistic attitude. We thought that the best we could do was palliative therapy or hormonal therapy and see how they do. This study shows that even patients with advanced prostate cancer can be cured.” Caution with Hormones In another study, researchers suggested that treatment with radiation and hormones can be a problem—especially among men over age 70 being treated for early-stage therapy. In that population, there was a 20% increased risk of mortality if the men received anti-androgen therapy before being treated with radioactive seed implantation when compared with men receiving brachytherapy alone. “Our study shows that for men over 70 with early-stage prostate cancer, androgen-deprivation therapy as a form of treatment may do more harm than good,” said Amy Dosoretz, MD, a clinical fellow in radiation oncology at Brigham and Women's Hospital of Harvard Medical School. “In older patients, the risks of androgen deprivation need to be carefully weighed by doctors when designing the proper treatment plan.” The cohort study involved 1,702 men at least 70 years old with localized prostate cancer who were treated with either hormones and brachytherapy or brachytherapy alone at centers within the 21st Century Oncology consortium between 1991 and 2005. A total of 916 men received both treatments, and their outcomes were compared with the 786 men treated with only brachytherapy. “In the past, hormone therapy has been given to these patients prior to brachytherapy, to try to make the procedure technically easier,” Dr. Dosoretz explained during a press briefing. “Recent studies have alerted us to the fact that hormone therapy has more risks than previously appreciated.” The median duration of hormone therapy was 3.5 months, and the patients were followed for a median of five years. The use of hormone therapy resulted in an increased risk of death—a hazard ratio of 1.2, which did reach statistical significance. Age was also a risk factor, with a hazard ratio of 1.1, and a Gleason score of seven or higher had a hazard ratio for death from any cause of 1.2. Mixed Results in Rectal Cancer Treatment for rectal cancer creates a gray area for doctors and patients, and another study reported at the meeting illustrates the decision-making conflict: While adding radiation therapy to surgical treatment decreases the risk of recurrence, the treatment was found to increase the risk of sexual and bowel dysfunction. “We know that this and other trials have consistently shown that radiation before surgery reduces the risk of local cancer returning, but this has to be balanced against any negative side effects,” said David Sebag-Montefiore, MD, a radiation oncologist at St. James' Institute of Oncology in Leeds, UK. “The results of our quality-of-life study should help doctors and patients to discuss both the benefits and risks of preoperative radiation before surgical removal of rectal cancer.”Figure: ANDERS WIDMARK, MD: “Our findings show that 18 percent of patients who underwent hormone therapy alone died of prostate cancer versus 8.5 percent of those who had both hormone and radiation treatment.”In the Medical Research Council CR07 trial, Dr. Sebag-Montefiore scrutinized data from 1,350 patients in the UK, Canada, South Africa, and New Zealand. A total of 674 patients were randomly assigned to the routine use of a one-week course of radiotherapy before surgery (preoperative), and 676 patients were assigned to selective use of radiotherapy after surgery (postoperative) to reduce the risk of recurrence. In the postoperative group, patients at high risk of a local recurrence received 25 treatments of radiotherapy daily over a five-week period combined with chemotherapy after surgery. The results were mixed: About 78% of patients given preoperative radiation and selective use of postoperative therapy were alive without cancer recurrence after five years compared with 72% of patients who received postoperative chemotherapy only. After five years, there was a 4.4% incidence of late recurrence among patients who received preoperative radiation compared with 10.6% among those who received postoperative radiotherapy. Disease-free survival after three years was 77.5% among those who received preoperative therapy compared with 71.5% among those who were treated with radiation after surgery. However, Dr. Sebag-Montefiore noted, those receiving preoperative therapy experienced a decline in male sexual function at three months and this appeared to be due to surgery. There was also a difference in bowel function due to the preoperative radiotherapy at two years among those who had preoperative radiation. After two years about 52% of men who had preoperative radiation reported unintentional release of stools compared with 39% of men receiving selective radiation.Figure: ANTHONY ZIETMAN, MD: “There is nothing more controversial in oncology than prostate cancer and the management of prostate cancer. For locally advanced hormone cancer, we have had a fatalistic attitude. We thought that the best we could do was palliative therapy or hormonal therapy and see how they do. This study shows that even patients with advanced prostate cancer can be cured.”Dr. Sebag-Montefiore concluded that while preoperative radiation reduced late recurrence and disease-free survival, it still did not show evidence of a difference in overall survival. While overall bowel function was similar, incontinence was more frequent among those who received preoperative radiation. Whole-Brain RT: Deterioration in Quality of Life without Survival Benefit In treating brain metastases of other cancers, the routine procedure of adding whole-brain radiation to stereotactic radiosurgery appears to be a bad idea, according to a study presented by Eric L. Chang, MD, Associate Professor of Radiation Oncology at the University of Texas M. D. Anderson Cancer Center. “It's logical to assume that if a patient has one symptomatic metastasis to the brain, that there are many micrometastases that are too small to pinpoint, but will develop after time. That's the rationale for whole-brain radiation. Whether immediate whole-brain radiation therapy is indicated after stereotactic radiosurgery for patients with one to three newly diagnosed brain metastases is controversial and the subject of intense debate.” He said that those advocating whole-brain radiation highlight the importance of disease control, while those who caution against the treatment underscore the potential for toxicity among patients whose life expectancy is not prolonged. Dr. Chang found that whole-brain radiation causes memory and cognition problems in patients within four months of treatment—and the median life expectancy of these patients is more than five months so that memory loss adversely impacts the quality of life that remains for these individuals. “The patient's quality of life deteriorates, without a benefit of survival,” he said. “The results of this study show that initial stereotactic radiosurgery alone, coupled with close observation, could become the standard of care for patients newly diagnosed with brain metastases to best preserve neurocognitive function.” The study involved 58 patients newly diagnosed with one, two, or three brain metastases, randomized to receive stereotactic radiosurgery combined with whole-brain radiation or stereotactic radiosurgery alone from January 2001 to September 2007. Patients were asked to perform the Hopkins Verbal Learning Test, which is used to measure decline in learning and memory by detecting a greater than five-point drop within four months of baseline. Dr. Chang said the trial was difficult to accrue, with only 58 of the 90 patients originally sought for the trial enrolled in seven years. But even so, the independent data monitoring committee recommended halting the trial due to a 96% probability that cognitive decline objectively measured by the Hopkins test at four months was worse for the patients randomized to the group receiving whole-brain radiation. Those patients receiving both stereotactic radiosurgery and whole-brain radiation had a 49% decline in learning and memory functioning at four months, compared with patients who underwent stereotactic radiosurgery alone. That group of patients experienced a 23% decline in neurocognitive functioning. Median follow-up was 7.5 months. The patients' median age was 63 (range of 35 to 82), equally divided by sex. About three-fourths of the patients were white. About half the patients had one lesion. More than half the patients had metastases from lung cancer. Patients also had brain metastases from melanoma, breast, renal, and other cancers. More than 80% of the patients also had liver metastases.Figure: AMY DOSORETZ, MD: “Our study shows that for men over 70 with early-stage prostate cancer, androgen-deprivation therapy as a form of treatment may do more harm than good.”Figure. DAVID: SEBAG-MONTEFIORE, MD: “We know that this and other trials have consistently shown that radiation before surgery reduces the risk of local cancer returning, but this has to be balanced against any negative side effects. The results of our quality-of-life study should help doctors and patients to discuss both the benefits and risks of preoperative radiation before surgical removal of rectal cancer.”Median survival was 15.2 months for patients receiving just stereotactic radiosurgery compared with 5.6 months for patients receiving whole-brain radiation; the one-year survival rate was 61% for those receiving stereotactic surgery alone compared with 19% for those receiving whole-brain radiation. Dr. Chang said that patients who received whole brain radiation did achieve better control of tumor in the brain, but that can be at the expense of a decline in mental functioning with no gain in survival. “These data suggest that decline in learning and memory is primarily due to whole-brain radiation therapy rather than brain tumor relapse,” Dr. Chang said. Shortening Radiation Course Women who undergo radiation therapy following breast cancer surgery face a treatment schedule that can last for as long as six weeks—a hardship on patients who may live considerable distances from treatment center. Timothy J. Whelan, MD, Professor and Head of the Department of Radiation Oncology at Juravinski Cancer Center of McMaster University in Ontario, said that many women roll the dice with their health because the long-term radiation therapy is too great a convenience burden. “Whole-breast irradiation is an integral part of breast-conserving therapy, and randomized trials demonstrate that radiation therapy in these women reduces the risk of local recurrence, prevents mastectomy, and improves overall survival.” To overcome the reluctance of women to forego radiation treatment, he and his colleague embarked on a long-term clinical trial to test whether increasing the dose of radiation in each fraction could allow the course of treatment to be reduced. He said that as many as 20% of women who are candidates for radiation therapy do not undergo the treatment. “We followed more than 1,200 women for 12 years to determine the long-term side effects of this strategy,” Dr. Whelan said. “We compared the effectiveness of accelerated whole-breast radiation with the standard treatment.” Instead of 25 radiation sessions in which 2.0 Gray doses were delivered for a total dose of 50 Gy, women could be assigned to receive 2.7 Gy for 15 sessions for a total dose of about 42.5 Gy. After 10 years of follow-up, about 6.2% of women in the accelerated treatment group experienced a local recurrence of breast cancer, compared with 6.7% of those who underwent standard therapy, a statistically nonsignificant difference. “Both groups of patients had good cosmetic outcomes and limited radiation morbidity,” Dr. Whelan said. After 10 years post-therapy, 71% of women who received standard therapy and 70% of women who underwent accelerated therapy rated the cosmetic outcome as good or excellent. Overall survival at 10 years was about 85% in both groups. In addition to the convenience factor, Dr. Whelan said that the accelerated whole-breast radiation also was performed at a cost that was two-thirds that of the standard treatment schedule. Similarly, the rates of local recurrence and adverse events were similar in both groups. The researchers assigned 612 women to receive standard whole-breast irradiation and enrolled 622 women in the accelerated radiation arm of the trial. They were recruited from April 1993 to September 1996. About one-quarter of the women in the trial were under age 50 years; about one-third of the women had tumors that were at least 2 cm in diameter; about a quarter of the women were estrogen receptor negative; about 20% had a high-grade cancer; and 41% were also taking tamoxifen and about 75% also had chemotherapy. “Accelerated hypofractionated whole breast radiation should be offered to select women with early-stage breast cancer,” Dr. Whelan said. One-day Radiation? Still, an even greater reduction in irradiation time might be possible, according to a report of a single-arm breast brachytherapy trial employing the MammoSite technology system.Figure: TIMOTHY J. WHELAN, MD: “Accelerated hypofractionated whole breast radiation should be offered to select women with early-stage breast cancer.”Figure: ERIC L. CHANG, MD: “The results of this study show that initial stereotactic radiosurgery alone, coupled with close observation, could become the standard of care for patients newly diagnosed with brain metastases to best preserve neurocognitive function.”“Not only does this treatment make radiation treatment much more convenient, it may actually increase the rate of breast conservation, since some women choose mastectomy because they live too far from a radiation center and cannot afford the time and expense of six to seven weeks of living or traveling to the center,” said Peter Beitsch, MD, a surgical oncologist at Medical City Dallas Hospital. “Also, there are many women who for a host of reasons don't receive the necessary postoperative radiation and the shortened course should hopefully allow more women to receive the therapy that they need.” The overall four-year actuarial survival rate was about 94% among the 1,440 women included in the MammoSite registry, a rate that compares well with historical data for standard treatment of breast cancer, Dr, Beitsch said. “Single-institution trials have reported their local/regional recurrence rates and survival, but the numbers of patients in these trials are small. This study reports the recurrence and survival data from the American Society of Breast Surgeons MammoSite Registry Trial.” The MammoSite system received FDA approval in 2002, and the developer, Proxima, opened the registry in May 2002, before it was taken over by the American Society of Breast Surgeons in November 2003. Dr. Beitsch said a total of 121 physicians from 97 institutions have now enrolled patients into the registry. The suggested criteria for entry into the registry are for patients to be older than 45, to have negative margins after breast-conserving surgery, and to have at least 7 mm of skin spacing between the balloon surface and the surface of the skin. In the registry data presented by Dr. Beitsch were 1,255 women with invasive ductal carcinoma and 194 cases of ductal carcinoma in situ. The median age of the women in the registry was 65 and the median tumor size was 1 cm, although the tumors ranged in size from 0.1 to 4.5 cm. He said that four-year data since removal of the MammoSite device was available for 539 women. To date, 27 local recurrences (1.9%) have been reported, nine of them occurring at the original tumor site, with six node recurrences were reported. The overall survival rate was 96%, and breast cancer specific survival was 99.2% based on three-year actuarial rates, he said. Among the first 400 patients who were treated with the system, overall survival was 93.1%, and cancer specific survival was 99.6%, based on four-year actuarial rates, he said. Moderator's Comments Dr. Zietman, who moderated a press briefing on the breast cancer radiation trials, suggested that the Canadian study is likely to be adopted more rapidly by clinicians. “American radiation oncologists have been on a winning horse for many years, and before you change from a winning horse you really have to be confident you are changing to something faster,” he said. “For the woman who lives a distance from a center or who is a single mother, it will absolutely be respectful to offer the shortened course of treatment, and there is now data for this. From cases like that, radiation oncologists will gain confidence for this shorter course of radiation therapy. The Canadian trial is randomized, which we love; and it is long term, which we also love, because breast cancer is a disease that is measured in decades.”Figure: PETER BEITSCH, MD: “Not only does this [MammoSite] treatment make radiation therapy much more convenient, but it may also actually increase the rate of breast conservation, since some women choose mastectomy because they live too far from a radiation center and cannot afford the time and expense of six to seven weeks of living or traveling to the center. Also, there are many women who for a host of reasons don't receive the necessary postoperative radiation, and this shortened course should hopefully allow more women to receive the therapy that they need.”Dr. Zietman was more cautious in considering the MammoSite treatment: “Everyone is very intrigued by balloon brachytherapy,” he said. “We now have three to four years follow-up with it, but we need a bit more before there is complete confidence. We really need to know exactly who is both served by balloon brachytherapy and who may be underserved.” However, Dr. Zietman said he would offer balloon brachytherapy for women who, because of inconvenience, would not get any radiotherapy at all after breast-conserving therapy.

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