Cosmetic outcomes were significantly worse and low-grade late toxicities were slightly more prevalent among women who underwent accelerated partial breast irradiation (APBI) than among those treated with more traditional whole-breast irradiation (WBI), according to interim findings from the first large randomized study comparing the two treatments.
Researchers with the Randomized Trial of Accelerated Partial Breast Irradiation (RAPID) trial compared the two techniques in 2,135 women over age 40 who first underwent breast-conserving surgery for invasive ductal carcinoma or ductal carcinoma in situ, of 3 cm or less, before being randomized to receive either three-dimensional conformal radiation therapy (3D-CRT) APBI or WBI.
The multi-institution study is evaluating cosmesis, late toxicity, and cancer recurrence in the patients over a 10-year period. The interim findings, available online ahead of print in the Journal of Clinical Oncology ( doi: 10.1200/JCO.2013.50.5511 ), were based on a median follow-up of three years.
Women in the APBI group had more adverse cosmetic outcomes as assessed by separate panels of nurses and physicians, and by the patients themselves. Trained nurses found cosmesis problems in 29 percent of the APBI group compared with 17 percent in the WBI cohort at three months, and 32 percent versus 13 percent after five years.
Although patients reported similar rates —26 vs. 18 percent—physicians, examining digital images of the women, found increased cosmesis in 35 vs. 17 percent of the WBI-treated women.
Although more severe late radiation toxicity (grade 3) was uncommon in either group, the researchers reported that grades 1 and 2 toxicities were slightly more common among APBI patients. When late radiation toxicities such as telangiectasia, breast induration, fat necrosis, or breast pain were evaluated at three years, grade 3 events occurred in 1.4 percent of APBI patients, but in none of the WBI women. After five years the difference in rates remained similar.
“Although this is interim data, we feel that the findings indicate that clinicians and patients should not use 3D-CRT APBI unless participating in a clinical trial,” lead author Ivo A. Olivotto, MD, of the British Columbia Breast Cancer Agency, said in an interview.
Several possibilities might explain the higher toxicity in APBI patients, he said: For example, 3D-CRT may not have been sufficiently conformal, with the radiation dose of 38.5 Gy in 10 fractions possibly too high. Another is that the six-hour interfraction interval may not have been long enough to allow normal breast tissues to repair. Because cosmetic outcome is based so much on comparing the symmetry between two breasts, treating just part of one breast may have made any distortion from the radiation more visible, he explained.
Cancer Recurrence Rare
“This is the first randomized study and the most robust data to report this finding. The average follow-up was three years, but we have tracked some of these women now for six or seven years and there have been very few recurrences in either group. The study design is to follow all patients for 10 years, and while we have a statistical plan for tracking recurrence, we just have not seen enough to compare.”
He noted that there were very consistent observations of cosmetic problems made by patients themselves, trained nurses, or physicians looking at photographs taken for the purpose of evaluating cosmesis.
Half of the women had no cosmetic problem while others had less than ideal outcomes due to surgery rather than radiation, he said.
“This technique seemed like a good idea in 2005, but we would not recommend it now because there is this question of adverse cosmesis results, defined as a fair or poor global cosmetic score.”
In 2009, the American Society for Radiation Oncology published a consensus statement on selecting patients and best practices for APBI, concluding that APBI has several benefits, including a decreased overall treatment time and a decrease in the radiation delivered to healthy tissue and adjacent organs (OT, 9/10/09 issue). The document said at that time, however, that the long-term comparisons of safety and effectiveness compared with WBI were unknown.
Whether the results of the current study will change the recommendations remains to be seen.
Results from a number of previous small, single-institution trials have suggested that cosmetic results from APBI might be an issue, said the coauthor of an accompanying editorial, Reshma Jagsi, MD, PhD, Associate Professor of Radiation Oncology at the University of Michigan University Hospital.
“I think we were all hoping that with a large randomized trial we would see better results. But this is sobering,” she told OT.
The bottom line, she said, is that women who want accelerated partial breast irradiation with 3-D conformal radiation therapy should be made aware of the results of the study and be enrolled in clinical trials if they want to pursue treatment.
“APBI is an excellent subject for further investigation. These were interim toxicity results, but the findings are compelling. Cosmetic results are the toxicity in this case, and patients need to be fully informed about this.”
That said, she noted that comparison outcomes are still not available, either in the Canadian study or in large U.S. studies: “I do not think the technology is wrong-headed, but we need more research in order to refine this treatment.”
Her coauthor, Bruce G. Haffty, MD, Professor and Chairman of the Department of Radiation Oncology at Rutgers Cancer Institute of New Jersey and the Robert Wood Johnson Medical School, in New Brunswick, agreed that additional research is still needed, but said that he found the results convincing.
“I think this study was very well done, not only because it was randomized but because this interim analysis was planned, looking at cosmetic changes in both arms before and after treatment. Subjects who underwent WBI did not change, while those in the partial irradiation group did change, and this was confirmed by the three groups that examined the patients or images and largely concurred in their evaluations.”
What is not available, and is needed, he said, is information on whether dosimetry parameters played any role in poorer outcomes. He also said he felt the researchers may have been “a little strong” in concluding that APBI should not be performed outside of a clinical trial.
“I believe that patients should be informed that there are uncertainties based on this study and earlier, smaller reports of cosmetic problems. There just is not as much data on 3D-CRT compared with WBI. I would say that it is safe, but that the [supporting] data is not as developed. There are still a number of questions yet to be answered.”
ASTRO Guideline Update?
The Chair of ASTRO's Clinical Guidelines Committee, Maj. Benjamin D. Smith, MD, Assistant Professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center, who presented an abstract of the study at the 2011 CTRC-AACR San Antonio Breast Cancer Symposium, was asked about the possibility of ASTRO changing its statement. He said the organization is developing a formal process for monitoring all of its clinical guidelines and updating guidelines as appropriate when new data are published.
“The results of the RAPID trial are important and will be seriously considered by ASTRO as we try to determine the optimal timing for updating the APBI guideline,” he said.
“It is my personal opinion that all forms of APBI are best delivered within the context of a formal mechanism, such as a clinical trial, that monitors and reports patient outcomes,” he said, noting that existing data regarding external-beam partial breast irradiation (PBI) are conflicting, with some groups reporting excellent outcomes and other groups reporting meaningful risks of toxicity.
“In light of this ongoing uncertainty, additional research is warranted to help determine whether external-beam PBI itself is a treatment modality that should be abandoned, or whether minor modifications to treatment planning protocols and delivered doses could yield a treatment that achieves the goals of being safe, effective, convenient, and non-invasive.”