Studies Raise Concerns about Partial-Breast Radiation Therapy
The trend in surgery for early-stage breast cancer over the last 30 years can be summed up in one word: less. Breast-conserving surgery (BCS) plus radiation therapy has supplanted removal of the breast (mastectomy) as the standard of care. More recently, sentinel-lymph node biopsy has largely replaced the more invasive axillary lymph node dissection as the method for determining a tumor's spread and guiding adjuvant therapy.
In the last decade, researchers have begun to focus on whether "less" can also apply to radiation therapy. Studies have consistently shown the benefit of radiation therapy after BCS. But although the therapy is effective, traditional radiation to the whole breast requires up to 7 weeks of treatment, for 5 days each week. This schedule can approach the impossible for many women, such as those in rural areas who live far from a treatment center, those who continue to work during treatment, those who lack reliable transportation, and many others.
If the time required for radiation therapy could be shortened, many women could benefit. Recent randomized studies have shown that delivering whole-breast radiation therapy over 3 weeks (hypofractionation) is as safe and effective for some women as delivering it over 6 to 7 weeks. Another approach being studied is accelerated partial-breast irradiation (APBI), in which radiation is given only to the area immediately surrounding the tumor site instead of to the whole breast over a short period of time (a week or less). Both hypofractionation and APBI use larger doses of radiation per individual treatment session (fraction) than traditional whole breast irradiation.
"The majority of women are still getting whole-breast irradiation, but in the community there's no question that partial-breast irradiation is catching on," said Dr. Thomas Julian, associate director of medical affairs for the National Surgical Adjuvant Breast and Bowel Project (NSABP).
Like most treatments, APBI has advantages and disadvantages. In addition to the advantage of a woman being able to complete radiation therapy in a week or less, APBI may reduce radiation exposure to other organs near the breast, such as the lungs and heart. But on the downside, long-term data on the safety and effectiveness of APBI have not yet emerged from the large randomized trials currently under way.
Too Much, Too Soon?
Recently, concerns have been raised that the use of one type of APBI, breast brachytherapy, may be outpacing the available evidence on the technique's safety and efficacy. In breast brachytherapy, small radioactive seeds are temporarily implanted in the cavity left after surgery to deliver highly localized radiation over a period of several days.
After the Food and Drug Administration (FDA) cleared a device called the MammoSite® balloon catheter for breast brachytherapy in 2002, the use of breast brachytherapy started to rise. Unlike anticancer drugs, which must be approved by the FDA, devices used to facilitate treatment can be cleared without proof of their efficacy compared with standard care, though they must meet basic safety requirements. Medicare approved reimbursement of MammoSite treatment in 2004, after which use of breast brachytherapy rose further.
Several new studies have tracked the increases in the use of breast brachytherapy. A study published in January 2011 with data from almost 7,000 Medicare beneficiaries with supplemental insurance reported an increase in breast brachytherapy from less than 1 percent of patients in 2001 to 10 percent in 2006.
Another study, published last August, that analyzed data from more than 120,000 patients in the Surveillance, Epidemiology, and End Results (SEER) database found that its use rose from less than 1 percent in 2000 to 6.8 percent of patients in 2007.
Last month at the 2011 San Antonio Breast Cancer Symposium (SABCS), research presented by Dr. Benjamin Smith and his colleagues from the University of Texas M. D. Anderson Cancer Center suggested that this rise in the use of brachytherapy may have a measurable downside.
The researchers reviewed Medicare claims for women older than 66 who were diagnosed with invasive breast cancer between 2000 and 2007. All 130,535 women included in the study had BCS followed by either APBI or whole-breast irradiation. In 2000, less than 1 percent of women underwent APBI, whereas in 2007, 13 percent had this form of radiation therapy.
The researchers used subsequent mastectomy as a surrogate for breast cancer recurrence. Within 5 years of follow-up, 4 percent of women who had undergone APBI required a subsequent mastectomy, compared with 2 percent of those who had had whole-breast irradiation. Women who had undergone APBI also had a higher risk of both immediate and late side effects from treatment, including post-operative complications, infections, rib fractures, and breast pain.
"Our results suggest a higher risk of mastectomy in patients treated with brachytherapy. The most intuitive explanation for that is that some patients who are treated with brachytherapy had residual tumor cells in the breast…outside the confines of the target volume for brachytherapy," said Dr. Smith at a press conference at SABCS.
During the press conference, Dr. Smith noted several limitations of the study. He stressed that in addition to being observational, the study had limited follow-up time and did not control for hormone therapy use, although it did control for chemotherapy use. He also pointed out that the data "do not apply to all partial-breast irradiation techniques," which can include external-beam radiation techniques as well as intraoperative radiation therapy.
But what concerns Dr. Smith is that "our data indicated that APBI using brachytherapy was both less effective and had a worse side-effect profile—that [combination] starts to change how you think about a therapy," he said in a follow-up conversation.
"I think that the doubling of the mastectomy rates is a big deal, [even though] it's retrospective data," said Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of the Radiation Research Program in NCI's Division of Cancer Treatment and Diagnosis. If doctors could predict which women need radiation therapy to prevent recurrence, and measured the rate of subsequent mastectomies among those women, the difference would be higher than 2 percent, explained Dr. Vikram. (Since doctors cannot predict which women need radiation therapy to prevent recurrence, it is part of standard care for all women after BCS.)
Waiting on the Evidence
Without evidence from randomized trials to guide whether breast brachytherapy can be used safely in some women, doctors have had to rely on their own experiences and results from some smaller, single-institution studies. In 2009, Dr. Smith and other members of the American Society for Radiation Oncology (ASTRO) released an opinion-based consensus statement that attempted to identify women who can be safely treated with APBI (including, but not limited to, brachytherapy) outside a randomized clinical trial.
The statement also defined two other groups: a "cautionary" group, "for whom caution and concern should be applied when considering APBI outside of a clinical trial," and an "unsuitable" group, for whom APBI outside a clinical trial is not warranted.
Whether these guidelines will affect the use of breast brachytherapy remains to be seen. In a paper published January 4 in the Journal of the National Cancer Institute, researchers from Brigham and Women's Hospital in Boston analyzed data from the SEER database and found that two-thirds of patients treated with breast brachytherapy between 2000 and 2007 would have been classified as part of the cautionary or unsuitable groups as defined in the ASTRO guidelines.
"There's no question that hard outcome data [for partial-breast irradiation] from clinical trials is needed," said Dr. Julian. A large, NCI-sponsored randomized trial, NSABP B-39/RTOG-0414, that is comparing whole-breast irradiation with accelerated partial-breast irradiation for women with early-stage breast cancer should provide such data.
The trial will not look at breast brachytherapy alone; participating physicians have the option of using one of two different brachytherapy systems or using 3-D conformal radiation therapy, an external-beam technique, to deliver APBI. Interestingly, with the trial nearing completion of patient accrual, only one-quarter of participants in the APBI arm have received brachtherapy so far, reported Dr. Julian. The majority received APBI with external-beam radiation therapy equipment.
"External-beam radiation is the easiest approach for radiation oncologists to use because they have the equipment already in place," explained Dr. Julian. Academic centers, such as the ones participating in the trial, also have less of a financial incentive to put in brachytherapy catheters, he added.
But with the large number of participants planned for enrollment in the trial, the researchers hope "that we will have the ability to draw conclusions about the safety and efficacy" of APBI using brachytherapy as well as APBI using external-beam radiation, Dr. Julian concluded.
"We would certainly like to see people waiting for the trial data before broad implementation, but there is more than 10 years of partial-breast irradiation experience that shows that in low-risk women the recurrence outcomes are fairly good, comparable to what happens in low-risk patients who were treated with whole breast radiation. However, for higher-risk women, the data are just not available," he concluded.
Some doctors feel more strongly that the available evidence does not support the risk of using an unproven technique outside a clinical trial. "If you are looking for hard evidence, for now you should consider breast brachytherapy with caution," opined Dr. Vikram—especially, he added, because randomized trials have already shown excellent early results for hypofractionation and intraoperative partial-breast irradiation, where radiation therapy is completed during surgery. These may be safer options for a woman looking to avoid 7 weeks of whole-breast radiation, he said.
The wait for long-term brachytherapy data will be a long one. Although the treatment phase of NSABP B-39/RTOG-0414 is coming to a close, and several other large APBI trials under way in Canada and Europe are also nearing completion, it may be as long as a decade before mature results are available.
Because advances in hormone therapy and chemotherapy have greatly extended the average time to breast cancer recurrence, "anything you start reporting at 2 or 3 years of follow-up is really not enough time," said Dr. Julian. "You have to look beyond that, at the 5- and 10-year event rates, to see what is actually happening."