The manuscript by Goyal, Kearney, and Haffty reviews an important and active area of research in radiation oncology-accelerated partial-breast irradiation (APBI). As the authors note, conventional radiation therapy to the whole breast following breast-conserving surgery results in high rates of local control for patients with early-stage breast cancer and yields modest improvements in survival for at least those facing higher baseline risks of locoregional recurrence. Interest in APBI stems from a desire to minimize the cost, inconvenience, and/or toxicity associated with conventional therapy while maintaining the high rates of cancer control that conventional therapy has allowed. This interest, in turn, may increase the access of certain populations who would otherwise undergo mastectomy to breast-conserving therapy and might decrease the numbers of women who undergo lumpectomy alone when adjuvant local therapy is indicated. Moreover, because chemotherapy is being utilized in increasing numbers of patients with earlier-stage disease, the potential for utilizing APBI so that neither radiation nor chemotherapy is delayed by the other is appealing.
The authors review the evidence suggesting that the majority of local recurrences following breast-conserving therapy occur in the region of the tumor bed. We feel that those studies detailing the sites of failure after breast-conserving surgery alone are more compelling than ones that report the locations of recurrences after whole-breast irradiation. After all, finding that most local recurrences after whole-breast irradiation occur in the region of the tumor bed might simply suggest that whole-breast irradiation is more effective at eliminating what might be a lower burden of microscopic residual disease far removed from the primary site than it is at eliminating what might be a higher burden of disease closer to the primary site. Findings that most recurrences occur near the original tumor bed even when radiation therapy has not been administered offer more persuasive support for the investigation of APBI, and the authors cite several studies that suggest this.
Nevertheless, we believe that some of the data cited by the authors and others in support of the investigation of APBI actually provide reasons to be cautious about the general use of this technique. In particular, the authors discuss a randomized trial conducted by the Milan Cancer Institute comparing quadrantectomy with axillary dissection and whole-breast radiotherapy to surgery alone in patients with tumors less than 2.5 cm in size, noting that
"...failures beyond the lumpectomy cavity occurred in 2.9% of patients, consistent with previously published data of 1.5% and 3.5%.... These data suggest that the true benefit of radiotherapy may be to decrease the recurrence of tumor at or near the tumor bed, but may not prevent the development of new, second primary breast cancers that may occur elsewhere in the irradiated breast."
We feel that it is important to emphasize that the surgical procedure in the Milan study was a quadrantectomy, defined as a "wide excision, including a small portion of the overlying skin and of the underlying fascia," similar to the sector resection procedure performed in Sweden and not the more limited lumpectomy procedure commonly performed in the United States. Thus, even the tissue remaining near the tumor bed in the Milan study would likely be outside the region targeted by many partial-breast irradiation techniques in this country, which treat only the region immediately adjacent to the more limited lumpectomy bed.
Therefore, we believe that the Milan study's findings regarding overall recurrence rates are at least as important as the findings regarding the location of these failures. The rates of in-breast recurrence were significantly higherwith a crude cumulative incidence of 23.5% at 10 yearsin the group of patients treated with quadrantectomy alone in this study, as compared with only 5.8% in the radiation-treated arm, suggesting that failure to provide treatment outside the index quadrant can result in preventable recurrences, particularly in younger women. To the extent that partial-breast irradiation provides a "radiation quadrantectomy" or even less, we believe that the results of the Milan III trial should temper the enthusiasm for partial-breast irradiation until mature outcomes data become available.
Given concerns about potentially preventable recurrences outside the index quadrant and the potential for a detriment in survival, it is critical to ensure that APBI is investigated only in patients who are at low risk for disease extension beyond the region of the immediate tumor bed. As the authors note, there has been interest in more clearly defining the group of patients in whom APBI might safely be administered. Ultimately, the appropriate patient selection for this technique will be informed by the results of ongoing trials. In the meantime, practitioners must rely on consensus guidelines, pathologic analyses, and other available data, as detailed by Goyal, Kearney, and Haffty.
As the authors note, the American Brachytherapy Society and American Society of Breast Surgeons have issued general guidelines that suggest limiting the use of APBI to patients with small tumors, ductal histology, negative lymph nodes, and negative margins. Even within this favorable subgroup, we believe that patients should only be treated with APBI after being cautioned that it continues to be an investigational technique for which mature outcomes data are not yet available. We agree with the authors about advising enrollment of patients for APBI on clinical trials when possible.
1. Clarke M, Collins R, Darby S, et al, for the Early Breast Cancer Trialists' Collaborative Group: Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: An overview of the randomised trials. Lancet 366:2087-2106, 2005.
2. Veronesi U, Marubini E, Mariani L, et al: Radiotherapy after breast-conserving surgery in small breast carcinoma: Long-term results of a randomized trial. Ann Oncol 12:997-1003, 2001.
3. Memorandum to NSABP Principal Investigators and Program Coordinators, from Judy Langer, Regulatory Specialist, NSABP Operations Center. December 21, 2006. Re: NSABP B-39/RTOG 0413 Impending Closure of Accrual to Specific Populations (Second Notice). Available at www.rtog.org/members/protocols/0413/B-39%20L-R%20Group% 20Closure%20Notice%20Reminder_12-21-06.pdf. Accessed March 2, 2007.