OR WAIT null SECS
Breast-conservation therapy (BCT), consisting of lumpectomy followed by whole-breast irradiation (WBI), is the standard of care for women with early-stage breast cancer. However, many women who are candidates for BCT either choose mastectomy or lumpectomy alone for myriad reasons. Accelerated partial-breast irradiation (APBI) is a collection of radiotherapy techniques that deliver higher daily doses of radiation to the surgical cavity with margin over a shorter time than WBI, reducing total treatment time from 6-6.5 weeks to 1-2 weeks. Advocates of APBI state that early results of this approach demonstrate excellent local control, minimal acute toxicity, and are associated with more convenience for the patient. Phase III randomized clinical trials are currently underway to assess local control, acute and chronic toxicities, and quality of life associated with APBI compared to WBI. In this review, we hope to clarify the rationale behind APBI and discuss in depth data concerning various partial-breast irradiation techniques that are being used throughout the United States and around the world.
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.
The authors provide an excellent overview of the various techniques by which APBI may be accomplished. It is important to note that each technique has potential limitations that must be assessed with further investigation. For example, with respect to interstitial brachytherapy, the need for operator proficiency, the invasive nature of the procedure, and the potential for impaired cosmesis due to dose inhomogeneity (particularly with low-dose-rate treatment) are potential drawbacks. With respect to the MammoSite device, concerns have been raised regarding whether the balloon can conform to the specific surgical cavity and deliver an adequate dose to the desired tissue depth, the potential for fibrosis and tissue necrosis related to placement of the balloon (and source) too close to the skin, rupture of the balloon by surgical clips, and the absence of published clinical data suggesting long-term efficacy.
Conformal external-beam radiotherapy provides greater dose homogeneity, as noted by the authors, but faces the challenges of reproducibly immobilizing and localizing the target, as well as uncertainty regarding optimal radiation doses. Finally, intraoperative radiotherapy provides better target visualization, localization, and immobilization, but concerns exist regarding the shallow depth of coverage and the potential late effects of the extremely high fraction sizes administered. Further investigation is necessary to better delineate whether certain techniques are superior to others for the administration of APBI.
As growing numbers of radiation treatment facilities begin to offer partial-breast irradiation to patients, and increasing media attention leads many patients to inquire about this form of treatment, it is important for all caregivers of breast cancer patients to understand the rationale for this strategy, as well as the various techniques involved. It is also essential, however, for all those in the oncology community to recognize the still investigational nature of this type of treatment.
At the present time, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39 trial, which has done an excellent job of accruing lower-risk patients (those over 50 with hormone-receptor-positive, node-negative tumors, or ductal carcinoma in situ), has closed accrual for these low-risk patients. Therefore, practitioners wishing to offer APBI to their low-risk patients before the results of that trial mature must be careful to obtain detailed informed consent. Further follow-up and outcomes data are necessary to confirm the equivalence of APBI in terms of local control and to determine appropriate patient-selection criteria, dose, technique, and fractionation. Patients wishing to receive APBI must be informed that if a greater number of local failures occur with partial-breast techniques, it is possible that there might also be an adverse impact on survival. Randomized studies like those underway are necessary to offer definitive evidence regarding these important outcomes.
Clearly, APBI may prove to be an exciting alternative to whole-breast radiotherapy, and in appropriately selected patients may provide equivalent results. Still, continued study is necessary, as only after mature data from randomized trials have been analyzed can the safety and efficacy of this treatment strategy be determined.
Reshma Jagsi, MD, DPHIL
Lori J. Pierce, MD
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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.