To our knowledge, this is the largest database to date of patients who developed an IBTR after APBI. The results indicate that patients who received APBI had outcomes comparable to the outcomes of patients who received up-front WBI after appropriate salvage treatment.9-11 Similar rates of local control, DFS, CSS, and OS were observed compared with the rates in published historic controls (see Historic Perspective, below). However, results from large phase 3 trials with extended follow-up will be needed to help differentiate the subtle differences that may exist between IBTRs that develop after APBI versus those that develop after WBI, which potentially may have an impact on treatment decisions. Furthermore, our analysis supports the use of repeat BCT, because nearly 75% of recurrences were categorized as new primaries and, thus, amenable to repeat breast-conserving surgery with repeat APBI. Although the number of events was small, patients who had E failures had improved DFS and CSS after IBTR compared with patients who had TR/MM. Also, when evaluating treatment options, it may be important to consider the interval between initial treatment and recurrence, because our data indicated that patients who had later failures had improved DFS at 3 years, although the analysis included a limited number of patients. This is similar to data presented by Haffty et al, who observed increased 5-year survival rates in patients who developed IBTRs >4 years after initial treatment.12
Approximately 10% of patients who receive BCT will develop a subsequent IBTR. Currently, the standard treatment remains salvage mastectomy, because repeat attempts at BCT potentially may result in an unacceptable cosmetic outcome. Furthermore, normal tissue toxicity concerns regarding reirradiation exist, potentially limiting the use of a second attempt at BCT in these patients.13 Reported outcomes after salvage mastectomy for IBTRs have indicated chest wall recurrence rates from 7% to 25%, highlighting the persistent risk of local recurrence even with this approach.6-8 Data from Yale University evaluating 116 patients who underwent salvage mastectomy and had 166 months of follow-up indicated a 6.9% rate of local recurrence and a 10-year survival rate of 65.7%.6 Furthermore, an analysis by Voogd et al of 208 patients who underwent salvage mastectomy indicated a chest wall recurrence rate of approximately 25% with nearly 5 years of follow-up.8 Although our current analysis did not examine rates of local recurrence after salvage treatment, our rates of DFS and CSS were comparable to the rates reported in those series.
More recently, repeat breast conservation has been used after IBTR both with excision alone and with various techniques of reirradiation. With regard to excision alone, outcomes have varied significantly with local recurrence rates of 7% to 50%.6-8 In a series from Yale University, the local recurrence rate was 7%; whereas, in 1 of the largest series from Japan, the recurrence rate was nearly 50%. These results highlight the variability in outcomes after excision alone.6, 14 In reviewing the studies described above, survival does not appear to be adversely impacted after a second attempt at BCT (despite the highly variable rates of local recurrence). It is important to realize that patients who undergo local excision alone after IBTR have rates of local recurrence comparable to the rates reported in patients who undergo breast-conserving surgery without the use of postoperative RT de novo. Currently, information about the outcomes of patients who develop an IBTR and receive reirradiation using APBI or alternative techniques are limited; however, reirradiation potentially may reduce the local recurrence rates produced by excision alone (Table 3).9-11, 15-18 Although our analyses were limited by a small number of patients (n = 9), the patients in our series who underwent repeat BCT had excellent outcomes at 2 years.
Table 3. Studies With Repeat Breast-Conservation Therapy Using Accelerated Partial Breast Irradiation
|University of Pittsburgh (Deutsch 20029)||39||EBRT WBI, 50 Gy + 10 Gy||51.5||LC rate, 80% at 5 y|
|Beth Israel Medical Center (Chada 200910)||15||LDR, 30-45 Gy||36||LC rate, 89% at 3 y|
|University of Nice (Hannoun-Levi 201015)||42||HDR IB||21||LC rate, 97% at 2 y|
|Drexel University (Trombetta 201111)||36||21 Patients, LDR IB PBI; 11 patients, MammoSite; 4 patients, 3D-CRT PBI||37||35 of 36 Patients disease free at 3 y|
|Barcelona Medical Institute for Radiotherapy and Oncology (Guix 201016)||36||HDR IB, 30 Gy × 10||120||LC rate, 89.4% at 10 y|
|University of Wisconsin (Adkison 201017)||11||HDR, 3.4 Gy × 10||53.7||100% disease free at 4 y|
|University of Paris (Maulard 199518)||15||LDR, 30 Gy||40||79% LC at 4 y|
One of the largest series reported to date on the use of repeat BCT comes from a retrospective study that was performed at the University of Pittsburgh. In that study, 39 patients who developed IBTRs after WBI received repeat full-dose, external-beam irradiation (50 Gray [Gy] in 25 fractions). With more than 4 years of follow-up, a second IBTR developed in 20.5% of patients. The 5-year OS and DFS rates were 77.9% and 68.5%, respectively. Just as critical, no radiation-induced necrosis developed, and cosmesis was reported as good/excellent in 69% of patients based on physician assessment.9
Chadha et al evaluated the role of repeat BCT with local surgery and brachytherapy for patients who presented with a local recurrence/new primary after standard WBI. Fifteen patients in that analysis received low-dose-rate brachytherapy after undergoing lumpectomy. At a median follow-of 36 months (in the group that received 30 Gy), 1 patient had a documented in-breast failure for an overall in-breast control rate of 89%. In terms of toxicities, no episodes of grade 3 or 4 fibrosis, telangiectasia, ulcers, or necrosis were reported.10
There are limitations to our current analysis. Although data were collected prospectively through the ASBS registry, this was an unplanned retrospective analysis. Furthermore, because of the small number of failures experienced, the power to detect significant differences is limited. Also, no data were available on local control after salvage therapy, and information about outcome was unavailable for 12 of the 50 patients who developed an IBTR. Although the patients were separated into a TR/MM group and an E failure group, a limitation of this analysis was the lack of truly objective criteria, because the division of IBTRs was based strongly on clinical assessment. In the future, objective standards, including loss-of-heterozygosity testing, may be used to better delineate new primaries. Finally, limited numbers of patients underwent repeat BCT; therefore, the outcomes presented require further data to validate our findings. However, despite the small numbers, to our knowledge, the current study represents the largest series in the literature to date.
Finally, only data from ongoing phase 3 trials comparing APBI with WBI can objectively differentiate potential small differences in outcome after IBTR that may exist based on the initial RT technique used, as noted previously. Nonetheless, the results from this study, along with the previous reports discussed above, suggest that clinical outcomes after IBTR with APBI are comparable to the outcomes achieved with WBI at 5 years of follow-up. The Radiation Therapy Oncology Group (RTOG) recently started enrolling patients on protocol RTOG 1014 to prospectively examine the feasibility and acute toxicity of repeat BCT after IBTR using an external-beam, partial breast irradiation technique. In that trial, RT is delivered in 150-centigray fractions twice daily up to a total dose of 45 Gy. It is hoped that, with the added benefits of decreased treatment time and reduced normal tissue toxicity, the use of repeat BCT will continue to increase in well selected patients with early stage breast cancer.
In conclusion, with 5 years of follow-up in a large group of selected patients, APBI produced clinical outcomes and patterns of failure comparable to those reported with WBI. Just as critical, those patients who developed an IBTR after APBI had excellent 3-year survival outcomes after salvage treatment, which, again, was similar to the outcomes of those who developed an IBTR after WBI.