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© 2001 American Society for Clinical Oncology Accelerated Treatment of Breast CancerFrom the Departments of Radiation Oncology, Pathology, and Surgery and the Research Institute, William Beaumont Hospital, Royal Oak, MI. Address reprint requests to Frank A. Vicini, MD, Department of Radiation Oncology, William Beaumont Hospital, 3601 W 13 Mile Rd, Royal Oak, Michigan 48073; email: fvicini{at}beaumont.edu
PURPOSE: Radiation therapy (RT) restricted to the tumor bed, by means of an interstitial implant, and lasting 4 to 5 days after lumpectomy was prospectively evaluated in early-stage breast cancer patients treated with breast-conserving therapy (BCT). The goals of the study were to determine whether treatment time can be reduced and whether elective treatment of the entire breast is necessary. MATERIALS AND METHODS: Between January 1993 and January 2000, 174 cases of early-stage breast cancer were managed with lumpectomy followed by RT restricted to the tumor bed using an interstitial implant. Each brachytherapy patient was matched with one external-beam RT (ERT) patient derived from a reference group of 1,388 patients treated with standard BCT. Patients were matched for age, tumor size, histology, margins of excision, absence of an extensive intraductal component, nodal status, estrogen receptor status, and tamoxifen use. Median follow-up for both the ERT and brachytherapy groups was 36 months. RESULTS: No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT and brachytherapy patients (1% v 0%, P = .31 and 2% v 1%, P = .63, respectively). In addition, there were no statistically significant differences noted in rates of distant metastasis (6% v 3%, P = .24), disease-free survival (87% v 91%, P = .55), overall survival (90% v 93%, P = .66), or cause-specific survival (97% v 99%, P = .28). CONCLUSION: Accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach.
BREAST-CONSERVING therapy (BCT) was found to result in survival equivalent to that achieved with mastectomy, among patients with early-stage breast cancer, in six prospective randomized trials as well as in multiple retrospective studies in the United States and Europe.1-10 Conventional radiation therapy (RT) after lumpectomy consists of 5 weeks of daily external-beam RT (ERT) of the whole breast followed by 1 to 2 weeks of RT to the tumor bed. Despite the undisputed efficacy of this treatment approach, the necessity of electively treating the entire breast for presumed occult disease is uncertain. Because 5 weeks of whole-breast RT results in one of the most significant impediments to the widespread use of breast-conserving techniques, acceleration of treatment by confining RT to the tumor bed has recently been explored.11-24 To this end, we initiated two pilot trials in 1993 and 1995 in which we investigated the efficacy of RT restricted to the lumpectomy bed using an interstitial implant, with treatment completed in 4 to 5 days. Interim results using these techniques showed minimal toxicity and a high degree of reproducibility.21-24 Through this study, we updated the overall experience using these techniques, and we compared outcome with a reference group of patients treated with ERT and matched for multiple, critical prognostic factors. If proven equivalent to standard BCT, this treatment approach could theoretically improve the documented underutilization of BCT by significantly shortening overall treatment time, eliminate delays associated with integrating systemic and local therapies that can potentially affect tumor control rates, and reduce unnecessary heart and lung toxicity associated with whole-breast ERT.
Between January 1993 and January 2000, at William Beaumont Hospital, Royal Oak, Michigan, 174 patients with stage I or II breast cancer underwent lumpectomy followed by RT restricted to the tumor bed by means of an interstitial implant. All patients were treated on three different institutional review board–approved protocols, and informed consent was obtained from all patients. All patients underwent at least an excisional biopsy, defined as a gross total resection of the primary tumor. A total of 108 patients (62%) underwent re-excision because of close, positive, or uncertain margins; re-excision was performed at the discretion of the surgeon or radiation oncologist. All patients underwent axillary lymph node dissection confined to levels I and II of the axilla. All slides for each patient were reviewed by one pathologist before RT (N.S.G.). Our radiation techniques have previously been reported.21,23 All patients were treated prospectively according to one of three different protocols specifically addressing the use of brachytherapy alone in patients with early-stage breast cancer. Eligibility criteria for each of these protocols have previously been reported.21 A total of 120 patients (69%) were treated on an inpatient basis with a low-dose-rate implant that delivered 50 Gy over 96 hours, at a rate of 0.52 Gy/h. The remaining patients were treated on an outpatient basis with a high-dose-rate implant that delivered 32 Gy in eight fractions, each separated by 6 hours (46 patients [26%]), or 34 Gy in 10 fractions, each separated by 6 hours (eight patients). Regardless of the radiation technique used, every implant was designed to irradiate the lumpectomy cavity plus at least a 1- to 2-cm margin. Quality control criteria have previously been reported.22,24 A total of 19 patients (11%) received adjuvant systemic chemotherapy after the completion of brachytherapy. An additional 91 patients (52%) received adjuvant tamoxifen therapy. Patients were seen every 3 months by their radiation oncologist or surgeon during the first 2 years and every 6 months thereafter. Baseline mammography was performed 6 months after completion of brachytherapy and yearly thereafter. Cosmetic results were evaluated by the treating radiation oncologist using the system developed by the Harvard Group.
Matched-Pair Analysis Ipsilateral treatment failure was defined as reappearance of cancer in the treated breast before or at the time of metastases. Ipsilateral treatment failures were classified by clinical location in relation to the initial boost volume according to the criteria described by Recht et al.26 True recurrence or marginal miss was defined as recurrence within or immediately adjacent to the boost volume (or the primary tumor site, in patients who did not undergo boost RT). An elsewhere failure was defined as ipsilateral breast tumor recurrence several centimeters from the primary site that was generally believed to be a new primary cancer or multicentric cancer. Contralateral breast treatment failure was defined as subsequent development of breast cancer in the opposite, untreated breast. Overall survival rates reflect all deaths, cancer related or otherwise. Cause-specific survival (CSS) rates were based on deaths attributed to breast cancer.
Actuarial rates of ipsilateral breast treatment failure, contralateral breast treatment failure, disease-free survival (DFS), overall survival, and CSS were calculated by the Kaplan-Meier method.27 The statistical significance of differences between actuarial curves was calculated using the log-rank test.28 The association of categorical variables with each treatment group was analyzed using Fisher’s exact test (two-tailed). For categorical variables, Student’s unpaired t test was used to determine the significance of the differences between two sample means. P
Characteristics Patient, tumor, and treatment-related characteristics for both brachytherapy and ERT patients are presented in Tables 1 and 2. Thirty-two brachytherapy patients (18%) were observed for at least 5 years, and 65 patients (37%) were observed for at least 4 years. One regional failure and no local failures were detected in brachytherapy patients. The 5-year actuarial rate of locoregional failure was 1% in that group. Distant metastases developed in three brachytherapy patients, for a 5-year distant metastasis (DM) rate of 3%. The 5-year DFS rate among brachytherapy patients was 91%, and the 5-year CSS rate was 99%. No adverse sequelae were noted, and cosmetic results were judged good or excellent in 90% of brachytherapy patients ( Table 3).
Matched-Pair Analysis Table 4 lists critical variables selected for the matched-pair analysis. There were no statistically significant differences between brachytherapy and ERT patients in terms of patient age (P = .17), tumor size (P = .86), margins of excision (P = 1.00), nodal status (P = .76), estrogen receptor status (P = .52), use of adjuvant tamoxifen (P = .91), and use of systemic chemotherapy (P = .26). Because ERT patients were observed for a substantially longer time than were brachytherapy patients (median, 6 v 3 years), the latter group’s follow-up was truncated in a separate analysis, to match the follow-up of the matching brachytherapy patients.
Tables 5 and 6 list treatment outcomes of the brachytherapy group and the group of 174 matched ERT patients. No statistically significant differences were noted in the 5-year actuarial rates of ipsilateral breast treatment failure or locoregional failure between ERT or brachytherapy patients (1% v 0%, P = .31 and 2% v 1%, P = .63, respectively). In addition, there were no statistically significant differences in DM (6% v 3%, P = .24), DFS (87% v 91%, P = .55), overall survival (90% v 93%, P = .66), or CSS (97% v 99%, P = .28) rates between the two groups.
The goals of the current study were to determine whether irradiation of only the tumor bed over 4 to 5 days after lumpectomy results in 5-year actuarial rates of local tumor control and cosmetic outcome equivalent to those achieved with conventional whole-breast irradiation performed over 5 to 6 weeks. In only three of the 174 patients treated using this accelerated treatment approach did distant metastases occur, and no local recurrences were observed after a median follow-up of 3 years. When patients in the study group were compared with a reference group of 174 patients treated with conventional ERT and matched for multiple critical prognostic factors and follow-up, no statistically significant differences in locoregional failure, DFS, DM rate, overall survival, CSS, or cosmetic results were noted. These findings support the concept of accelerated treatment of breast cancer and restriction of irradiation to the tumor bed. However, longer follow-up will be needed to confirm the long-term efficacy of this treatment approach and the advantages and disadvantages of accelerated treatment. The impetus for development of accelerated treatment programs for the treatment of early-stage breast cancer is the fact that a substantial number of women potentially suitable for BCT may not actually receive it and that a significant proportion of women undergoing breast-conserving surgery fail to undergo postoperative irradiation. In several recent studies, 15% to 30% of women treated with breast-conserving surgery for early-stage disease failed to undergo breast irradiation.29-31 The factors responsible for the underutilization of breast-conserving techniques or postlumpectomy RT are multifactorial but primarily relate to the logistical problems associated with performing whole-breast radiotherapy over an extended period (generally 5 to 7 weeks).32 If a tumoricidal dose of radiation could be delivered to the breast over a significantly shortened period with equivalent cosmetic results, the quality of life of many breast cancer patients would likely be improved. This approach would also make conservation an option for more women who currently choose mastectomy because of distance from treatment centers, time away from work, and other considerations. In addition, the controversies and logistical problems associated with integrating local and systemic therapies could be avoided. Although conventional BCT includes elective treatment of the entire breast with RT for presumed occult disease, the efficacy of treating tissue remote from the lumpectomy cavity has never been established. The existence of foci of cancer that are remote from the tumor bed has been consistently noted in several extensive pathologic studies of mastectomy specimens.33,34 However, patients treated with lumpectomy alone have low rates of recurrence in these remote sites (ie, elsewhere failures), rates similar to those seen after whole-breast RT. In effect, the biologic significance of these occult areas of carcinoma is uncertain, suggesting that in certain selected patients, whole-breast RT may not be needed. Reducing the volume of breast tissue requiring a tumoricidal dose of radiation may make it possible to administer larger doses of radiation per fraction (accelerated treatment) without significant additional toxicity. In this study, selection criteria were highly restrictive and follow-up was relatively short. Therefore, it is difficult to know whether the results obtained are due in part to the patients’ low risk, inadequate follow-up, or chance alone. Only a randomized trial with treatment stratified by multiple prognostic factors can objectively address the efficacy of this treatment approach. If such a trial were performed, accrual of approximately 180 patients per arm over 5 years would be needed (assuming 2 years of accrual and 3 years of follow-up before a final analysis). Using local control as the primary end point, and anticipating a local recurrence rate of 5% in the control (conventional RT) arm, one could detect a statistically significant difference of 10% (local recurrence rate of 15%) in the brachytherapy arm with 90% power and alpha = 0.05.35 Certainly, the number of patients required to prove equivalency in a phase III trial would be significantly greater. However, the goal of our matched-pair analysis was to provide a reasonably objective estimate (without conducting a randomized trial) of the true efficacy of accelerated treatment by controlling for all prognostic factors (including potential follow-up) that would likely be used in an ideal phase III study. In addition, the number of patients analyzed should provide sufficient statistical power to generate realistic comparisons. Even though the results of our matched-pair analysis were quite good, one might still suspect that selection bias was responsible (in part) for the results achieved. However, these findings certainly support the initiation of phase III trials addressing this issue. Because the 5-year actuarial rate of local recurrence in both our brachytherapy and ERT patients was low, one might argue that wide excision alone could be a reasonable option for these highly selected, low-risk patients. Unfortunately, several prospective randomized trials designed specifically to address this issue could not identify any subset of patients from whose treatment RT could be confidently omitted.36-41 As noted in Tables 7, 8, and 9, recurrence rates without postoperative RT ranged from 4% to 43% in these trials.42-54 Given that recent data clearly demonstrate a profoundly negative effect of local recurrence on both the rate of DM and overall survival, it is unlikely that RT can be confidently omitted from the treatment of any group of patients.55,56 RT restricted to the tumor bed alone and performed over 4 to 5 days might be an efficacious treatment alternative in these low-risk patients, a treatment that is intermediate between 61/2 weeks of whole-breast RT and observation alone.
Several other groups have also explored the concept of accelerated treatment of breast cancer using both brachytherapy and ERT techniques.57 Table 10 lists the major groups that have addressed this issue. Unfortunately, most trials have involved few patients and relatively short follow-up. However, most groups have reported control rates and cosmetic results comparable to those achieved with standard ERT. Several approaches are currently being investigated. Recent work at our institution has suggested that it is possible to deliver external-beam radiation to the tumor bed alone and in an accelerated fashion, using three-dimensional technology and with the aid of intensity-modulated RT. The advantages of this approach are that additional invasive procedures are not used and that most radiation facilities already have the technologic tools needed. However, more work will be required both to validate this accelerated treatment approach and to define the technology most suited for its widespread implementation.
In conclusion, accelerated treatment of breast cancer using an interstitial implant to deliver radiation to the tumor bed alone over 4 to 5 days seems to produce 5-year results equivalent to those achieved with conventional ERT. Extended follow-up will be required to determine the long-term efficacy of this treatment approach and the potential advantages and disadvantages of accelerated treatment.
We thank Vicky Dykes for her secretarial assistance in the preparation of this manuscript.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 mm, tumor size < 3.0 cm, performance of an axillary lymph node dissection, and cancer involvement of 
three lymph nodes). Each brachytherapy patient was then randomly matched with a unique patient from the group of 447 ERT patients who met brachytherapy protocol criteria. The RANDOMIZE statement was used with the RND function within Microsoft Visual Basic (Microsoft Corporation, Redmond, WA) to generate random numbers between 1 and 447. Patients were matched for age (± 10 years), tumor size (± 5 mm), nodal status (negative v positive [one to three nodes], estrogen receptor status [positive v negative v unknown]), and use of adjuvant tamoxifen. 
