ARTICLE

Limited-Field Radiation Therapy in the Management of Early-Stage Breast Cancer

Frank A. Vicini, Larry Kestin, Peter Chen, Pamela Benitez, Neal S. Goldstein, Alvaro Martinez

Affiliation of authors: F. A. Vicini, L. Kestin, P. Chen, A. Martinez (Department of Radiation Oncology), P. Benitez (Department of Surgery), N. S. Goldstein (Department of Anatomic Pathology), William Beaumont Hospital, Royal Oak, MI.

Correspondence to: Frank A. Vicini, MD, Department of Radiation Oncology, William Beaumont Hospital, 3601 W. 13 Mile Rd., Royal Oak, MI 48072 (e-mail: fvicini{at}beaumont.edu).


    ABSTRACT
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Background: Several phase III trials have demonstrated equivalent long-term survival between breast conserving surgery plus radiation therapy and mastectomy in patients with early-stage breast cancer but have not provided information on the optimal volume of breast tissue requiring post-lumpectomy radiation therapy. Therefore, we examined the 5-year results of a single institution’s experience with radiation therapy limited to the region of the tumor bed (i.e., limited-field radiation therapy) in selected patients treated with breast-conserving therapy and compared them with results of matched breast-conserving therapy patients who underwent whole-breast radiation therapy. Methods: A total of 199 patients with early-stage breast cancer were treated prospectively with breast-conserving therapy and limited-field radiation therapy using interstitial brachytherapy. To compare potential differences in local recurrence rates based on the volume of breast tissue irradiated, patients in the limited-field radiation therapy group were matched with 199 patients treated with whole-breast radiation therapy. Match criteria included tumor size, lymph-node status, patient age, margins of excision, estrogen receptor status, and use of adjuvant tamoxifen therapy. Local–regional control and disease-free and overall survival were analyzed using the Kaplan–Meier method, and the statistical significance of differences between treatment groups was calculated using the log-rank test. All statistical tests were two-sided. Results: Median follow-up for surviving patients was 65 months (range = 12–115 months). Five ipsilateral breast failures (i.e., recurrences) were observed in patients treated with limited-field radiation therapy. The cumulative incidence of local recurrence was 1% (95% confidence interval [CI] = 0% to 2.8%). On matched-pair analysis, the rate of local recurrence was not statistically significantly different between the patient groups (1% [95% CI = 0% to 2.4%] for the whole-breast radiation therapy patients versus 1% [95% CI = 0% to 2.8%] for the limited-field radiation therapy patients; P = .65). Conclusions: Limited-field radiation therapy administered to the region of the tumor bed has comparable 5-year local control rates to whole-breast radiation therapy in selected patients.



    INTRODUCTION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
The equivalence of conservative surgery plus radiation therapy to mastectomy in the management of women with early-stage breast cancer has been demonstrated in several phase III trials (1,2). Despite the undisputed efficacy of conservative surgery plus radiation therapy, the requisite amount of clinically uninvolved breast tissue surrounding the lumpectomy cavity that needs to be irradiated after conservative surgery has never been definitively established. Traditionally, standard radiation therapy after conservative surgery has included elective treatment of the whole breast for presumed occult disease (3). This additional prophylactic treatment of clinically uninvolved breast tissue with radiation therapy is generally considered to be responsible for a substantial part of the acute and chronic toxicity associated with conservative surgery plus radiation therapy and for the protracted time commitment required for its completion.

In recognition of these problems, limiting the radiation field to the region of the tumor bed (i.e., limited-field radiation therapy) after conservative surgery has been investigated as a possible option for the management of selected low-risk patients. If proven efficacious, such an approach could theoretically increase use of the breast-conserving therapy option to more women, could offer the potential advantages of reduced treatment-related toxicities, could improve the quality of life of cancer patients, and could provide a logistically simpler and more practical method for breast-conserving therapy. Therefore, we examined the 5-year results of a single institution’s experience with limited-field radiation therapy in selected patients treated with breast-conserving therapy and compared them with results of matched breast-conserving therapy patients who underwent whole-breast radiation therapy.


    PATIENTS AND METHODS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Study Participants

One hundred ninety-nine consecutive patients with invasive early-stage breast cancer were prospectively treated at William Beaumont Hospital with limited-field radiation therapy using interstitial brachytherapy directed only at the region of the tumor bed as part of their breast-conserving therapy from 1993 to 2001. The study population included 158 women who were prospectively enrolled to undergo one of three investigational review board–approved limited-field radiation therapy protocols. All eligible patients had stages I/II breast cancer as defined by the International Union Against Cancer (UICC), fifth edition guidelines (4) and had undergone gross total resection of the primary tumor. Re-excisions to achieve negative surgical margins were performed as needed. Eligibility criteria for the three limited-field radiation therapy protocols included having infiltrating ductal carcinomas less than 3.0 cm in diameter, having negative surgical margins (>=2 mm), being over 40 years of age, and having negative lymph nodes. The timing of radiation after lumpectomy as a selection criterion was dropped from the protocols early on. Patients with an extensive intraductal component, infiltrating lobular histology, ductal carcinoma in situ, or clinically significant areas of lobular carcinoma in situ were excluded.

An additional 41 patients who did not meet all eligibility criteria for the limited-field radiation therapy protocols were also included in this analysis. These patients were given the opportunity to be treated with limited-field radiation therapy for compassionate reasons, such as refusing mastectomy and/or refusing conventional whole-breast radiation therapy. Reasons for not meeting the eligibility criteria for the limited-field radiation therapy protocols in these 41 patients included negative but close (0–2 mm) margins (four patients, 2%), non-infiltrating ductal histology (21 patients, 11%), timing of limited-field radiation therapy after lumpectomy (four patients, 2%), participation in other studies (eight patients, 4%), or unspecified (four patients, 2%). These additional non-protocol patients were added to this analysis because the reasons for their ineligibility were minor and their inclusion would unlikely affect the recurrence rate. All patients provided written informed consent before entering into the study.

Patients were followed every 3 months by their radiation oncologist or surgeon during the first 2 years after treatment and every 6 months thereafter. Baseline mammography was performed at 6 months after the completion of limited-field radiation therapy and yearly thereafter. Follow-up was complete through September 2002.

Treatment Regimens

All patients were treated with radiation techniques according to the guidelines of one of three different protocols for limited-field brachytherapy. A total of 120 patients (60%) were treated as inpatients with a low-dose-rate implant that delivered 50 Gy over 96 hours at 0.52 Gy/hour. Seventy-nine patients (40%) were treated as outpatients with a high-dose-rate implant that delivered either 32 Gy in eight fractions (separated by 6 hours; 71 patients) or 34 Gy in 10 fractions (separated by 6 hours; eight patients).

Regardless of the radiation therapy technique used, every implant was designed to irradiate the lumpectomy cavity with at least a 1- to 2-cm margin. Quality-control criteria for these implants have been previously reported (5,6). A total of 139 (70%) patients received adjuvant therapy after completion of limited-field radiation therapy: 25 patients (13%) received adjuvant systemic chemotherapy, and 114 patients (57%) received adjuvant tamoxifen therapy.

Matched-Pair Analysis

To compare the rate of local recurrence in a comparable group of patients treated with whole-breast radiation therapy, each limited-field radiation therapy patient was matched with one whole-breast radiation therapy patient at William Beaumont Hospital. The patient database at William Beaumont Hospital includes information from 1980 through 1997 and consists of 1503 consecutive patients treated with whole-breast radiation therapy (all treatment data were collected retrospectively). Each whole-breast radiation therapy patient underwent lumpectomy and axillary lymph node dissection followed by standard whole-breast external beam radiation therapy at a median total dose to the tumor bed of 60 Gy. Of these whole-breast radiation therapy patients, 709 (47%) were initially selected according to the following limited-field radiation therapy protocol selection criteria: infiltrating ductal histology, absence of an extensive intraductal component, negative margins, tumor size less than 3.0 cm, the performance of an axillary lymph node dissection, and three or fewer involved lymph nodes.

Each limited-field radiation therapy patient was randomly matched to a unique patient from among the 709 whole-breast radiation therapy patients who met the following additional matching criteria. Patients were matched one-to-one according to age (±10 years), tumor size (±5 mm), lymph node status (negative versus 1–3 positive lymph nodes), estrogen receptor status (positive, negative, or unknown), and the use of adjuvant tamoxifen therapy (yes versus no). Outcome (i.e., any type of tumor recurrence) was blinded for both the whole breast and limited-field radiation therapy patients when matching was performed. The RANDOMIZE statement was used with the RND function within Microsoft Visual Basic (Microsoft, Redmond, WA) to generate random numbers between 1 and 709 and to match patients.

Outcome Measures

An ipsilateral failure was defined as the recurrence of cancer in the treated breast before or at the time of regional failure or metastases. Ipsilateral failures were classified by clinical location in relation to the initial tumor bed boost volume in whole-breast radiation therapy patients (or the lumpectomy cavity for limited-field radiation therapy patients), according to criteria described by Recht et al. (7). A "true recurrence/marginal miss" was defined as a recurrence within or immediately adjacent to the boost volume (or the primary tumor site in patients who were not boosted). An "elsewhere failure" was defined as an ipsilateral breast recurrence several centimeters from the primary site that was felt to be a new primary cancer. "Contralateral breast failure" was defined as the development of breast cancer in the opposite, untreated breast.

Overall survival (OS) was defined as all deaths from any cause. Cause-specific survival was defined as all deaths attributed only to breast cancer. Disease-free survival (DFS) was defined as all events attributed to breast cancer, i.e., local, regional, or distant recurrences. Cosmetic results were assessed using the Harvard Group criteria (8). Late toxicities were graded using a modified Radiation Therapy Oncology Group acute/chronic radiation morbidity scale: grade 0 = no observable radiation effects, grade I = mild radiation effects, grade II = moderate radiation effects, and grade III = severe radiation effects.

Statistical Analysis

The estimated likelihood of events for ipsilateral breast failure, contralateral breast failure, DFS, OS, and cause-specific survival were calculated by the Kaplan–Meier method (9), and the statistical significance of differences between treatment groups was calculated using the log-rank test (10). The association of categorical variables (e.g., margin status) with treatment group was analyzed using Fisher’s two-tailed exact test. The statistically significant differences between two sample means for continuous variables (e.g., patient age in years) were analyzed using Student’s unpaired t test. Regression analysis was performed using the Cox proportional hazards model (11). All time intervals were calculated from the date of completion of radiation therapy. A P value of <=.05 was considered to be statistically significant. Statistical analyses were performed using SYSTAT version 10.0 (SPSS Inc., Chicago, IL), and all statistical tests were two-sided.


    RESULTS
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Patient Characteristics of the Limited-Field Radiation Therapy Patients

Table 1Go displays the patient and treatment-related characteristics of patients in the limited-field radiation therapy group. Median follow-up was 65 months (range = 12–115 months) for surviving patients and 60 months (range = 1–116 months) for all patients. Twenty-nine patients (15%) have been followed for at least 8 years, 49 patients (25%) for at least 7 years, and 70 patients (35%) for at least 6 years. No patient was lost to follow-up.


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Table 1. Patient and treatment-related characteristics of patients treated with limited-field radiation therapy
 
Treatment Outcome for the Limited-Field Radiation Therapy Patients

A total of five ipsilateral breast recurrences were observed, translating into a 5-year actuarial ipsilateral breast tumor recurrence rate of 1% (95% CI = 0% to 2.8%). Two of the recurrences were thought to represent a recurrence of the primary lesion, and three were considered to be new cancers in nonirradiated breast tissue. Cosmetic results in 79 patients who had been followed for 5 or more years were considered to be good or excellent in 99% (78/79) of patients and fair in 1% (1/79) of patients. Four percent (8/199) of patients developed asymptomatic fat necrosis, 4% (8/199) developed grade II fibrosis (no grade III), and 6% (12/199) developed grade I/II persistent edema.

Patient Characteristics From the Matched-Pair Analysis

The distribution of critical variables that could potentially affect outcome from the matched-pair analysis of patients treated with limited-field and whole-breast radiation therapy is shown in Table 2Go. There were no statistically significant differences between limited-field and whole-breast radiation therapy patients in age at diagnosis (P = .10), tumor size (P = .52), tumor grade (P = .07), margins of excision (P = 1.0), estrogen receptor status (P = 1.0), number of positive lymph nodes (P = 1.0), or use of adjuvant tamoxifen therapy (P = 1.0). Patients who had whole-breast radiation therapy had a statistically significantly longer follow-up (mean ± standard deviation: 8.9 ± 4.0 years versus 5.0 ± 2.3 years, P<.001), underwent re-excision less frequently (11% versus 42%, P<.001) and received adjuvant systemic chemotherapy less frequently (4% versus 13%, P = .01) than did patients who had limited-field radiation therapy.


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Table 2. Patient characteristics from the matched-pair analysis of patients treated with whole-breast (WB) and limited-field (LF) radiation therapy
 
Treatment Outcomes From the Matched-Pair Analysis

Treatment outcomes from the matched-pair analysis of patients treated with limited-field and whole-breast radiation therapy are shown in Table 3Go. There was no statistically significant difference in median time to local recurrence between the limited-field radiation therapy group and that of the whole-breast radiation therapy group (5.0 years [range 1.5–7.6 years] versus 5.7 years [1.6–7.3 years]; P = .82). No statistically significant differences in the 5-year actuarial rates of ipsilateral breast tumor recurrences or regional failure were found between whole-breast and limited-field radiation therapy patients (1% [95% CI = 0% to 2.4%] versus 1% [95% CI = 0% to 2.8%], P = .65 and 1% [95% CI = 0% to 1.5%] versus 1% [95% CI = 0.1% to 2.1%], P = .54, respectively). There were also no statistically significant differences in 5-year actuarial rates of distant metastases (5% [95% CI = 2.2% to 8.4%] versus 3% [95% CI = 0.5% to 5.9%], P = .17), DFS (91% [95% CI = 86.5% to 94.7%] versus 87% [95% CI = 81.5% to 92.1%]), OS (93% [95% CI = 89.7% to 96.7%] versus 87% [95% CI = 82.1% to 92.7%], P = .23), or cause-specific survival (97% [95% CI = 95.0% to 99.8%] versus 97% [95% CI = 93.8% to 99.9%], P = .34) between whole breast and limited-field radiation therapy patients. There was, however, a statistically significant difference in the 5-year actuarial rate of contralateral breast failure between whole breast and limited-field radiation therapy patients (4% [95% CI = 1.0% to 6.4%] versus 1% [95% CI = 0% to 2.4%], respectively).


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Table 3. Treatment outcomes from the matched-pair analysis of patients treated with whole-breast (WB) and limited-field (LF) radiation therapy*
 
Factors Associated With Local Recurrence Subtype

To determine whether there was an association between pathologic and clinical variables and the development of ipsilateral breast tumor recurrence by subtype (i.e., true recurrence/marginal miss and elsewhere and contralateral breast failures), Cox proportional hazard regression analysis was performed on data from all patients combined (n = 398) (Table 4Go). Only the lack of adjuvant tamoxifen therapy use was statistically significantly associated with the development of new primary breast cancers (elsewhere failure) in the ipsilateral breast (P = .003). Elective treatment of the whole breast had no additional benefit in reducing the rate of development of any type of local recurrence. The use of whole-breast radiation therapy was statistically significantly associated with contralateral breast failure (P = .05).


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Table 4. Univariate analysis of variables associated with ipsilateral breast tumor recurrence (IBTR) by recurrence subtype in whole-breast (WB) and limited-field (LF) radiation therapy patients (n = 398) using Cox proportional hazards regression analysis*
 

    DISCUSSION
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Radiation therapy limited to the region of the tumor bed after lumpectomy in early-stage breast cancer patients treated with breast-conserving therapy produced 5-year actuarial ipsilateral breast tumor recurrence rates similar to those among patients who elected to have whole-breast radiation therapy. In addition, the rate of development of new primary cancers after breast-conserving therapy (with or without the use of whole-breast radiation therapy) was associated only with the use of adjuvant tamoxifen therapy. These results suggest that, in appropriately selected early-stage breast cancer patients, limited-field radiation therapy may be adequate in controlling residual disease after breast-conserving therapy, and they raise the question of whether whole-breast radiation therapy is necessary in certain low-risk patients.

The rationale for elective treatment of the whole breast after conservative surgery stems from the findings of pathologic studies of mastectomy specimens in women with localized breast cancer and from preoperative radiologic imaging of patients selected for conservative surgery (3,13,14), which demonstrated the existence of unsuspected foci of carcinoma in 16%–37% of women. This finding initially led to the notion that breast-conserving therapy was an inappropriate treatment option for women with early-stage disease. However, the type and location of local recurrences in studies of standard breast-conserving therapy have suggested that these areas of clinically occult carcinoma were either of limited clinical significance or were encountered less frequently when patients were more carefully selected and evaluated to rule out multicentric disease. The lack of clinically significant benefit in elective treatment of the whole breast is clearly demonstrated in randomized trials comparing patients treated with conservative surgery plus radiation therapy with those treated with conservative surgery alone. In randomized studies with long-term follow-up, the rate of development of new primary tumors in the ipsilateral breast (far removed from the primary lesion) was similar between studies regardless of the use of whole-breast radiation therapy (Table 5Go). In addition, in long-term studies of standard breast-conserving therapy using whole-breast radiation therapy, the rate of development of new primary cancers in the treated breast was similar to that observed in the contralateral breast (28). The fact that no clinically significant benefit in elective treatment of the whole breast was observed in either of these types of trials raises the question as to the efficacy of electively treating the whole breast for presumed occult disease.


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Table 5. Incidence of new primary breast cancers (i.e., elsewhere failures) in ipsilateral breast cancer (crude rates)*
 
Two recently published phase III trials (1,2,29) that have documented equivalent cause-specific survival between women treated with mastectomy and women treated with breast-conserving therapy (after 20 years of follow-up) also demonstrated the lack of a clinically significant benefit of radiation therapy electively delivered to the whole breast for presumed occult disease. In the study by Veronesi et al. (1), the incidence of new cancers in the treated breast was similar to that in the contralateral breast (0.42 versus 0.66 per 100 person-years of observation, respectively), suggesting that elective treatment with radiation therapy beyond the quadrantectomy (i.e., surgical) bed provided minimal additional benefit. In the study by Fisher et al. (2), the rate of local recurrence beyond the first 5 years of treatment was similar regardless of the use of whole-breast radiation therapy, suggesting again that the efficacy of additional treatment with radiation therapy in preventing new cancers in the ipsilateral breast was minimal.

The importance of the current study is that it represents, to our knowledge, the largest group of patients treated with limited-field radiation therapy and it has the longest follow-up, which is critical in assessing the potential efficacy of limited-field radiation therapy before proceeding with phase III clinical trials. Clearly, there are statistical limitations associated with matched-pair analyses. For example, critical variables (i.e., length of follow-up, use of re-excision) that could affect outcome may not be balanced between treatment groups. Nevertheless, this type of analysis provides a reasonably objective estimate (short of a randomized trial) of the true efficacy of limited-field radiation therapy because all major prognostic factors associated with local recurrence were controlled for. Although the rate of contralateral breast failure was higher in patients treated with whole-breast radiation therapy, these results must be viewed cautiously because this study did not control for all potential variables that might affect the rate of contralateral failure in each treatment group.

Aside from the current study, several additional studies (12,15,30) have evaluated the efficacy of limited-field radiation therapy restricted to the region of the lumpectomy cavity (tumor bed) after conservative surgery. In the largest study (with the longest follow-up), King et al. (27) evaluated the efficacy of limited-field radiation therapy after conservative surgery in a series of 51 patients. With a median follow-up of 74 months, limited-field radiation therapy (using an interstitial implant) produced a 5-year actuarial rate of local recurrence of only 1.4%. Other studies (12,15) have reported similar results, but patient numbers and follow-up have been even smaller.

The success of these single-institution trials has led to the development and initiation of several phase III trials (31,32) exploring the efficacy of limited-field radiation therapy after conservative surgery using different techniques and radiation fractionation schedules. The European Institute of Oncology (Milan, Italy) is randomly assigning patients to receive either standard whole-breast radiation therapy delivered after quadrantectomy or quadrantectomy followed by a single, intra-operative fraction of radiation therapy (21 Gy) delivered exclusively to the quadrantectomy bed (31). At the National Institute of Oncology (Budapest, Hungary), patients are being randomly assigned to receive either standard whole-breast radiation therapy after surgery or partial-breast irradiation limited to the surgical bed delivered with an interstitial implant or external beam radiation therapy (26). Finally, at University College (London, U.K.), patients are being randomly assigned to receive either standard whole-breast radiation therapy after surgery or surgery followed by a single, intra-operative fraction of radiation therapy (5 Gy) (32). Although the radiation therapy techniques, doses, treatment volumes, and patient selection criteria differ substantially among the three trials, data from these studies will potentially provide invaluable information on the requisite volume of breast tissue requiring treatment and the range of patients appropriately managed with limited-field radiation therapy.

It is important to point out that limiting radiation therapy to the region of the tumor bed after conservative surgery can potentially have enormous advantages for women diagnosed with breast cancer. First, meta-analyses on the use of radiation therapy for breast cancer patients have shown a reduction in cancer-specific mortality during the first 5–10 years after treatment that is partially offset by the late effects of radiation therapy on adjacent tissues (30). Because it remains uncertain if the additional volume of normal tissue that is irradiated (to encompass the whole breast for presumed occult disease) provides any additional benefit in reducing breast cancer recurrence, the potential detrimental effects of additional radiation therapy might be of great concern. Second, a standard course of adjuvant radiation therapy after conservative surgery generally requires up to 6–7 weeks to complete, which can therefore cause a substantial burden to patients. Hence, if a simpler, less burdensome, and quicker technique for the delivery of radiation could be offered to patients with early-stage breast cancer, such an approach could theoretically increase the breast-conserving therapy option to more women and could offer the potential advantages of reduced treatment-related toxicities, improvements in the quality of life, and a logistically simpler and more practical method for breast-conserving therapy.

We thank Christina Mitchell, RN, and Michelle Wallace, RN, for their assistance in data management.


    REFERENCES
 Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Manuscript received January 31, 2003; revised June 16, 2003; accepted June 27, 2003.


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