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10.1245/ASO.2006.04.002
Annals of Surgical Oncology 13:794-801 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Tumor Bed Boost Omission After Negative Re-Excision in Breast-Conservation Treatment

Douglas W. Arthur, MD1, Laurie W. Cuttino, MD1, Andrew C. Neuschatz, MD2,3, Derrick T. Koo, MD1, Monica M. Morris, MD1, Harry D. Bear, MD, PhD4, Brian J. Kaplan, MD4, Kathy Dawson, PhD5 and David E. Wazer, MD2,3

1 Deparment of Radiation Oncology, Virginia Commonwealth University, Medical College of Virginia Campus, 401 College Street, Box 58, Richmond, Virginia 23298
2 Radiation Oncology, New England Medical Center, Tufts University School of Medicine, 750 Washington Street, Boston, Massachusetts 02111
3 Brown University School of Medicine, Rhode Island Hospital, 593 Eddy Street, Providence, Rhode Island 02903
4 Division of Surgical Oncology, Virginia Commonwealth University, Medical College of Virginia Campus, 401 College Street, Box 11, Richmond, Virginia 23298
5 Division of Biostatistics, Virginia Commonwealth University, Medical College of Virginia Campus, 401 College Street, Box 32, Richmond, Virginia 23298

Correspondence: Address correspondence and reprint requests to: Douglas W. Arthur, MD; E-mail: darthur{at}mcvh-vcu.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: We evaluated the necessity of a tumor bed boost after whole-breast radiotherapy for early-stage breast cancer after breast-conserving surgery and negative re-excision.

Methods: Of patients treated at the Virginia Commonwealth and Tufts Universities with breast-conservation therapy for early-stage breast cancer between 1983 and 1999, 205 required re-excision of the tumor cavity to obtain clear margins and were found to be without residual disease. Adjuvant conventionally fractionated whole-breast radiotherapy was given to a total dose of 50 Gy in 25 fractions. The tumor bed boost was omitted.

Results: The median follow-up was 98 months (range, 6–229 months). The tumor histological diagnosis was primarily infiltrating ductal carcinoma (183 cases; 89%). Nodal involvement was documented in 49 cases (24%). There were four documented recurrences at the tumor bed site. Five in-breast recurrences were documented to be in a location removed from the tumor bed. The overall Kaplan-Meier 15-year in-breast control rate was 92.4%, and the freedom from true recurrence rate was 97.6%.

Conclusions: The findings support the concept that postlumpectomy radiotherapy can be tailored according to the degree of surgical resection. There is an easily identifiable subgroup of patients who can avoid a tumor bed boost, thus resulting in a reduced treatment time and improved cosmesis, while maintaining local control rates that approach 100%. The data suggest that in patients who undergo a negative re-excision, treatment with whole-breast radiotherapy to 50 Gy is a sufficient dose to maximally reduce the risk of local recurrence.

Key Words: Breast-conservation therapy • Radiotherapy • Lumpectomy • Radiation boost


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
After lumpectomy, with or without adjuvant radiotherapy, the site of failure within the breast is predominantly at the site of the primary tumor removal.1–4 The location of the in-breast failure after treatment has become of interest, because it has been suggested that a true recurrence/marginal miss (in-breast failure at the site of lumpectomy) represents a true recurrence of the primary disease, whereas an "elsewhere failure" (in-breast failure at a location removed from the site of lumpectomy) represents the development of a new primary lesion.5–8 Although not always reported, the incidence of disease failure within the breast but beyond the region of lumpectomy, so-called elsewhere failures, after breast-conserving treatment remains consistent, at 1% to 5%, and occurs at this rate with or without whole-breast radiotherapy.8–10 Although controversial, it has been suggested that these failures represent new primary disease. This implies that the benefit of whole-breast radiotherapy is solely at the site of initial involvement.11 Because the rate of elsewhere failures seems to be consistent regardless of treatment and because the variability of overall in-breast failures is dependent on the rate of true recurrence, it could be postulated that local control rates are directly related to the relative aggressiveness of the combined treatment approach used in treating the tumor bed. This more aggressive treatment can take the form of either more extensive surgery or higher doses of radiotherapy. As a result, the practice of breast-conservation treatment has evolved from gross tumor excision followed by moderate-dose whole-breast radiotherapy to complete excision of the primary lesion with microscopically negative margins followed by whole-breast radiotherapy with the addition of a boost dose delivered to the lumpectomy site plus margin.

As local control rates have improved, it is unknown whether to credit an improved surgical approach, the boost dose delivered, or the combination. The cost-effectiveness of using a boost has been challenged,12 and, until recently, there has been little evidence relating improved local control rates to the additional dose delivered with a tumor bed boost. Recent reports of three prospective randomized trials investigating the application of an electron boost versus no electron boost to the tumor bed show statistically significant improvements in local control.13–15 Although boosting the initially involved area of the breast results in improved control rates, a question that remains is whether all patients potentially benefit or whether a subgroup of good-prognosis patients can be identified in whom the boost dose could be safely omitted. The selective omission of the boost would reduce the time and cost of treatment. Although not all boost studies suggest an adverse effect on cosmesis, the omission of a boost could result in improved cosmetic outcomes for those women.15

Tufts/Brown Universities, since 1983, and Virginia Commonwealth University, since 1989, have treated early-stage breast cancer patients according to a margin-directed boost treatment policy.16–21 The design of this treatment policy was based on the assumption that as the microscopically measured surgical margin of the lumpectomy specimen decreased, the amount of residual microscopic disease remaining in the breast at the site of lumpectomy increased. Therefore, the level of radiation dose delivered as a boost was increased for narrower margins. Conversely, as the measured microscopic surgical margin increased, the boost dose could be decreased. Unique to this policy was that a boost dose was omitted altogether if the surgeon performed a re-excision as a separate procedure and no residual disease was encountered. The safety of omitting the boost dose in a subgroup of patients is the focus of this study. This is a report on the combined breast-conserving treatment experience in a select group of patients with early-stage breast cancer. All patients had a negative re-excision and whole-breast radiotherapy only. No additional boost dose was delivered. Patient and tumor characteristics in relationship to treatment outcome were analyzed.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Radiation Treatment
Between 1983 and 1999, patients with a diagnosis of stage I and II breast carcinoma at the Virginia Commonwealth, Tufts, and Brown Universities were treated according to a prospectively applied, margin-directed boost treatment policy that has been described previously.16–21 After treatment options were discussed and informed consent for treatment was obtained, all patients were initially treated according to policy with 50 to 50.4 Gy in 25 to 28 fractions. An additional dose to the surgical bed was individualized for each patient and was dependent on the surgical margin measured at the time of microscopic examination of the excision specimen. With a microscopic margin of >5 mm, patients received an additional electron boost dose of 10 Gy in 5 fractions; for a margin of 2 to 5 mm, they received an additional 14 to 16 Gy in 7 to 8 fractions; and if the surgical margin was <2 mm, an additional 20 Gy was delivered with electrons in 10 fractions or by brachytherapy implants. At all institutions, a re-excision of the lumpectomy cavity was routinely performed when the microscopic margin assessment of the lumpectomy specimen revealed a positive margin or if the initial margins were indeterminate. If, after thorough pathologic evaluation, no disease was encountered in the re-excision specimen, the surgical bed boost was omitted from the radiation treatment course. This report focuses only on the patients who underwent a re-excision that was documented to be free of malignancy.

During the time interval studied, 204 patients with 205 stage I or II breast carcinomas were treated with whole-breast radiotherapy only after a re-excision of the lumpectomy cavity in which no malignant cells were documented to be present in the re-excision specimen. Seventy-nine of these patients were treated at the Virginia Commonwealth University, and 126 were treated at Tufts and Brown Universities.21 With institutional review board approval, this treatment experience was reviewed to evaluate whether a surgical bed boost can be omitted in properly selected patients. All patients were treated with a 4- or 6-MV linear accelerator delivering 50 to 50.4 Gy in 25 to 28 fractions. Medial and lateral tangential fields were used to treat the entire breast. The breast tissue extent and treatment coverage of breast tissue were determined clinically. Before 1989, wedges were the only form of compensation used. After 1989, dose homogeneity was maximized by using multislice computed tomography–based planning coupled with lung correction, wedges, and custom lead compensation. No boost dose was delivered in this select group of women.

Systemic Therapy
Systemic therapy was delivered at the discretion of the medical oncologist involved in each case. Typically, cyclophosphamide, methotrexate, and fluorouracil or doxorubicin-based regimens were administered. Most patients started chemotherapy after recovering from surgery, and radiotherapy was delivered after the completion of chemotherapy. Tamoxifen was added with increasing frequency through the treatment experience. Initially, patients were selected on the basis of menopausal status and disease stage; however, decisions to start tamoxifen increasingly became dependent on estrogen receptor status alone. As shown in Table 1Go, 47 patients received adjuvant chemotherapy, 75 received tamoxifen, and 102 patients did not receive any form of systemic therapy.


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  		TABLE 1. Patient and treatment characteristics
 
Follow-Up
Patients were seen 1 month after treatment to ensure resolution of acute toxicity. Each patient was then followed up at 3-month intervals for 2 years, at 6-month intervals until 5 years, and then yearly thereafter. Mammograms were obtained at 6 months after treatment and then yearly. Patients were evaluated for possible in-breast, regional, and/or distant failures. All in-breast failures were confirmed pathologically and further defined as true recurrences or elsewhere failures on the basis of the location within the treated breast.5 True recurrences were defined as recurrent disease encountered in the treated breast at or immediately adjacent to the site of lumpectomy. Elsewhere failures were defined as disease failure in the treated breast anywhere beyond the lumpectomy site and immediately surrounding breast tissue.

Statistical Evaluation
Kaplan-Meier (K-M) curves were generated to summarize the survival rates over time. Several event times were considered in this study (time to death, true recurrence, in-breast failure, and distant failure).22 For each event, an overall K-M curve was generated that included 95% confidence intervals. To examine the possible relationship between patient characteristics and outcome, values were collapsed into two strata. Age was divided into <50 and ≥ 50 years, and tumor size was divided into ≤ 1 and >1 cm. The addition of chemotherapy and/or tamoxifen was also evaluated.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
This unique patient cohort was made up of 205 treated breasts. The median age of the 204 patients was 55 years (range, 27–84 years). All had infiltrating histological characteristics, with infiltrating ductal carcinoma in 89%. Most lesions (77%) were <2 cm, and all of these patients had a pathologically negative re-excision performed as a separate procedure after the original lumpectomy. All patients had axillary node evaluation, and 76% were determined to be node negative. Patient characteristics are listed in Table 1Go. All patients completed radiation treatment delivery. Minimal to moderate skin toxicity was encountered, as expected, and was managed with conservative skin care.

The median follow-up for the entire patient cohort was 98 months, with a range of 6 to 229 months. The 15-year K-M disease-free survival was 78%, and overall survival was 82.4%, with a significantly lower K-M overall survival rate in patients who presented with positive nodes as compared with those who presented with negative nodes (50% vs. 92%, respectively; P < .001). Distant metastases were documented in 22 patients. There were only nine in-breast failures, and the 15-year K-M in-breast control rate was 92.4%. As a result of the low rate of in-breast failures, there was no detectable effect of local failure on the actuarial disease-free or overall survival. There was no difference in outcome related to tumor size. Age <50 years had a negative effect on local control, with an in-breast disease control rate of 87% for women <50 years versus 96% for women ≥50 years (P = .0158). There were seven in-breast failures in women <50 years old, of which only three were considered true recurrences and in the immediate vicinity of the lumpectomy site. As expected, patients with positive nodes experienced a worse distant disease-free and overall survival, and the use of tamoxifen improved survival.

To assess the potential effect of the addition of a boost dose to the surgical bed, attention was given to the location of in-breast failure. Of the nine in-breast failures, only four were documented to be true recurrences; the remaining five were registered as elsewhere failures. The 15-year K-M true recurrence–free rate was 97.5%, and the elsewhere failure–free rate was 94.6%. Although not statistically assessable because of the few events encountered, a potential difference in the time to true recurrence and time to elsewhere failure was noted, as shown in Table 2Go. All true recurrences were encountered within the first 5 years of follow-up, whereas four out of the five elsewhere failures occurred between 7 and 11 years after treatment. The ages of those who experienced an in-breast failure were similar between those documented to have a true recurrence (35, 46, 47, and 54 years old) and an elsewhere failure (27, 45, 46, 49, and 55 years old). The possible effect of systemic management on the local failure rate and pattern is depicted in Table 3Go. Although review of the crude in-breast failure numbers suggests that women who did not receive systemic therapy experienced treatment failure more frequently, the differences were not statistically significant on analysis. Furthermore, because the decisions to add systemic therapy or not were based on multiple tumor and patient risk factors, comparisons based on treatment may not be meaningful. There were no contralateral breast failures documented in this group of patients.


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  		TABLE 2. Interval (months) to in-breast failure
 

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  		TABLE 3. Systemic treatment versus failure pattern
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The addition of a boost dose to the surgical bed after whole-breast radiotherapy in early-stage breast cancer has been controversial. To deliver a boost or not, the definition and localization of the boost target, the method of dose delivery, the level of the boost dose, and the perceived benefit versus the costs (economic and cosmetic) are some of the issues that have been continually debated.23–25 Those opposed to a boost often reference the results of the National Surgical Adjuvant Breast and Bowel Project B-06 trial, which randomized patients to mastectomy versus lumpectomy only versus lumpectomy followed by whole-breast radiotherapy. No boost dose was used. Local control rates with lumpectomy followed by radiotherapy not only were superior to those with lumpectomy alone, but were also statistically comparable to the local control rates achieved with mastectomy and were comparable to the local control rates that have been reported when a boost was incorporated in the treatment scheme.26 Negative margins for this trial were essentially defined as "no tumor on ink," without reference to the distance of the tumor from the surgical margin. However, it is often overlooked that doses >50 Gy were frequently delivered as a result of the technical methods of dose delivery. In this trial, uncompensated tangential fields (no wedge filters used) were prescribed to midplane at a point two thirds of the distance from the skin to the base of the tangent at the central axis.27 As a result, the anterior aspect of the treated breast received a daily dose and total dose that exceeded the prescription dose, thus making it likely that doses >50 Gy were often delivered to the surgical bed. The degree of this inhomogeneity would have been variable, because it is dependent on the size and shape of the breast, but this effect is difficult to quantitate. This consequence was further accentuated in patients treated with cobalt 60. Therefore, the homogeneous dose now delivered with wedge filters, customized lead compensation, or intensity-modulated radiotherapy does not compare to the inhomogeneous doses delivered in that study, and, therefore, it may be inappropriate to use the results of National Surgical Adjuvant Breast and Bowel Project B-06 to justify boost omission.

In contrast, physicians who advocate the addition of a boost have historically based their decision on the rationale that most in-breast failures occur at the site of lumpectomy and that a higher rate of local control should be achieved by increasing the dose delivered to the area where the burden of microscopic disease is the greatest. Results from three prospective randomized trials suggest that this hypothesis is valid, and a statistically significant improvement in local control can be demonstrated when a boost dose is applied.13–15 The first of these studies was published in 1997 from Lyon, France.13 In this trial, 1024 patients with invasive breast cancer ≤3 cm in size were prospectively randomized to receive whole-breast radiotherapy plus or minus a tumor bed boost. All patients were treated with whole-breast wedge-compensated tangential fields to 50 Gy delivered in 2.5-Gy fractions, 4 days per week over 5 weeks. Those randomized to a tumor bed boost then received a boost of 10 Gy delivered in four fractions. Fields were designed and the dose was prescribed on the basis of clinical assessment of the target. The median follow-up was 3.3 years. The 5-year actuarial local failure rate was 3.6% if a boost was delivered and was 4.5% if no additional dose was delivered (P = .044). There was no difference in disease-free survival or overall survival between the two groups.

Polgar et al.14 reported on a prospective randomized trial in which 104 patients received whole-breast radiotherapy to 50 Gy followed by a tumor bed boost and 103 patients received whole-breast radiotherapy to 50 Gy only. Microscopic margin assessment was not a requirement for this study. The tumor bed boost was delivered as 16 Gy with electrons or 12 to 14.5 Gy with high-dose-rate brachytherapy. At a median follow-up of 5.3 years, the crude rate of local recurrence was 6.7% (7 of 104) with and 15.5% (16 of 103) without a boost, and the 5-year probability of local control was 92.7% vs. 84.9% (P = .049), respectively.

The European Organization for Research and Treatment of Cancer (EORTC) has reported on a large prospective randomized trial that evaluated disease recurrence rates after breast-conservation treatment with or without the delivery of additional radiation (>50 Gy).15 All 5569 patients had stage I or II breast cancer and underwent macroscopic tumor resection. Boost dose levels were dependent on microscopic assessment; patients were divided into those with microscopically complete and microscopically incomplete resection. Only the 5318 patients who had a microscopically complete resection were included in this article. Patients were randomly assigned to 50 Gy of whole-breast radiotherapy only or 50 Gy of whole-breast radiotherapy followed by a 16-Gy electron boost. The dose was delivered at a rate of 2 Gy per fraction. With a median follow-up of 5.1 years, the overall 5-year actuarial local failure rate was 4.3% in those who received a boost and 7.3% in those who did not (P < .001). Overall, 5.5% of patients experienced an in-breast failure. This was composed of a true-recurrence incidence of 2.6% (47% of in-breast failures were located in the tumor bed) and an elsewhere failure incidence of 2.9% (53% of in-breast failures located at a distance from the tumor bed). The local control benefit achieved with the addition of a boost was age dependent. The largest benefit was realized in patients <40 years old, with a nonsignificant benefit in patients >60 years old. In patients <40 years old, the local recurrence rate was 19.5% without and 10.2% with a boost (P = .002); for those >60 years old, local recurrence rates were 4.0% without and 2.5% with a boost (P = .14). However, local control is not the only factor to consider. In a previous report, the EORTC evaluated the effect that this additional dose had on the cosmetic outcome. The boost dose had a negative effect on cosmetic outcome when evaluated at 3 years.28,29

These prospective randomized trials demonstrate that the addition of a tumor bed boost improves local control rates, but potentially, as suggested at least by the EORTC, at the cost of a worsened cosmetic outcome. The absolute improvement in local control was in the range of 2% to 4% in the two trials that required microscopically negative surgical margins, but it is not clear whether all patients require a boost to maximize local control or whether there is a subset of patients in whom a boost can be omitted without compromising disease control. An increase in the overall treatment cost, coupled with data suggesting a negative effect on cosmetic outcome, implies that it may be desirable to omit a boost in selected patients if a reliable method of identifying which patients do and do not benefit from doses delivered >50 Gy can be established. The EORTC data suggest that age >60 years could be used as a determining factor; however, by making treatment recommendations based on generalized patient groupings, one loses the ability to individualize treatment delivery according to tumor characteristics for a specific patient who may benefit from additional doses >50 Gy. Presently, we lack the investigative tools needed to identify and quantify residual disease accurately after lumpectomy and thus provide the information necessary to tailor treatment delivery and provide the ability to define the amount of surgery and/or the dose level needed to optimize disease control on an individual basis. The best surrogate to date is the pathologic evaluation of the lumpectomy specimen, because it provides the best method currently available for estimating the risk of residual microscopic disease in each patient. In support of this concept, patients documented to have positive microscopic margins are reported to have higher local failure rates after standard radiation treatment.21 At the other end of the spectrum, a negative re-excision represents the lowest risk or amount of residual microscopic disease that would be encountered. The dose most commonly used to treat a region that is at risk for microscopic disease is 45 to 50 Gy, and it stands to reason that in this group of patients, in whom the amount of disease has been surgically reduced to a level of minimal risk, additional doses > 50 Gy would not be necessary to achieve excellent control rates.

The use of the pathologic assessment results to determine whether or not a boost is necessary was suggested by Pezner et al.30 in their treatment experience with early-stage breast cancer. In this group of patients, lumpectomy was followed by 50 Gy delivered to the entire breast without a tumor bed boost. Tumor-free inked specimen margins were achieved in all of the 153 breasts treated. The reported actuarial 5-year local control rate was 95%. A local control rate of 96% was experienced in patients for whom clear margins were achieved at the time of the initial resection. Patients who achieved clear margins at re-excision were found to have a local control rate of 94%; however, if no residual cancer was seen in the re-excision specimen, then the local control rate was 97%, as opposed to 88% when residual cancer was found.

The patient cohort evaluated in this article represents a unique data set in which, in all of the 205 cases, a negative re-excision was documented and no additional dose was delivered >50 Gy. The local disease failure pattern suggests that this represents a subgroup of patients in whom the residual tumor burden has been reduced to a minimal level and eradicated with 50 Gy delivered to the entire breast in most cases. At the 5-year follow-up interval, the in-breast control rate was 97%. With additional follow-up, the true recurrence–free rate remained at 97%; however, the overall in-breast control rate decreased to 93% as a result of elsewhere failures. As Table 2Go suggests, treatment experiences with ≤5-year follow-up may find an increase in the in-breast failure rate with additional follow-up as the rate of elsewhere failures, probably representing new primary disease, continues to increase. The frequency of elsewhere failures would not have been altered with the addition of a tumor bed boost, because the elsewhere failures occurred beyond the boundaries of a reasonable electron field. In this study, whether or not a tumor bed boost should be added in women <50 years old is also questionable. Although an increased incidence of in-breast failure is documented, when evaluated more closely, most of these in-breast failures are located elsewhere within the breast, and, therefore, the effect of adding a tumor bed boost is uncertain.

When the location of the in-breast failure and the potential effect of the addition of a tumor bed boost within this patient cohort were evaluated, the rate of true recurrence (within a standard boost field) was only 2.5%, as compared with the elsewhere failure rate of 5.4%. It should be noted that the evaluation and documentation of local recurrence can be a difficult task, and this may be viewed as a limitation of this study. Although all patients were followed up closely, the discovery of a distant metastasis often overshadows the surveillance of the treated breast for subsequent local failures, and the continuance of mammographic follow-up and thorough breast examination documentation may become inconsistent. For similar reasons, the data generated with actuarial analysis of local failures should also be accepted with the acknowledgment that the outcome data may represent an underestimate of local failure rates. However, this is consistent with many studies that consider in-breast tumor recurrences only when they occur as first events. The reliability of actuarial analysis is based on the censoring mechanism being independent of the event of interest. An actuarial survival analysis is concerned with examining the time until death. If, at the time of analysis, this event has not occurred, then the patient is censored at the time of last follow-up, with the important assumption that the event will occur at some point. However, when the time to local recurrence is studied, patients are censored at the time of last follow-up and at the time of death with and without disease. We certainly cannot assume that if these patients were to continue to live, a local recurrence would occur at some point in time. As a result, the accuracy of the actuarial local failure analysis is limited by the fact that the event of interest is dependent on the censoring events.31

Optimal in-breast control rates and cosmetic outcomes seen in breast-conservation therapy for early-stage breast cancer result from an appropriate balance between the extent of surgical resection and the intensity of postlumpectomy radiotherapy. The data presented in this article suggest that the extent of postlumpectomy radiotherapy can be limited by omitting a tumor bed boost in patients who undergo a thorough surgical resection, signified by a re-excision with no residual malignancy identified. It is recognized that the reliability of this conclusion is based on a complete re-excision of the tumor bed and pathologic assessment of the re-excision specimen. If either of these two essential components is lacking, then a tumor bed boost should be considered. By identifying a subgroup of patients for whom the tumor bed boost can be safely omitted, we are able to tailor treatment delivery better to the individual patient. This will allow the ability to maintain excellent local control rates while avoiding any potential negative cosmetic effects and reduce both the overall treatment time and cost associated with the additional dose delivered >50 Gy.

Received for publication April 1, 2005. Accepted for publication November 21, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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