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A correction has been published: N Engl J Med 2002;346(5):388.
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Background Radiotherapy prevents local recurrence of breast cancer after breast-conserving surgery. We evaluated the effect of a supplementary dose of radiation to the tumor bed on the rates of local recurrence among patients who received radiotherapy after breast-conserving surgery for early breast cancer.
Methods After lumpectomy and axillary dissection, patients with stage I or II breast cancer received 50 Gy of radiation to the whole breast in 2-Gy fractions over a five-week period. Patients with a microscopically complete excision were randomly assigned to receive either no further local treatment (2657 patients) or an additional localized dose of 16 Gy, usually given in eight fractions by means of an external electron beam (2661 patients).
Results During a median follow-up period of 5.1 years, local recurrences were observed in 182 of the 2657 patients in the standard-treatment group and 109 of the 2661 patients in the additional-radiation group. The five-year actuarial rates of local recurrence were 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), yielding a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose. Patients 40 years old or younger benefited most; at five years, their rate of local recurrence was 19.5 percent with standard treatment and 10.2 percent with additional radiation (hazard ratio, 0.46 [99 percent confidence interval, 0.23 to 0.89]; P=0.002). At five years in the age group 41 to 50 years old, no differences were found in rates of metastasis or overall survival (which were 87 and 91 percent, respectively).
Conclusions In patients with early breast cancer who undergo breast-conserving surgery and receive 50 Gy of radiation to the whole breast, an additional dose of 16 Gy of radiation to the tumor bed reduces the risk of local recurrence, especially in patients younger than 50 years of age.
In the absence of data from randomized trials, there is no uniformity in the dose of radiation and the schedules of fractionation that are used after breast-conserving surgery. To investigate the effect of an additional dose of radiation (a boost) aimed at the tumor bed after the administration of 50 Gy to the whole breast, the European Organization for Research and Treatment of Cancer (EORTC) designed the present trial. We report the first analysis of outcomes in patients with completely excised primary tumors who were randomly assigned to receive the standard therapy — 50 Gy of radiation to the whole breast — or standard therapy plus an additional dose of radiation of 16 Gy directed at the tumor bed.
Methods
Study Design
Between 1989 and 1996, we enrolled 5569 patients with stage I or II breast cancer who had undergone macroscopically complete surgical removal of the tumor and axillary dissection. The 5318 patients in whom the tumor had been completely excised on microscopical examination (as judged on the basis of the pathology report) were randomly assigned to undergo 50-Gy irradiation of the whole breast with or without an additional dose of 16 Gy to the tumor bed; 2661 patients were assigned to the additional-radiation group and 2657 to the standard-treatment group. Patients with a microscopically incomplete excision were assigned to receive booster doses of 10 or 26 Gy; these 251 patients were excluded from the analyses reported here. At randomization, patients were stratified according to age, menopausal status, the presence or absence of an intraductal component in and around the invasive tumor, clinical tumor size, clinical nodal status, and center. The sample size was calculated so as to give the study a 90 percent probability of detecting a 5 percent improvement in 10-year survival. An independent data monitoring committee was convened before 10 years had elapsed. The committee advised that we publish the data on local control of the cancer after a median of five years of follow-up, since a statistically significant effect of the higher dose of radiation on the rate of local recurrence was clearly demonstrated and since it was concluded that these results were unlikely to change with additional follow-up.
Eligibility
Patients with breast cancer of clinical stage T1–2,N0–1,M0 were eligible for the trial.11 Patients older than 70 years of age, or those with pure carcinoma in situ, multiple tumor foci in more than one quadrant, a history of other cancers, an Eastern Cooperative Oncology Group (ECOG) performance score higher than 2, residual microcalcifications on mammography, or gross residual disease in the breast after lumpectomy (unless reexcision had been performed) were ineligible. Oral informed consent was obtained according to the guidelines of the EORTC and the local and national rules of the participating centers. Patients came from 31 centers in nine countries. There were major violations of eligibility criteria in the cases of 26 patients — residual microcalcifications on postoperative mammography (6 patients), previous history of a malignant tumor (5 patients), pure intraductal carcinoma in situ (3 patients), stage T3 tumor (2 patients), clinically fixed axillary nodes (2 patients), and various other violations (8 patients). In addition, 107 patients were older than 70 years, and for 343 patients the delay between surgery and the start of radiotherapy was longer than that allowed by the protocol. The latter two groups were considered to have minor deviations from the protocol. All patients, whether eligible or ineligible, were included in the analysis.
Treatment
The protocol called for patients to undergo surgical excision of the primary tumor, with a 1-cm margin of macroscopically normal tissue (lumpectomy), and an axillary dissection. Any removal of additional breast tissue after the excision of the primary tumor was termed a reexcision, whether it was performed during the same session or later. Postoperative mammography was required if suspicious microcalcifications were seen before lumpectomy. The surfaces of specimens were routinely marked with India ink in the participating centers. Any invasive carcinoma that was found on microscopical examination to have crossed the inked margin was defined as incompletely excised. Patients with a microscopically incomplete excision underwent randomization separately to an additional dose of radiation of either 10 Gy or 26 Gy. Patients with axillary lymph-node involvement received adjuvant systemic therapy: premenopausal patients received chemotherapy, and postmenopausal patients received tamoxifen. Patients not given adjuvant chemotherapy began radiotherapy within nine weeks after lumpectomy. For patients who received adjuvant chemotherapy, a delay of up to six months before irradiation was allowed. Irradiation of the whole breast was performed with the use of two tangential megavoltage photon beams (high-energy x-ray or tele-cobalt). A total dose of 50 Gy over a five-week period, with a dose of 2 Gy per fraction, was delivered at the intersection of the central axes of the beams.12 The additional dose of 16 Gy was given to the center of the area from which the tumor had been excised; it was given in eight equal external-beam fractions with fast electrons or tangential photon fields, or alternatively, by means of an iridium-192 implant with a dose rate of 10 Gy per 24 hours.12,13,14,15
The target area for the additional dose of radiation was the site of the primary tumor, with a margin of 1.5 cm around the primary tumor after microscopically complete excision and of 3.0 cm after incomplete excision or in case of invasive cancer with extensive ductal carcinoma in situ.
Quality Assurance
At the start of the trial, the participating physicians received guidelines,13,14 a quality-assurance program was implemented to confirm that breast irradiation was carried out in a standard fashion in all centers,14,15,16,17 a team of physicists verified the calibration of the beams in the participating centers, and a program was set up for thermoluminescent dosimetry. If a major deviation between the calculated doses and the delivered doses was detected, a local audit was held to identify the reason. A central pathology review was performed by one pathologist at the Netherlands Cancer Institute.
Statistical Analysis
All analyses were conducted according to the intention-to-treat principle. The randomization was performed centrally at the EORTC Data Center by means of the minimization technique.18 The time to local recurrence was calculated from the date of randomization. All recurrences in the treated breast, before or after the detection of distant metastases, were taken into account. Data for patients who remained free of local disease were censored as of the date when the last follow-up information was obtained. The primary analysis of time-to-event end points was performed with the use of a two-sided log-rank test at the 5 percent level of significance.19
Analysis was performed on subgroups defined by the factors that had been used for stratification before randomization: age, menopausal status, presence or absence of ductal carcinoma in situ, clinical tumor size, and nodal status. The probability of event-free survival was estimated with the Kaplan–Meier technique. For the analysis of prognostic factors, we used a Cox proportional-hazards regression model, stratified according to treatment-group assignment.20 These latter analyses included all 5569 patients. Univariate and multivariate analyses were conducted to determine which factors were associated with local control of the cancer. A univariate analysis was conducted first, and then a backward-selection procedure was used to determine the composition of the multivariate models. Initially, all the variables that were significant at the 0.05 level in the univariate analysis were entered in the model. The least significant variables were then sequentially removed from the model. The last variables to be removed were checked for reentry into the model, in order to validate the final model. For the multivariate analyses, the models obtained with both the 0.05 and 0.01 levels of significance are described.
Results
Characteristics of the Patients, the Tumors, and the Treatments
Characteristics of the patients were similar in the two groups (Table 1). To achieve a microscopically complete resection, reexcision was required in 24 percent of the patients. In 99 percent of the patients, axillary dissection was performed. The median number of axillary nodes examined was 12 (range, 0 to 49), and in 60 percent of the patients more than 10 lymph nodes were examined. A total of 13 percent of the patients had a hematoma or breast infection as a complication. Another 17 percent had a seroma or an infection of the axillary wound. The median interval between lumpectomy and the start of radiotherapy was 39 days (range, 3 to 156) for patients who did not receive postoperative chemotherapy and 52 days (range, 14 to 469) for those who did receive postoperative chemotherapy. The median dose of radiation delivered to the tumor bed was 50 Gy (range, 2 to 73) in the standard-treatment group and 66 Gy (range, 23 to 79) in the additional-radiation group. Axillary irradiation was given to the 272 patients who did not undergo a complete axillary dissection or to patients with positive lymph nodes in the highest level of the axillary surgical specimen. Irradiation of the internal mammary lymph nodes was performed in 1089 of the patients. In the standard-treatment group, 53 (2 percent) nevertheless received an additional dose, and the treatment was not documented in 24 patients (1 percent). In the additional-radiation group, 26 patients (1 percent) received no additional dose and for 21 patients (0.8 percent) the information was missing. These patients' treatments were considered to be protocol violations; however, they were included in the intention-to-treat analysis. In 90 percent of the patients in this group, external irradiation was used for the additional dose (63 percent with electrons and 27 percent with photons), and in 8 percent an interstitial implant was used; no information was available on the method of delivery of the additional dose for the remaining 1 percent. Details regarding systemic adjuvant therapies are presented in Table 2.
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The median duration of follow-up was 5.1 years (maximum, 10.2 years), by which point 479 of the 5318 patients with a microscopically complete resection had died and 291 had had local recurrences.
Local Control
Local recurrence was observed in 182 of the 2657 patients assigned to receive only the initial 50 Gy of irradiation of the whole breast and in 109 of the 2661 patients assigned to receive 50 Gy plus an additional dose of 16 Gy. This incidence corresponds to five-year actuarial rates of local recurrence of 7.3 percent (95 percent confidence interval, 6.8 to 7.6 percent) and 4.3 percent (95 percent confidence interval, 3.8 to 4.7 percent), respectively (P<0.001), and a hazard ratio for local recurrence of 0.59 (99 percent confidence interval, 0.43 to 0.81) associated with an additional dose (Figure 1). Local recurrence was the first event in 5.9 percent of the patients in the standard-treatment group and 3.3 percent of those in the additional-radiation group. In the standard-treatment group, 18 local recurrences were reported after another recurrence (i.e., a distant metastasis, a regional metastasis, or contralateral breast cancer); 9 such events occurred in the additional-radiation group. Overall, 47 percent of the local recurrences occurred in the primary tumor bed, 9 percent in the scar, and 29 percent outside the area of the original tumor, and 27 percent were diffuse throughout the breast. Analyses of subgroups defined according to the stratification factors (Table 3) found the largest clinical benefit from the higher dose of radiation in patients 40 years old or younger (Figure 2). The benefit of the additional dose in local control was independent of whether the patients received adjuvant systemic treatment. The hazard ratio was 0.66 (99 percent confidence interval, 0.47 to 0.93; P=0.002) for patients who received no adjuvant treatment, and 0.40 (99 percent confidence interval, 0.20 to 0.81; P=0.001) for patients who received adjuvant treatment.
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In the univariate Cox proportional-hazards regression analysis, patients were stratified according to treatment-group assignment. The following factors had a significant negative effect on local control: young age, premenopausal status, large tumor size (as determined by palpation or as pathologically measured), incomplete first excision of the tumor, absence of estrogen or progesterone receptors, and lack of systemic adjuvant treatment. The variables that reached the 0.05 level of significance in association with age or local control for the overall population were entered in the first step of the multivariate model. Except for the duration of the interval between lumpectomy and the start of radiotherapy, the total dose to the tumor bed, and the use or nonuse of axillary irradiation, all variables were entered in the first step of the multivariate analysis. The backward-elimination process showed that three variables were significant at P<0.05: older age (P<0.001; hazard ratio, 0.59 [95 percent confidence interval, 0.48 to 0.71]), the presence of palpable tumors (P=0.007; hazard ratio, 2.14 [95 percent confidence interval, 1.23 to 3.72]), and the presence of a progesterone receptor (P=0.004; hazard ratio, 0.66 [95 percent confidence interval, 0.49 to 0.87]), which indicates that the risk of local recurrence was highest in younger patients (Figure 3), in those in whom the tumor was palpable, and in those who lacked progesterone receptors. At a significance level of 0.01, the model retained the same factors, but at a significance level of 0.001 it retained only age (P<0.001; hazard ratio, 0.56 [99 percent confidence interval, 0.51 to 0.68]).
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Salvage Treatment for Local Recurrences
Salvage treatment for local recurrences consisted primarily of total mastectomy; some patients underwent conservative salvage operations. Mastectomy and lumpectomy were performed in 131 and 24 patients, respectively, among the 182 patients with local recurrence in the standard-treatment group, and 82 and 11 patients, respectively, among the 109 patients with local recurrence in the additional-radiation group; 34 patients received systemic treatment alone or combined with hormonal therapy; and in 9 patients no information was available regarding salvage therapy.
Side Effects of the Booster Dose
The higher dose of radiation was expected to increase the incidence and the degree of fibrosis and cause an unsatisfactory cosmetic result. To date, we have not seen a significant difference in the grades of fibrosis, as scored by physicians on a four-point scale (with 0 indicating the absence of fibrosis and 3 indicating severe fibrosis) between the patients who received the additional dose and those who did not. The grades of fibrosis in the whole breast for patients in the standard-treatment and additional-radiation groups were as follows: 1288 patients (48 percent) and 1339 patients (50 percent), respectively, had no fibrosis; 991 (37 percent) and 908 (34 percent), respectively, had minor fibrosis; 236 (9 percent) and 261 (10 percent), respectively, had moderate fibrosis; 24 (1 percent) and 32 (1 percent), respectively, had severe fibrosis; and in 118 (4 percent) and 121 (5 percent), respectively, the grade of fibrosis was unknown. The cosmetic results were the subject of separate studies and have been published elsewhere.21,22 Excellent or good cosmetic results were obtained in 86 percent of the patients in the standard-treatment group, as compared with 71 percent of the patients in the additional-radiation group. No other side effects of the additional dose have been observed.
Survival and Causes of Death
Survival free of distant metastases and overall survival were similar in the two treatment groups (P=0.93 and P=0.63, respectively), with five-year rates of 87 percent and 91 percent, respectively, in both groups (Figure 3). No analysis of subgroups defined according to the stratification factors was conducted. The causes of death were also similar in the two treatment groups. Of the 479 deaths, 361 — 186 in the standard-treatment group and 175 in the additional-radiation group — were due to breast cancer.
Discussion
Multiple randomized trials have conclusively demonstrated that breast irradiation markedly reduces the rate of local recurrence after conservation surgery for breast cancer, but these studies did not deal with the dose or fractionation of radiation. The decision to deliver an additional localized dose of irradiation is based on the fact that most local recurrences occur within the vicinity of the primary tumor. For this reason, additional treatment was prescribed in all but one of the randomized trials that established the equivalence of breast-conserving and radical surgical therapy.1,2,3,4,5 However, the National Surgical Adjuvant Breast and Bowel Project trials limited the dose of radiation to 50 Gy when the excised tumor had microscopically negative margins, a practice that has been adopted as standard therapy in published guidelines.23 Our trial investigated the benefits and risks of adding an additional 16-Gy dose to this standard 50-Gy irradiation of the whole breast in patients with completely excised early breast cancer. We found that an additional dose to the primary tumor area nearly halved the annual odds of local recurrence (hazard ratio, 0.59). Preliminary data from a smaller trial are similar to ours.24
A 41 percent reduction in the rate of local recurrences is substantial in relative terms, but the absolute benefit of additional treatment depends on each patient's risk of recurrence after receiving the initial 50 Gy of radiation. The only factor we could associate with the extent of the benefit of additional treatment was age. Since the unfavorable influence of young age on the risk of local recurrence and overall survival is well established,25,26,27,28,29 it was not unexpected that patients 40 years old or younger would derive the greatest absolute benefit from additional treatment; the cumulative five-year rate of local recurrence was 19.5 percent without an additional dose and 10.2 percent with an additional dose. Our analysis also indicated that breast cancer in younger patients is more responsive to radiation, but there is no clear radiobiologic explanation for this. We do not suggest that additional treatment is ineffective in older patients, but its efficacy does decrease with increasing age, perhaps because in older patients local control after 50 Gy of irradiation of the whole breast alone is excellent. In our opinion, the absolute benefit of the additional dose justifies its use in patients 50 years old or younger.
The excellent local control found in this study was probably due, at least in part, to the intensive quality-assurance program that monitored surgical and radiotherapy procedures and the evaluation of pathology specimens. Unlike many other breast-cancer trials, this study did not involve the use of systemic adjuvant therapy in most patients, although such therapy has been shown to improve local control. We found that systemic adjuvant treatment reduced the rate of local recurrence (hazard ratio, 0.75), although its significance disappeared in the multivariate analysis. The contribution of the additional dose to improved local control was similar regardless of whether patients received systemic adjuvant treatment. Nevertheless, since the patients were not stratified according to the use or nonuse of such treatment, it cannot be considered a substitute for the additional dose, particularly in young patients.
There are indications that the improvement in local control associated with breast irradiation after breast-conserving surgery or mastectomy translates into a survival advantage.6,30,31,32 In our trial, however, the five-year survival rate was identical in the two treatment groups. We believe that a follow-up period of at least 10 years would be needed to find a difference in overall survival, and we plan to follow our patients for at least 10 years.
Soft-tissue sarcomas are rarely seen after breast irradiation (incidence, less than 0.5 percent).33 A slight increase in the incidence of contralateral breast cancer was observed in women treated with radiation after mastectomy, probably as a result of the small dose of "scatter" radiation to the other breast.34 An increase in the incidence of second malignant tumors as a consequence of the higher additional dose has not yet been observed in our trial. However, it is unlikely that the delivery of an additional 16-Gy dose to a limited volume of tissue, with the use of modern irradiation techniques, will lead to a measurable increase in the risk of such tumors from that associated with 50 Gy of irradiation of the whole breast.
We found no significant increase in the degree of fibrosis in the treated breast among women who received an additional dose of radiation. However, a panel consisting of surgeons, radiation oncologists, and laypersons concluded that excellent or good cosmetic results were obtained in 86 percent of the patients in the standard-treatment group at three years, as compared with 71 percent of those in the additional-radiation group. The additional dose was, however, not the only factor with a negative influence on the cosmetic outcome. Other factors included the location of the primary tumor, the size of the tumor, the volume of tissue excised, and any complications of surgery.21,22 A 5-year follow-up period is too short to allow a definitive analysis of late effects of radiation,35 and a further analysis will be performed at 10 years. The reduction in the incidence of local recurrences associated with the additional dose far outweighs the slight increase in the poorer cosmetic outcome, especially in patients younger than 50 years of age.
Supported by grants (5R10-CA11488 through 5U10-CA11488-30) from the National Cancer Institute. The content of the article is solely the responsibility of the authors and does not necessarily reflect the official views of the National Cancer Institute.
We are indebted to the following persons for their help in the concept and design of the trial and their active participation: E. van der Schueren, Leuven, Belgium; B. Pierquin, Paris; R.P. Müller, Cologne, Germany; J. Kurtz, Geneva; D. Morgan, Nottingham, United Kingdom; J.B. Dubois, Montpellier, France; E. Salamon, Namur, Belgium; R.O. Mirimanoff, Lausanne, Switzerland; J.W.H. Leer, Leiden, the Netherlands; M. Bolla, Grenoble, France; A. Kuten, Haifa, Israel; A. Renaud, La Louvière, Belgium; U. Schulz, Krefeld, Germany; P.C.M. Koper, Rotterdam, the Netherlands; D. Van den Weyngaert, Antwerp, Belgium; G.A. Storme, Brussels, Belgium; G.H.M. Calitchi, Creteil, France; W. Budach, Berlin, Germany; S. Roth, Düsseldorf, Germany; M. Poulsen, Brisbane, Australia; M.A. Dominguez, Pamplona, Spain; E. Monpetit, Vannes, France; F. Kovner, Tel Aviv, Israel; A. Biete Sola, Barcelona, Spain; P. Calvo, Madrid, Spain; and C. Vrieling, Amsterdam, the Netherlands; and to J.L. Peterse for pathology review.
Source Information
From the Department of Radiation Oncology, the Netherlands Cancer Institute, Amsterdam (H.B., J.B.); the Department of Radiation Oncology, Dr. Bernard Verbeeten Institute, Tilburg (P.P.); the Department of Radiation Oncology, University Hospital Utrecht, Utrecht (H.S.); the Department of Radiation Oncology, Radiotherapeutisch Institute Limburg, Heerlen (J.J.); and the Department of Radiation Oncology, Joint Center for Radiotherapy Arnhem–Nijmegen, St. Radboud Hospital, Nijmegen (W.H.) — all in the Netherlands; the Department of Radiation Oncology, Centre Georges-François Leclerc, Dijon (J.-C.H., I.B.); and the Department of Radiation Oncology, Institut Curie, Paris (A.F.) — both in France; and the Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven (W.V.B.); and the European Organization for Research and Treatment of Cancer, Brussels (L.C., M.P.) — both in Belgium.
Address reprint requests to Dr. Bartelink at the Department of Radiation Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands, or at h.bartelink{at}nki.nl.
References
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