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© 2001 American Society for Clinical Oncology Differences in Risk Factors for Local and Distant Recurrence After Breast-Conserving Therapy or Mastectomy for Stage I and II Breast Cancer: Pooled Results of Two Large European Randomized TrialsFrom the Eindhoven Cancer Registry, Departments of Pathology, Radiation Oncology, and Surgery, the Netherlands Cancer Institute, Eindhoven; and Department of Radiation Oncology, Academic Medical Center, Amsterdam, the Netherlands; Departments of Pathology and Surgery, Rigshospitalet, Copenhagen, and Department of Radiation Oncology, Aarhus University Hospital, Aarhus, Denmark; and European Organization for Research and Treatment of Cancer Data Center, Brussels, Belgium. Address reprint requests to Joop van Dongen, MD, PhD, Department of Surgery, the Netherlands Cancer Institute/Antoni van Leeuwenhoekhuis, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; email: j.v.dongen{at}ikz.nl
PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P < .01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P < .01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P < .01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.
BREAST-CONSERVING therapy (BCT) and modified radical mastectomy (RM) for patients with early-stage carcinoma of the breast were compared in several prospective randomized trials carried out during the 1970s and 1980s.1-6 After 5 to 10 years of follow-up, none of these trials revealed a significant difference in overall survival or distant disease-free survival. These favorable results, which have been confirmed in a meta-analysis,7 explain why BCT is now considered routine procedure in most hospitals. When deciding between RM and BCT, the main concerns for both the physician and the patient are the cosmetic outcome and the risk of local recurrence in the preserved breast. In view of the fact that local recurrence is a distressing experience that—in most cases—requires salvage mastectomy, many authors have tried to identify factors associated with the increased risk of recurrence. The most important factors that are thought to be associated with local recurrence after BCT are as follows: young age (ie, <35 to 40 years),8-15 infiltrating tumor with an extensive intraductal component (EIC),15-19 vascular invasion,14,20 and microscopic involvement of the excision margins.11,21-24 As a consequence, many patients with one or a combination of these factors are offered RM instead of BCT. The reason is that the risk factors for local recurrence after BCT are assumed to play no or a much less significant role in the development of local recurrence after RM. However, local recurrence is also seen after RM, the risk being equal to or only slightly smaller than that after conservative surgery and radiotherapy according to randomized clinical trials. The risk factors for local recurrence after BCT and RM probably have a great overlap, but differences may exist. To optimize the selection of patients for either therapy, better understanding of such differences in the risk patterns for local recurrence is crucial. The best way to compare risk factors for local recurrence after BCT and RM is within the setting of a randomized clinical trial because random assignment of the two surgical procedures will create a more equal distribution of potential risk factors within the treatment groups. Furthermore, in trials, much attention is paid to the standardization of therapy. This is important because therapy technique is also a major prognostic factor for local control of disease. In the first half of the 1980s, the Breast Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer (EORTC) and the Danish Breast Cancer Cooperative Group (DBCG) each started a randomized trial, designated as the EORTC 10801 and DBCG-82TM protocols respectively, to investigate the efficacy of BCT compared with RM in stage I and II breast cancer. In both trials, BCT comprised attempted complete tumor excision, axillary dissection, 50-Gy whole-breast irradiation, and a booster dose to the tumor bed. Because of the relatively low risk of local recurrence, the numbers in the separate trials were too small to perform a thorough analysis of risk factors.5,6,25 To increase the statistical power, the data from the EORTC and DBCG trials were pooled. By linking the data sets, a study group of 1,772 patients was created with a median follow-up of 9.8 years. Uniform pathological evaluation of the primary tumor was performed for most of the cases of both trials to obtain information on a wide range of potential risk factors for local recurrence. The data offered an ideal opportunity to compare risk factors for local and distant recurrence after BCT and RM and to define guidelines for the decision making between both treatments.
Patients The study designs of the trials of the EORTC and the DBCG have been described in greater detail in earlier publications.5,6,25 The EORTC trial was started in 1980 and closed in 1986. During that period, 901 patients with stage I or II breast cancer were randomly assigned to either BCT or RM. Randomization was performed centrally by the EORTC Data Center in Brussels, stratified according to center, stage, and menopausal status. The DBCG trial was open for patient accrual from January 1983 to March 1989, and 905 patients were randomized. Randomization, which was decentralized, was carried out according to the principle of Zelen; in other words, randomization took place preoperatively and before the surgeon discussed the type of treatment with the patient. In the DBCG trial, however, there was a built-in proviso that patients randomly allocated to one surgical procedure could ask for the alternate operation in case of a strong preference. In both trials, the clinical tumor diameter was more than 2 cm in more than 50% of the cases. The exclusion criteria were comparable. The EORTC trial excluded patients 71 years or older; the DBCG trial, those 70 years or older. Other exclusion criteria were as follows: sarcoma of the breast or carcinoma in situ, signs of multicentricity by palpation or mammography, fixation of the tumor to the muscles, evidence of metastatic disease, concomitant malignancy or a history of other malignancies, and factors that precluded a satisfactory cosmetic outcome, such as a large tumor in a small breast. After randomization, seven patients (1%) had to be excluded from the DBCG trial and 27 (3%) from the EORTC trial. The main reasons for ineligibility were a too-advanced tumor stage or incorrect diagnosis. Thus, by combining the two trials 1,772 patients were available for analysis. Of these, 879 patients underwent BCT, and 893, RM. In the DBCG trial, 33 patients randomly assigned to RM desired BCT, and 55 patients initially allocated to BCT decided to undergo RM. In the EORTC trial 15 patients underwent BCT after having been randomized to the RM arm, and 13 patients assigned to BCT underwent RM.
Treatment In both trials, breast-conserving surgery was followed by whole-breast irradiation (generally starting within 2-6 weeks of surgery) with a prescribed dose of 50 Gy and an additional booster dose to the tumor bed. In the DBCG trial, the boost was given by external electron beams, and the applied dose was 10 or 25 Gy, depending on whether or not the surgical margins were microscopically tumor free. In the EORTC trial, the booster dose was administered by Iridium-192 implants and varied from 20 to 25 Gy, depending on the institute. In both trials, postmastectomy radiotherapy to the chest wall (50 Gy) was only given to high-risk groups showing locally incomplete operation and/or metastatic axillary lymph nodes. Irradiation of the axilla, parasternal, and subclavicular and supraclavicular lymph node regions, following either BCT or RM, was also restricted to these high-risk groups. Details on surgical and adjuvant systemic treatment have been presented elsewhere.5,6,25
Review
Statistical Analyses
No differences were observed in the distribution of age and disease characteristics when comparing patients according to treatment actually given ( Table 1).
During follow-up, 299 patients died after BCT and 297 after RM. There were 79 patients with local recurrence after BCT, 19 of whom (24%) simultaneously developed distant metastases, and 80 patients with local recurrence after RM, 26 of whom (33%) simultaneously showed distant metastases. Other characteristics of the patients with local recurrence after BCT and RM are presented in Table 2.
Distant metastases developed in 292 patients after BCT, compared with in 276 patients after RM. Actuarial local recurrence-free, distant recurrence-free, and overall survival rates at 5 and 10 years were not significantly different between BCT and RM ( Table 3). Table 1 shows the number and the 10-year actuarial rates of local recurrence and distant metastasis after BCT and RM according to age of the patient, size of the primary tumor, nodal status, histologic type, grade, presence of vascular invasion, and microscopic margin involvement.
Prognostic Factors for Local Recurrence Analysis by the Cox proportional hazards model, according to treatment actually given, demonstrated that patients no more than 35 years of age at surgery had a 9.24-times higher risk of developing local recurrence after BCT compared with that of patients older than 60 years (95% confidence interval [CI], 3.74 to 22.81; Table 4). After RM, however, the patients 35 years old or younger did not exhibit an increased risk of local recurrence compared with patients older than 60 years (hazard ratio [HR], 0.64; 95% CI, 0.15 to 2.71) (Table 4). The 10-year actuarial rate of local recurrence for patients 35 years or younger was 7% after mastectomy and 35% after BCT (Table 1). The risk of local recurrence after BCT for infiltrating ductal carcinomas with EIC was 2.52 times higher than that of those without EIC (95% CI, 1.26 to 5.00; Table 4); the 10-year actuarial rates were 21% and 9%, respectively (Table 1 and Fig 1a). After RM, infiltrating ductal carcinoma with EIC did not exhibit an increased risk of local recurrence, whereas lobular carcinoma was associated with a 2.69-times higher risk of recurrence (95% CI, 1.17 to 6.21) (Table 4). For these groups, the 10-year actuarial rates were 6% and 18% respectively (Table 1 and Fig 1b). The relative risk of local recurrence for patients with vascular invasion compared with those without vascular invasion was 2.3 after BCT as well as after RM (Table 4). As a consequence, the 10-year actuarial rates of local recurrence after BCT and RM were the same: 15% for patients with vascular invasion and 8% for those without vascular invasion (Table 1 and Fig 2). No significant associations were found between tumor size, nodal status, and histologic grade and the risk of local recurrence after either BCT or RM (Table 4). Further, risk of local recurrence was not significantly increased for patients showing microscopic involvement of the excision margins after BCT (Table 4).
Prognostic Factors for Distant Disease According to the results of the multivariate Cox proportional hazards survival analysis, tumor size, nodal status, histologic grade, and vascular invasion were all highly significant predictors of distant disease after BCT and RM ( Table 5). Histologic type was not significantly related to the risk of distant disease, neither after BCT nor after RM (Table 5). Young age and microscopic involvement of the excision margins were additional, independent predictors of distant disease after BCT (Table 5). For patients no more than 35 years of age, the risk of developing distant disease was more than twice that for patients at least 60 years old (95% CI, 1.26 to 3.96), and for patients with microscopic involvement of the excision margins, the risk of distant disease was 1.75 times higher than that for patients with tumor-free margins (95% CI, 1.17 to 2.62). The 10-year actuarial risk of distant disease after BCT was 60% for patients with microscopically involved margins, compared with 29% for those with tumor-free margins (Table 1).
The combined results of the trials of the EORTC and the DBCG demonstrate equal rates of local and distant recurrence after breast-conserving treatment (ie, tumor excision, followed by whole breast irradiation and a booster dose to the tumor bed) and RM for patients with stage I and II breast cancer after a median follow-up of 10 years, which is in agreement with the long-term results of other trials.29-32 Recently, a separate analysis of the EORTC-trial again has demonstrated similar survival rates after a median follow-up of 13.4 years.33 The objective of the present study was to compare risk factors for local and distant recurrence after BCT and RM; for this purpose, a randomized trial is the most appropriate setting. The results indicate that some of the local recurrences after BCT and RM can be attributed to the same features. Some risk factors, however, are specific for local recurrence after BCT and others for local recurrence after distant metastases, and these are the ones that can be used to define the guidelines for optimum local treatment. In the current study, age no more than 35 years and the presence of an EIC were associated with an increased risk of local recurrence after BCT, whereas lobular carcinoma appeared to be associated with a higher risk of local recurrence after RM. Notwithstanding the small numbers in this age group, younger patients had a significantly higher risk of local recurrence after BCT than did those >60 years. After 35 years, the risk decreased sharply, indicating that certain risk factors are typical of the younger age group. Although a number of histopathologic and treatment-related factors have been analyzed in an attempt to explain the higher risk of local recurrence after BCT for younger patients,13,15,19,34 the exact mechanism underlying this risk remains elusive. Just like young age, EIC is also an established risk factor for local recurrence after BCT,15-19 and as shown by our results, the higher risk is not present after RM. EIC has been demonstrated to be associated with prominent residual intraductal cancer in the breast.35,36 More recent studies have reported that EIC is no longer of prognostic value if negative margins can be obtained.14,23,37 Wide excisions are therefore recommended for patients with a tumor with EIC. However, especially for patients with larger tumors, more extensive procedures often are not compatible with an acceptable cosmetic result. Vascular invasion and, to a lesser extent, high histologic grade appeared to cause an increased risk of local recurrence, irrespective of the type of primary treatment. Apparently, some of the recurrences after BCT and RM are the result of a similar disease mechanism that is not affected by the extent of the primary treatment. Axillary nodal involvement does not appear to be associated with an increased risk of local recurrence, neither after BCT nor after RM, which may be the result of the adjuvant systemic treatment administered to the majority of the node-positive patients. A favorable effect of adjuvant systemic treatment on local recurrence risk has been suggested by several investigators.30,38,39 Moreover, for the node-positive patients in the RM group, the relatively low risk of chest wall recurrence might also be explained by the effect of adjuvant radiotherapy to the chest wall,40 which was given to the majority of this group. Lobular carcinoma appeared to be associated with an increased risk of local recurrence after RM, whereas no increased risk was seen after BCT. Satisfactory results of BCT for lobular carcinoma have also been noted by others41-44 and may reflect a higher sensitivity of lobular carcinoma to radiation. In contrast to BCT, RM was only followed by radiotherapy for high-risk patients, which might thus explain the relatively high risk of local recurrence after RM (17%) for patients with lobular carcinoma. The current study showed no independent predictive effect of microscopic involvement of the excision margins on the risk of local recurrence after BCT. The most likely explanation is the relatively high booster doses delivered to the primary tumor area, ranging from 20 to 25 Gy in the EORTC trial and from 10 to 25 Gy in the trial of the DBCG (depending on whether or not the surgical margins were microscopically tumor free), which may have eradicated most of the cancer foci left behind after a microscopically nonradical excision. Another explanation relates to the technical limitations of the evaluation of resection margins of the tumor specimens. Preferably, margin involvement is assessed on inked, fresh tissue. Retrospective evaluation is considered less accurate because of the limited number of slides that usually are available for review. It is therefore possible that sampling error has led to underestimation of the frequency of involved tumor margins, thus weakening the association with local recurrence. Although most local recurrences developed in the first 5 years after treatment, they also developed later, especially in the BCT group. In another report of the EORTC and DBCG trials, the prognosis of patients with an early locoregional recurrence after BCT appeared to be similar to that of patients with locoregional recurrence after RM.45 This strongly suggests that early locoregional relapses after BCT and RM have the same biologic characteristics. The late local recurrences after BCT, the majority of which occur at a clear distance from the primary tumor bed, probably represent second primary tumors with their own risk factors and a better prognosis than early recurrences. It seems likely that adequate local treatment will reduce the number of true recurrences but will have much less effect on the development of new primary tumors. As expected, the predictors for distant disease and the associated relative risks after BCT and RM were largely comparable. In addition to tumor size and nodal status, vascular invasion (ie, lymph vessel and/or angioinvasion) and histologic grade appeared to be of great value as independent predictors of the development of distant disease. Various studies have described a worse overall survival rate and an increased rate of distant metastases among patients with high histologic grade26,46-48 or vascular invasion, as measured by microvessel count.49-51 A striking finding was the fact that the risk of distant disease after BCT was nearly twice as high for patients with microscopically involved margins. Other investigators have also found a significant relationship between margin involvement and the risk of distant disease,14,23,24 which indicates that margin involvement in some way may be a marker of the aggressiveness of the tumor. Patients 35 years of age or younger appeared to have an increased risk of distant disease. The increased risk was much more prominent after BCT. In view of the high risk of local recurrence after BCT, the question arises whether local recurrence might be a source of distant spread in some patients in the youngest age group. Unfortunately, numbers in the current study did not allow us to find the answer to this question. The adverse effect of young age on prognosis has been noted in several other studies13,19,52-56 and suggests that breast cancer in younger women is a biologically more aggressive disease, possibly requiring more aggressive initial treatment. The favorable outcome of this study indicates that BCT, carried out according to the techniques described in this report, is a safe treatment option for the majority of patients with operable stage I and II breast cancer. However, from the viewpoint of local control, mastectomy may be preferred for patients with tumors containing an extensive intraductal component. The higher risk of local recurrence after BCT for patients 35 years of age or younger warrants further study to rule out the possibility of a negative impact of breast conservation on the survival of individual patients. Although histologic grade and vascular invasion are important predictors for the risk of distant failure, they appear to be of little value in making the decision between BCT and RM.
Supported by the Departments of Radiation Oncology and Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands, and the Danish Cancer Society, Copenhagen, Denmark. We are indebted to all collaborating investigators from the following participating hospitals: for the EORTC 10801 trial : Guy’s Hospital, London, United Kingdom; Netherlands Cancer Institute, Amsterdam, the Netherlands; University Hospital Gasthuisberg, Leuven, Belgium; University Hospital Tijgerberg, Republic of South Africa; Dr Daniël den Hoed Cancer Centre, Rotterdam, the Netherlands; St Lucas Hospital, Amsterdam, the Netherlands; Maria Hospital, Tilburg, the Netherlands; and University Hospital St Jan, Brugge, Belgium; for the DBCG-82TM trial: Aalborg Hospital, Aarhus University Hospital, Bispebjerg Municipal Hospital, Esbjerg Hospital, Finsen Institute, Frederiksberg Hospital, Frederikssund Hospital, Give Hospital, Glostrup Hospital, Grindsted Hospital, Hillerød Hospital, Horsens Hospital, Hoersholm Hospital, Odense University Hospital, Randers Hospital, Silkeborg Hospital, Skive Hospital, Vejle Hospital, and Viborg Hospital, all in Denmark.
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ABSTRACT
INTRODUCTION
