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© 1999 American Society for Clinical Oncology 10-Year Results After Sector Resection With or Without Postoperative Radiotherapy for Stage I Breast Cancer: A Randomized TrialFrom the Department of Surgery, Örebro Medical Center Hospital, Örebro; Departments of Surgery, Oncology, and Pathology, University Hospital, Uppsala; Departments of Pathology and Mammography, Falu Hospital, Falun; Department of Medical Epidemiology, Karolinska Institute, Stockholm, Sweden; and the Department of Epidemiology and Harvard Center for Cancer Prevention, Harvard School of Public Health, Boston, MA. Address reprint requests to Göran Liljegren, MD, PhD, Department of Surgery, Örebro Medical Center Hospital, S-701 85 Örebro, Sweden; email goran.liljegren{at}orebroll.se
PURPOSE: To study the long-term effectiveness of postoperative radiotherapy after sector resection for breast cancer in a randomized trial in which mammography is a major pathway to diagnosis.
PATIENTS AND METHODS: Three hundred eighty-one women with a unifocal breast cancer RESULTS: The local recurrence rate was 8.5% (95% confidence interval [CI], 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (P = .0001). Survival free from regional and distant recurrence was 83.3% in the XRT group (95% CI, 77.5% to 89.1%) and 80.0% in the non-XRT group (95% CI, 73.9% to 86.1%) (P = .23). Overall survival was 77.5% in the XRT group (95% CI, 70.9% to 84.1%) and 78% in the non-XRT group (95% CI, 71.7% to 84.3%) (P = .99). A subgroup analysis suggested that women older than 55 years of age without comedo or lobular carcinomas had a low risk of local recurrence of 6.1% (95% CI, 0.1% to 9.1%) in the XRT-group and 11.0% (4.0% to 18.0%) in the non-XRT group (P = .16). CONCLUSION: Sector resection plus radiotherapy resulted in an absolute reduction in local recurrence of 16% at 10 years compared with surgery alone. Women older than 55 years of age without comedo or lobular carcinomas may have a low risk of local recurrence. Postoperative radiotherapy was not shown to reduce distant recurrences or improve overall survival.
THE LONG-TERM effectiveness of routine postoperative radiotherapy after breast-conserving treatment of breast cancer has not previously been assessed in clinical trials carried out in the era of mammography screening or in patients treated surgically by a standardized sector resection. We report 10-year results of a clinical trial in which patients with stage I1 breast cancer were randomized to postoperative radiotherapy or follow-up only after sector resection with a strictly standardized technique and meticulous confirmation of complete excision.2 We also update an analysis of risk factors for local recurrence3 that attempted to define a subgroup of women who are at low risk for local relapse, even without postoperative radiotherapy.
Study Design The study design has previously been described in detail.4 Women younger than 80 years with a unifocal, mammographically visible breast cancer and with a maximal tumor diameter of 20 mm or less on the preoperative mammogram were eligible. All patients were subjected to a standardized sector resection, as previously described.5 Nonpalpable lesions were localized by the wire-hook technique6 or by the stereotactic application of dye (coal or methylene blue).7 To ensure complete tumor excision, the protocol stipulated perioperative x-ray of the specimen. The axilla was dissected to levels I and II.8 No adjuvant systemic therapy was given. Patients were eligible for randomization provided that the specimen was histopathologically free from multifocal in situ lesions and from invasive lesions outside 20 mm from the border of the primary tumor. The axillary nodes were required to be histopathologically free from metastases. Patients were ineligible if the tumor was transected during surgery. Full informed consent was required. The study was approved by the ethical committees with jurisdiction for the participating centers.
Randomization
Radiotherapy
Patient Accrual
Patient Selection
Evaluation Procedures
Estimates of disease-free survival took into account all types of regional and distant metastases (including regional recurrences in the axilla). Every patient contributed person-years to the date of the type of recurrence analyzed, regardless of whether another type of event preceded it; eg, if a local recurrence developed first, the patient was still eligible for analysis of distant metastases after the local recurrence. In two patients, death from disseminated disease was the first sign of relapse. In the analysis of risk factors for local recurrence, all histopathologic slides were reevaluated by the study pathologist (A.L.). To validate the histopathologic classification of tumor type, the slides from one of the participating centers (n = 71) were reevaluated by a second pathologist (H.N.). The preoperative mammograms and the perioperative specimen x-rays were reevaluated by the study mammographer (L.T.). Both pathologists and the mammographer were blinded to the patient outcome. All patient records were reviewed for identification of patient characteristics, tumor characteristics, and events during the primary treatment.
Definition of Evaluation Variables
Histopathologic tumor characteristics (Table 2).
Tumors containing intraductal carcinoma both inside and outside the index tumor were classified as positive for extensive intraductal component (EIC+). All other tumors were considered to be EIC-negative (EIC-). Tumors with estrogen receptor and progesterone receptor levels Mammographic tumor characteristics. The mammographic appearance on the preoperative mammogram was classified into five groups according to the appearance of the density (stellate or circular/oval), the presence of microcalcifications (inside or outside the density), and the presence of more than one tumor. In addition, parenchymal pattern on the preoperative mammogram was classified into five groups12 according to an evolution of Wolfe's patterns.13 We separated Wolfe's pattern DY into two groups, patterns 1 and 5. Our pattern 1 may be compared to Wolfe's QDY pattern, our pattern 2 is identical to Wolfe's N1 pattern, and our pattern 3 is identical to Wolfe's P1. Our pattern 4 matches Wolfe's P2 pattern, and pattern 5 corresponds to Wolfe's DY pattern. Pattern 1 may change into pattern 2 (ie, entirely fatty) or pattern 3 (ie, retroareolar linear pattern due to periductal elastosis) during a woman's lifetime. Mammographic tumor characteristics are listed in Table 3.
Statistical Analyses
Local Recurrences During the follow-up period, a local recurrence developed in 57 patients, 13 of whom had been randomized to the XRT group. Of these 13 women, one received no radiotherapy due to postoperative infection, whereas two other women refused radiotherapy. A fourth woman developed a local relapse during radiotherapy, at which time her therapy was discontinued. After 10 years, the local recurrence rate was 8.5% (95% CI, 3.9% to 13.1%) in the XRT group and 24.0% (95% CI, 17.6% to 30.4%) in the non-XRT group (Fig 1). The life-table curves were statistically significantly different (P = .0001). The estimated difference between the recurrence rates in the two groups at 10 years was 15.5% (95% CI, 13.7 to 17.3%). This difference implies that the number of patients who must be treated with postoperative radiotherapy to prevent one local recurrence (number needed to treat) is six. Thirty-eight (67%) of all local recurrences occurred in the surgical field. Two were in the cuticular scar, and two were in the skin overlying the surgical field. Thirteen tumor recurrences developed in the breast parenchyma outside the field of surgery, and one was in an intramammary lymph node. Five recurring tumors were multifocal; in one instance, the tumor was a lymphangiosarcoma in an irradiated breast. Three of the recurrences were in situ carcinomas.
In the XRT group, 10 of 13 women with local recurrences were treated with mastectomy. In the non-XRT group, 14 women with a local recurrence were treated with a second breast-conserving procedure, and postoperative radiotherapy was given to nine of these women. The remaining 30 women underwent mastectomy. Systemic treatment was administered to five women with a local recurrence in each treatment group. Two of the women from the XRT group received CMF combination chemotherapy (ie, intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2) in nine courses at 3-weekly intervals; the others were treated with tamoxifen (20 mg/d) for a minimum of 2 years.
Regional and/or Distant Recurrence
Contralateral Breast Cancer
Survival
Risk Factors for Local Recurrence Histopathologic tumor characteristics: univariate analysis (Table 2). Presence of a comedo type cancer was associated with a statistically increased risk for local recurrence compared with tubuloductal and ductal cancers (RH = 3.60; 95% CI, 2.0 to 6.4). The lobular type was also associated with a higher risk of local recurrence than that of the tubuloductal and ductal type (RH = 3.2; 95% CI, 1.4 to 7.1) Besides histopathologic type, lymphatic/vascular invasion compared with no lymphatic/vascular invasion (RH = 1.9; 95% CI, 1.1 to 3.5) and high tumor grade compared with intermediate and low tumor grade (RH = 2.5; 95% CI, 1.4 to 4.7) were the only other histopathologic statistically significant risk factors for a local recurrence. Validation of the histopathology by the second pathologist (H.N.) resulted in the same histopathologic type in 89% of the cases. Mammographic characteristics: univariate analysis (Table 3). Risk of local recurrence was higher if the tumor on the mammogram appeared as a circular/oval-shaped density compared with a stellate lesion (RH = 2.5; 95% CI, 1.4 to 4.5). Mammographic appearance of a stellate lesion with microcalcifications inside the lesion and microcalcifications outside the lesion were also associated with a higher risk of local recurrence compared with the appearance of a stellate lesion, but with wider confidence intervals. Mammographic parenchymal patterns (modified Wolfe's pattern), mammographic signs of multifocality, or margin less than 10 mm on the specimen x-ray were not identified as risk factors of local recurrence. Multivariate analysis. A multivariate Cox proportional hazards survival analysis of the risk factors that reached or approached statistical significance in the univariate analysis was also performed (Table 4). In the analysis, adjustment was made for treatment group and operation year. First age was analyzed, followed by stepwise introduction of tumor size, tumor grade, vessel invasion, and histopathologic type. Age was identified as a statistically significant risk factor with a 3% risk reduction per year of increasing age in all five models. High tumor grade elevated the risk by approximately 2.5 times in two of the three models in which it was used, but it was not a statistically significant risk factor when histopathologic type was also included in the multivariate model. When histopathologic type was introduced, the comedo type elevated the risk by 2.2 times and the lobular type by 2.5 times compared with tubuloductal and ductal type. Tumor size and vessel invasion were not significant risk factors for local recurrence in the multivariate analysis, nor were any of the mammographic risk factors that were statistically significant or that approached statistical significance in the univariate analysis (data not shown).
Identification of a low-risk population. Based on the risk factor analysis, we carried out a life-table analysis in a subgroup of women who were older than 55 years of age and without comedo or lobular carcinomas (46% of the study population; Fig 4). Among these women, the 10-year local recurrence rate was 6.1% (95% CI, 0.1% to 12.1%) in the XRT group and 11.0% (95% CI, 4.0% to 18.0%) in the non-XRT group. These two life-table curves were not statistically significantly different (P = .16). The difference between the groups implies that 20 women must be treated with postoperative radiotherapy to prevent one local recurrence in this subgroup of patients (number needed to treat = 20).
For the present analysis, several manual checks revealed that eight patients with medial located tumors, seven of whom were in the XRT group, received radiotherapy to parasternal lymph nodes. A reanalysis with those patient excluded did not change the presented results.
Since this trial started in 1981, five other randomized clinical trials have evaluated the role of routine postoperative radiotherapy after breast-conserving surgery.18-23 All of them, including a meta-analysis,24 show that postoperative radiotherapy to the remaining breast improves local tumor control but has no evident impact on survival. Our study is the only of these trials that explores the efficacy of routine postoperative radiotherapy in patients with stage I breast cancer and mammography as the main route to diagnosis. Our trial was designed to show whether a meticulous surgical technique can replace postoperative adjuvant radiotherapy to obtain local tumor control after breast-conserving surgery. The results from this study compared with the primary aim demonstrate that radiotherapy still should be standard therapy. However, we found a lower local recurrence rate in both treatment arms than in trials using lumpectomy rather than sector resection.19-23 Thus the surgical technique may influence local control independent of radiotherapy.2,18,20,23 Differences in the local recurrence rates between trials may also reflect patient selection. A substantial proportion (45%) of the participants in our study had their cancers detected at mammography screening. Hence, our results are likely to be applicable in a setting in which there is a mammography screening program in operation. Contrary to Clark et al,22 we identified a tentative subgroup with a low risk of local recurrence at 10 years. The prospective studies from the Milan Cancer Institute18,20 as well as several retrospective studies25-29 have identified low age as a risk factor. Because our study design stipulated the same meticulous surgical control of radicality for all patients, our findings contradict the idea that increase in risk with lower age is due to confounding by wider indications for breast conservation and lesser resections in younger patients. We speculate that higher levels of estrogen—and to some extent, progesterone—stimulate growth factors (insulin-like growth factor 1, insulin-like growth factor 2, epidermal growth factor, and transforming growth factor alpha) in stroma and epithelial cells.30 Also, the comedo and lobular type of tumors have been associated with higher risk for local relapse, but only in retrospective studies.31-36 The results from analyses on the association between mammographic characteristics and risk for recurrence have been conflicting,37-39 and our own results point only toward weak associations that tend to disappear after correction for histopathologic findings. Our results indicate that in a subgroup of patients, the cost-effectiveness of routine use of radiotherapy to the breast after a sector resection is low,40 because recurrence rate without irradiation is only approximately 1% per year. Our ad hoc–developed criteria are straightforward and can be independently tested in other clinical trials with ease. Any decision not to irradiate must be made after careful consideration of the clinical characteristics, surgical treatment, nature of the disease, and patient preferences. Older age cannot be used as the only criterion; the operative procedure must be locally radical, and the disease should be unifocal and stage I. Clearly, our results do not apply to patients with more advanced disease and do not address the effectiveness of radiotherapy given to regional lymph nodes, demonstrating survival gains by the addition of postoperative radiotherapy.24,41,42 In the patient domain evaluated in this clinical trial and in which mammography is a main route to diagnosis, the absolute gain by routine addition of postoperative radiotherapy is a reduction of local recurrences by approximately 16% at 10 years. Our trial was not designed to explore survival differences and cannot rule out a small advantage in survival by the addition of postoperative radiotherapy after sector resection.
Protocol committee: H.O. Adami, S. Graffman, L. Holmberg. Principal investigators: L. Holmberg, H.O. Adami, G. Liljegren. Study coordinators: G. Liljegren, L. Holmberg. Preparation of manuscript: G. Liljegren, L. Holmberg, J. Bergh, A. Lindgren, L. Tabár, H. Nordgren, H.O. Adami. Participating investigators: Central Hospital, Falun: A. Cohen, U. Ljungqvist; Department of Surgery, A. Lindgren, Department of Pathology, L. Tabár, Department of Mammography. Central Hospital, Västerås: L. Bergkvist, Department of Surgery; L. Johansson, Department of Oncology. University Hospital, Uppsala: L. Holmberg, Department of Surgery, J. Bergh, T. Jansson, Department of Oncology, H. Nordgren, Department of Pathology. Central Hospital, Eskilstuna: Å. Rimsten, Department of Surgery; B. Stenstam, Department of Oncology. Central Hospital, Karlstad: T. Jahnberg, Department of Surgery; M. Söderberg, Department of Oncology. Örebro Medical Center Hospital: G. Liljegren, Department of Surgery; G. Westman, Department of Oncology. Karolinska Institute, Stockholm: H.O. Adami, Department of Medical Epidemiology. Consulting statistician: B. Huitfeldt.
This study was supported by grants from the Swedish Cancer Society (project no. 1266-B94-15XEE) and from the Örebro County Medical Research Fund (project no. 200136). We thank A. Jennische, Department of Surgery, University Hospital, Uppsala, Sweden, for devoted and high-quality secretarial assistance.
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Ragaz J, Jackson SM, Nuh L, et al: Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med337:956-962, 1997 Submitted October 26, 1998; accepted April 14, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
20 mm in diameter on the preoperative mammogram and without histopathologic signs of axillary metastases were treated by sector resection plus axillary dissection. Of these patients, 184 women were randomized to receive postoperative radiotherapy to the breast (XRT group), and 197 women received no further treatment (non-XRT group). 
5 years ago. Mode of tumor detection was classified as either detected via screening or detected due to the presence of symptoms. Patient characteristics are listed in 
