Effect of adjuvant systemic treatment on cosmetic outcome and late normal-tissue reactions after breast conservation

To investigate whether adjuvant treatment with CMF or tamoxifen predisposes to an unfavorable cosmetic outcome or increased breast morbidity after radiotherapy in breast conservation. Data from 266 patients who entered a randomized breast conservation trial (DBCG-82TM protocol) was analyzed. The patients were treated with lumpectomy and axillary dissection followed by external beam radiotherapy to the residual breast. High-risk patients (n = 94), as well as 31 low-risk patients, received additional radiation to the regional lymph nodes. Adjuvant systemic treatment was given to all high-risk patients: premenopausal patients (n = 67) received eight cycles of CMF intravenously (600/40/600 mg per m2) every fourth week; postmenopausal patients (n = 27) received 30 mg of tamoxifen daily for one year. Clinical assessments included cosmetic outcome, breast fibrosis, skin telangiectasia, and dyspigmentation which were scored on a 4-point categorical scale after median 6.6 years. The observations were analyzed in multivariate logistic regression analysis which included potential risk factors on outcome related to systemic treatment, surgery, radiation technique, tumor, and patient characteristics. In premenopausal patients, systemic treatment with CMF independently predicted a fair/poor cosmetic outcome, RR = 2.2 (95% CI 1.2-4.2), as well as increased skin telangiectasia, RR = 3.3 (1.4-8.2). There was no impact of tamoxifen treatment on cosmetic outcome in postmenopausal patients (p = 0.32). However, univariate analysis showed that tamoxifen was significantly associated with breast fibrosis (p < 0.004), as was radiation to the regional lymph nodes (p < 0.0001). A strong interaction between axillary irradiation and tamoxifen treatment occurred since 26 of 27 high-risk postmenopausal patients had received both tamoxifen and axillary irradiation. In multivariate regression analysis, axillary irradiation independently predicted moderate/severe breast fibrosis with a relative risk of 5.0 (2.0-12.5) and 9.6 (3.3-27.7) in premenopausal and postmenopausal patients, respectively. To circumvent the strong interaction between tamoxifen treatment and axillary irradiation, a subsequent analysis omitting axillary treatment from the multivariate regression showed a significant effect of both tamoxifen and CMF on the occurrence of breast fibrosis with relative risks of 5.3 (CI 1.8-15.8) and 4.4 (1.8-10.3), respectively. Adjuvant systemic treatment with CMF given sequentially to radiotherapy independently predicted an adverse cosmetic outcome as well as increased skin telangiectasia after breast conserving treatment. Due to a strong interaction between tamoxifen administration and radiation to the regional lymph nodes, the effect of tamoxifen on the development of fibrosis could not be fully discerned in this study. Axillary irradiation increased the incidence of moderate to severe breast fibrosis in both premenopausal and postmenopausal patients.