Johansen Jørgen, Overgaard Jens, Overgaard Marie
Department of Oncology, Odense University Hospital, Odense, Denmark.
Acta Oncol. 2007;46(4):525-33. doi: 10.1080/02841860701291698.
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.
为研究在保乳放疗后，CMF或他莫昔芬辅助治疗是否会导致不良的美容效果或增加乳腺发病率。分析了266例进入随机保乳试验（DBCG - 82TM方案）患者的数据。患者接受肿块切除术和腋窝淋巴结清扫术，随后对残留乳腺进行外照射放疗。高危患者（n = 94）以及31例低危患者接受了区域淋巴结的额外放疗。所有高危患者均接受辅助全身治疗：绝经前患者（n = 67）每四周静脉注射8个周期的CMF（每平方米600/40/600mg）；绝经后患者（n = 27）每天服用30mg他莫昔芬，持续一年。临床评估包括美容效果、乳腺纤维化、皮肤毛细血管扩张和色素沉着异常，在中位时间6.6年后采用4分分类量表进行评分。观察结果在多因素逻辑回归分析中进行分析，该分析包括与全身治疗、手术、放疗技术、肿瘤和患者特征相关的结局潜在危险因素。在绝经前患者中，CMF全身治疗独立预测美容效果为一般/差，RR = 2.2（95%CI 1.2 - 4.2），以及皮肤毛细血管扩张增加，RR = 3.3（1.4 - 8.2）。他莫昔芬治疗对绝经后患者的美容效果没有影响（p = 0.32）。然而，单因素分析显示他莫昔芬与乳腺纤维化显著相关（p < 0.004），区域淋巴结放疗也是如此（p < 0.0001）。由于27例高危绝经后患者中有26例同时接受了他莫昔芬和腋窝放疗，腋窝放疗与他莫昔芬治疗之间存在强烈的相互作用。在多因素回归分析中，腋窝放疗独立预测绝经前和绝经后患者中度/重度乳腺纤维化的相对风险分别为5.0（2.0 - 12.5）和9.6（3.3 - 27.7）。为规避他莫昔芬治疗与腋窝放疗之间的强烈相互作用，随后一项从多因素回归中省略腋窝治疗的分析显示，他莫昔芬和CMF对乳腺纤维化发生均有显著影响，相对风险分别为5.3（CI 1.8 - 15.8）和4.4（1.8 - 10.3）。保乳治疗后，放疗后序贯给予CMF辅助全身治疗独立预测不良美容效果以及皮肤毛细血管扩张增加。由于他莫昔芬给药与区域淋巴结放疗之间存在强烈相互作用，本研究中他莫昔芬对纤维化发展的影响无法完全辨别。腋窝放疗增加了绝经前和绝经后患者中度至重度乳腺纤维化的发生率。
