多西他赛(多西紫杉醇)等紫杉类化疗药物对脂肪组织的亲和力较高,进入人体以后主要分布于脂肪组织,而非肿瘤组织,故胖瘦可能影响疗效。不过,胖瘦对早期乳腺癌术后多西他赛辅助化疗患者长期生存结局的影响尚不明确。
2020年7月2日,美国临床肿瘤学会《临床肿瘤学杂志》在线发表比利时鲁汶大学、布鲁塞尔自由大学、意大利米兰大学、国家肿瘤研究院、欧洲肿瘤研究院、普拉托医院、托斯卡纳肿瘤研究所、法国亨利·贝克勒尔癌症中心、爱尔兰都柏林大学圣文森特医院、澳大利亚墨尔本大学圣文森特医院彼得·麦卡伦癌症中心、纽卡斯尔大学、澳大利亚和新西兰乳腺癌研究协作组的国际乳腺癌协作组(BIG)02/98研究长期随访报告,根据化疗前体重指数,对早期乳腺癌术后多西他赛与非多西他赛辅助化疗患者的十年生存结局进行了比较。
BIG 02/98: An Intergroup Phase III Trial to Evaluate the Activity of Docetaxel, Given Either Sequentially or in Combination With Doxorubicin, Followed by CMF, in Comparison to Doxorubicin Alone or in Combination With Cyclophosphamide, Followed by CMF, in the Adjuvant Treatment of Node-positive Breast Cancer Patients (NCT00174655)
该国际多中心三期临床研究于1998年6月~2001年6月从21个国家入组早期早期乳腺癌术后患者2887例,按1∶1∶2∶2的比例随机分为4组进行辅助化疗:
多柔比星→环磷酰胺+甲氨蝶呤+氟尿嘧啶(CMF)
多柔比星+环磷酰胺→CMF
多柔比星→多西他赛→CMF
多柔比星+多西他赛→CMF
体重指数等于体重÷身高平方,是国际常用的人体胖瘦程度衡量指标。该研究将全部患者按化疗前体重指数分为3类:
正常:体重指数18.5~24.9kg/m²
超重:体重指数25.0~29.9kg/m²
肥胖:体重指数≥30kg/m²
主要研究终点为无病生存,次要研究终点为总体生存。对不同的治疗方案、体重指数、雌激素受体状态进行二级相互影响分析。
结果,经过中位10.1年随访,非多西他赛组不同体重指数患者相比,无病生存或总体生存比例相似。
多西他赛组患者随着体重指数增加,无病生存和总体生存比例减少、发病死亡和总体死亡风险增加:
体重指数超重与正常的患者相比:
发病死亡风险高12%(校正后风险比:1.12,95%置信区间:0.98~1.50,P=0.21)
总体死亡风险高27%(校正后风险比:1.27,95%置信区间:1.01~1.60,P=0.04)
体重指数肥胖与正常的患者相比:
发病死亡风险高32%(校正后风险比:1.32,95%置信区间:1.08~1.62,P=0.007)
总体死亡风险高63%(校正后风险比:1.63,95%置信区间:1.27~2.09,P<0.001)
对于雌激素受体阴性、雌激素受体阳性、多西他赛相对剂量强度≥85%的患者进行分析,可以获得相似结果。
如果同时考虑体重指数和雌激素受体状态,对无病生存和总体生存的影响显著(校正后P=0.06和0.04)。
因此,该大样本回顾研究结果表明,体重指数可以影响早期乳腺癌术后多西他赛辅助化疗患者的长期生存结局,故有必要对其他乳腺癌和其他紫杉类治疗方案开展进一步研究,根据人体脂肪比例对紫杉类药物治疗乳腺癌的风险效益比进行重新评估。
J Clin Oncol. 2020 Jul 2. Online ahead of print.
Differential Benefit of Adjuvant Docetaxel-Based Chemotherapy in Patients With Early Breast Cancer According to Baseline Body Mass Index.
Desmedt C, Fornili M, Clatot F, Demicheli R, De Bortoli D, Di Leo A, Viale G, de Azambuja E, Crown J, Francis PA, Sotiriou C, Piccart M, Biganzoli E.
Laboratory for Translational Breast Cancer Research, Leuven, Belgium; Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; University of Milan, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; European Institute of Oncology, University of Milan, Milan, Italy; Hospital of Prato, Instituto Toscano Tumori, Prato, Italy; Centre Henri Becquerel, Rouen, France; St Vincent's University Hospital, Dublin, Ireland; Peter MacCallum Cancer Centre, St Vincent's Hospital, University of Melbourne, Australia; Breast Cancer Trials Australia and New Zealand, University of Newcastle, Australia.
PURPOSE: Lipophilic drugs, such as taxanes, have a high affinity for adipose tissue and a resulting higher volume of distribution. Here, we reanalyzed clinical trial data to investigate whether the efficacy of docetaxel-based chemotherapy differs from non-docetaxel-based chemotherapy in patients with breast cancer according to their baseline body mass index (BMI).
PATIENTS AND METHODS: We retrospectively analyzed data from all of the patients in the adjuvant BIG 2-98 trial (N = 2,887) comparing non-docetaxel- to docetaxel-containing chemotherapy. BMI (kg/m2) was categorized as follows: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Disease-free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint. A second-order interaction was assessed among treatment, BMI, and estrogen receptor (ER) status.
RESULTS: There was no difference in DFS or OS according to BMI in the non-docetaxel group, while reduced DFS and OS were observed with increasing BMI category in the docetaxel group. Adjusted hazard ratios for DFS and OS were, respectively, 1.12 (95% CI, 0.98 to 1.50; P = .21) and 1.27 (95% CI, 1.01 to 1.60; P = .04) for overweight versus lean groups and were 1.32 (95% CI, 1.08 to 1.62; P = .007) and 1.63 (95% CI, 1.27 to 2.09; P < .001), respectively, for obese versus lean groups. Similar results were obtained when considering ER-negative and ER-positive tumors separately and when considering only patients who received a relative dose intensity ≥ 85% for docetaxel. A joint modifying role of BMI and ER status on treatment effect was evident for DFS (adjusted P = .06) and OS (adjusted P = .04).
CONCLUSION: This retrospective analysis of a large adjuvant trial highlights a differential response to docetaxel according to BMI, which calls for a body composition-based re-evaluation of the risk-benefit ratio of the use of taxanes in breast cancer. These results now must be confirmed in additional series.
ClinicalTrials.gov identifier: NCT00174655
PMID: 32614702
DOI: 10.1200/JCO.19.01771
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