University of Texas MD Anderson Cancer Center, Houston, TX, USA.
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lancet Oncol. 2018 Mar;19(3):310-322. doi: 10.1016/S1470-2045(18)30078-0. Epub 2018 Feb 12.
Obesity has been linked to increased mortality in several cancer types; however, the relation between obesity and survival outcomes in metastatic melanoma is unknown. The aim of this study was to examine the association between body-mass index (BMI) and progression-free survival or overall survival in patients with metastatic melanoma who received targeted therapy, immunotherapy, or chemotherapy.
This retrospective study analysed independent cohorts of patients with metastatic melanoma assigned to treatment with targeted therapy, immunotherapy, or chemotherapy in randomised clinical trials and one retrospective study of patients treated with immunotherapy. Patients were classified according to BMI, following the WHO definitions, as underweight, normal, overweight, or obese. Patients without BMI and underweight patients were excluded. The primary outcomes were the associations between BMI and progression-free survival or overall survival, stratified by treatment type and sex. We did multivariable analyses in the independent cohorts, and combined adjusted hazard ratios in a mixed-effects meta-analysis to provide a precise estimate of the association between BMI and survival outcomes; heterogeneity was assessed with meta-regression analyses. Analyses were done on the predefined intention-to-treat population in the randomised controlled trials and on all patients included in the retrospective study.
The six cohorts consisted of a total of 2046 patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy between Aug 8, 2006, and Jan 15, 2016. 1918 patients were included in the analysis. Two cohorts containing patients from randomised controlled trials treated with targeted therapy (dabrafenib plus trametinib [n=599] and vemurafenib plus cobimetinib [n=240]), two cohorts containing patients treated with immunotherapy (one randomised controlled trial of ipilimumab plus dacarbazine [n=207] and a retrospective cohort treated with pembrolizumab, nivolumab, or atezolizumab [n=331]), and two cohorts containing patients treated with chemotherapy (two randomised controlled trials of dacarbazine [n=320 and n=221]) were classified according to BMI as normal (694 [36%] patients), overweight (711 [37%]), or obese (513 [27%]). In the pooled analysis, obesity, compared with normal BMI, was associated with improved survival in patients with metastatic melanoma (average adjusted hazard ratio [HR] 0·77 [95% CI 0·66-0·90] for progression-free survival and 0·74 [0·58-0·95] for overall survival). The survival benefit associated with obesity was restricted to patients treated with targeted therapy (HR 0·72 [0·57-0·91] for progression-free survival and 0·60 [0·45-0·79] for overall survival) and immunotherapy (HR 0·75 [0·56-1·00] and 0·64 [0·47-0·86]). No associations were observed with chemotherapy (HR 0·87 [0·65-1·17, p=0·61] for progression-free survival and 1·03 [0·80-1·34, p=0·01] for overall survival). The association of BMI with overall survival for patients treated with targeted and immune therapies differed by sex, with inverse associations in men (HR 0·53 [0·40-0·70]), but no associations observed in women (HR 0·85 [0·61-1·18, p=0·03]).
Our results suggest that in patients with metastatic melanoma, obesity is associated with improved progression-free survival and overall survival compared with those outcomes in patients with normal BMI, and that this association is mainly seen in male patients treated with targeted or immune therapy. These results have implications for the design of future clinical trials for patients with metastatic melanoma and the magnitude of the benefit found supports further investigation of the underlying mechanism of these associations.
ASCO/CCF Young Investigator Award, ASCO/CCF Career Development Award, MD Anderson Cancer Center (MDACC) Melanoma Moonshot Program, MDACC Melanoma SPORE, and the Dr Miriam and Sheldon G Adelson Medical Research Foundation.
肥胖与多种癌症类型的死亡率增加有关；然而，肥胖与转移性黑色素瘤患者的生存结果之间的关系尚不清楚。本研究的目的是研究在接受靶向治疗、免疫治疗或化疗的转移性黑色素瘤患者中，体重指数（BMI）与无进展生存期或总生存期之间的关系。
本回顾性研究分析了转移性黑色素瘤患者的独立队列，这些患者被分配接受靶向治疗、免疫治疗或化疗的随机临床试验，以及一项接受免疫治疗的回顾性研究。根据世界卫生组织的定义，患者按照 BMI 分为消瘦、正常、超重或肥胖。没有 BMI 的患者和消瘦的患者被排除在外。主要结局是按治疗类型和性别分层，BMI 与无进展生存期或总生存期之间的关系。我们在独立队列中进行了多变量分析，并在混合效应荟萃分析中合并了调整后的危险比，以提供 BMI 与生存结果之间关系的精确估计；通过荟萃回归分析评估了异质性。在随机对照试验的预设意向治疗人群和回顾性研究中所有纳入的患者中进行了分析。
这六个队列共纳入了 2046 名接受靶向治疗、免疫治疗或化疗的转移性黑色素瘤患者，纳入时间为 2006 年 8 月 8 日至 2016 年 1 月 15 日。1918 名患者纳入分析。两个队列包含接受靶向治疗的随机对照试验的患者（599 名接受达布拉非尼加曲美替尼治疗，240 名接受维莫非尼加考比替尼治疗），两个队列包含接受免疫治疗的患者（一项接受伊匹单抗加达卡巴嗪治疗的随机对照试验，331 名接受 pembrolizumab、nivolumab 或 atezolizumab 治疗的回顾性队列），两个队列包含接受化疗的患者（两项接受达卡巴嗪治疗的随机对照试验，320 名和 221 名），根据 BMI 分为正常（694 名，36%）、超重（711 名，37%）或肥胖（513 名，27%）。在汇总分析中，与正常 BMI 相比，肥胖与转移性黑色素瘤患者的生存改善相关（无进展生存期的平均调整危险比[HR]0·77[95%CI 0·66-0·90]和总生存期的 0·74[0·58-0·95]）。与肥胖相关的生存获益仅限于接受靶向治疗的患者（无进展生存期的 HR 0·72[0·57-0·91]和总生存期的 0·60[0·45-0·79]）和免疫治疗（无进展生存期的 HR 0·75[0·56-1·00]和总生存期的 0·64[0·47-0·86]）。在化疗组中没有观察到相关性（无进展生存期的 HR 0·87[0·65-1·17，p=0·61]和总生存期的 1·03[0·80-1·34，p=0·01]）。接受靶向和免疫治疗的患者的 BMI 与总生存期之间的关联因性别而异，男性（HR 0·53[0·40-0·70]）呈负相关，而女性（HR 0·85[0·61-1·18，p=0·03]）无相关性。
我们的研究结果表明，在转移性黑色素瘤患者中，与正常 BMI 的无进展生存期和总生存期相比，肥胖与无进展生存期和总生存期的改善相关，而且这种关联主要见于接受靶向或免疫治疗的男性患者。这些结果对转移性黑色素瘤患者的未来临床试验设计具有启示意义，并且发现的获益幅度支持进一步研究这些关联的潜在机制。
ASCO/CCF 青年研究员奖、ASCO/CCF 职业发展奖、MD 安德森癌症中心（MDACC）黑色素瘤登月计划、MDACC 黑色素瘤 SPORE 以及 Miriam 和 Sheldon G. Adelson 医学研究基金会。
