Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.
Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis.
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DOI：
10.1016/s1470-2045(18)30078-0
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发表时间：
2018-03
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影响因子：
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通讯作者：
Davies MA
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作者：
McQuade JL;Daniel CR;Hess KR;Mak C;Wang DY;Rai RR;Park JJ;Haydu LE;Spencer C;Wongchenko M;Lane S;Lee DY;Kaper M;McKean M;Beckermann KE;Rubinstein SM;Rooney I;Musib L;Budha N;Hsu J;Nowicki TS;Avila A;Haas T;Puligandla M;Lee S;Fang S;Wargo JA;Gershenwald JE;Lee JE;Hwu P;Chapman PB;Sosman JA;Schadendorf D;Grob JJ;Flaherty KT;Walker D;Yan Y;McKenna E;Legos JJ;Carlino MS;Ribas A;Kirkwood JM;Long GV;Johnson DB;Menzies AM;Davies MA
肥胖与几种癌症的死亡率增加有关；然而，肥胖与转移性黑色素瘤存活之间的关系尚不清楚。本研究的目的是研究转移性黑色素瘤的BMI、无进展生存期（PFS）和总生存期（OS）之间的关系。这项研究包括6个独立队列，共1918例转移性黑色素瘤患者。其中包括两个靶向治疗队列[达非尼和曲美替尼（n=599）和vemurafenib和cobimetinib （n=240）的随机对照试验（RCT）]，两个免疫治疗队列[伊匹单抗+达卡巴嗪（DTIC）的RCT （n=207）和抗pd -1/PDL-1治疗的回顾性队列（n=331）]，以及两个化疗队列[RCT DTIC队列（n=320和n=221）]。BMI分为正常（BMI 18 ~ <25, 1918年n=694, 36.1%）超重（BMI 25 ~ 29.9, n=711, 37.1%）或肥胖（BMI≥30,n=513, 26.7%）。主要结局是BMI、PFS和OS之间的关联，并按治疗类型和性别分层。这些探索性分析基于先前报道的随机对照试验的意向治疗数据。BMI对PFS和OS的影响在独立队列中通过多变量调整的Cox模型进行评估。为了更精确地估计BMI与预后之间的关系，以及BMI、性别和治疗类型之间的相互作用，在混合效应荟萃分析中结合校正风险比，并通过荟萃回归分析探讨异质性。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率提高相关[PFS和OS的平均调整风险比（HR）和95% CI分别为0.77（0.66-0.90）和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[PFS和OS分别为0.72（0.57-0.91）和0.60(0.45-0.79)]和免疫治疗[0.75（0.56-1.00）和0.64(0.47-0.86)]的患者。与化疗无相关性[0.87（0.65-1.17）和1.03 (0.80-1.34)]；PFS和OS的交互作用p分别为0.61和0.01。BMI与靶向和免疫治疗的预后效果因性别而异，男性呈显著的负相关[PFS 0.67（0.53-0.84）和OS 0.53(0.40-0.70)]，但女性无明显的负相关[PFS 0.92（0.70-1.23）和OS 0.85(0.61-1.18)，相互作用的性别p分别为PFS和OS = 0.08和0.03]肥胖与转移性黑色素瘤的PFS和OS改善相关，在接受靶向或免疫治疗的男性中观察到强烈的相关性。检测到的巨大益处支持了对这些意想不到的观察结果的潜在机制进行调查的必要性ASCO/CCF青年研究者奖和ASCO/CCF职业发展奖授予JLM
Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM