《柳葉刀腫瘤分冊》2018年2月12日在線先發

http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30078-0/fulltext

在靶向治療、免疫治療或化療的轉移性黑色素瘤患者中體質指數與患者轉歸的相關性：一項回顧性多隊列分析

背景

肥胖與某些類型癌症的死亡率增加有關，但在轉移性黑色素瘤中，肥胖與生存轉歸的關係尚不明。本研究旨在在接受靶向治療、免疫治療或化療的轉移性黑色素瘤患者中，了解體質指數（BMI）與無進展生存或總生存的相關性。

方法

這項回顧性研究在隨機化臨床試驗和一項對免疫治療患者進行的回顧性研究中，分析了分配到靶向治療、免疫治療或化療組的轉移性黑色素瘤患者的獨立隊列。參照WHO對低體重、正常體重、超重或肥胖的定義，按照BMI對患者進行分類，剔除沒有BMI數據的患者和低體重患者。主要終點為BMI與無進展生存或總生存的相關性，根據治療類型、性別進行亞組分層。我們在獨立隊列中進行了多變數分析，並結合混合效應薈萃分析中調整后的風險比，以提供一簡單的BMI與生存轉歸相關性的估算值，用薈萃回歸分析評價異質性。在隨機對照臨床試驗中，對事先確定的意向性治療患者群進行分析，在回顧性研究中，對納入的所有患者進行分析。

結果

2006年8月8日至2016年1月15日期間靶向治療、免疫治療或化療的、共計2046名轉移性黑色素瘤患者構成6個隊列，1918名患者納入分析，兩個隊列包含來自靶向治療（達拉非尼+曲美替尼[n=599]、威羅菲尼+考比替尼[n=240]）隨機對照試驗的患者，兩個隊列包含免疫治療的患者（伊匹單抗+氮烯咪胺的一項隨機對照試驗和用派姆單抗、納武單抗或阿特朱單抗治療的一個回顧性隊列[n=331]），兩個隊列包含接受化療的患者（氮烯咪胺的2項隨機對照試驗[n=320、n=221]），對這些隊列按照BMI正常（694名[36%]患者）、超重（711名[37%]）、或肥胖（513名[27%]）進行分類。在匯總分析中，與正常BMI相比較，在轉移性黑色素瘤患者中，肥胖與生存改善相關（對於無進展生存，平均調校后的風險比[HR]為0.77[95%CI，0.66-0.90]；對於總生存，HR為0.74[0.58–0.95]）。與肥胖相關的生存獲益僅限於靶向治療的患者（無進展生存的HR為0.72[0.57-0.91]，總生存的HR為0.60[0.45-0.79]）和免疫治療的患者（HR，0.75 [0.56–1.00]、0.64[0.47–0.86]）。發現（BMI）與化療沒有相關性（無進展生存的HR為0.87 [0.65–1.17，交互作用p=0.61]，總生存的HR為1.03[0.80–1.34，交互作用p=0.01]）。對於靶向治療、免疫治療的患者，BMI與總生存的相關性因性別不同而有所區別，男性為負相關（HR，0.53[0.40–0.70]），但未觀察到在女性中的相關性（HR，0.85[0.61–1.18，交互作用p=0.03]）。

解釋

我們的結果表明，在轉移性黑色素瘤患者中，與正常BMI患者相比較，肥胖與無進展生存改善、總生存改善相關，這種相關性主要見於靶向治療或免疫治療的男性患者。這些結果對於未來針對轉移性黑色素瘤患者的臨床試驗設計具有意義，所發現的獲益程度支持進一步進行這些相關性的基本機制的研究。

南南和北北

Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis

Background

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.

Methods

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.

Findings

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, pinteraction=0·61] for progression-free survival and 1·03 [0·80–1·34, pinteraction=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, pinteraction=0·03]).

Interpretation

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.

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