Daly Louise E, Power Derek G, O'Reilly Áine, Donnellan Paul, Cushen Samantha J, O'Sullivan Kathleen, Twomey Maria, Woodlock David P, Redmond Henry P, Ryan Aoife M
School of Food and Nutritional Sciences/APC Microbiome Institute, University College Cork, Cork, Ireland.
Department of Medical Oncology, Cork University Hospital, Cork, Ireland.
Br J Cancer. 2017 Jan;116(3):310-317. doi: 10.1038/bjc.2016.431. Epub 2017 Jan 10.
Body composition is an important predictor of drug toxicity and outcome. Ipilimumab (Ipi), a monoclonal antibody used to treat metastatic melanoma, has specific toxicities. No validated biomarkers that predict Ipi toxicity and efficacy exist. Also, the impact of Ipi on body composition has not been established.
Patients with metastatic melanoma treated with Ipi between 2009 and 2015 were included. Body composition was assessed by computed tomography at baseline and after four cycles of Ipi. Sarcopenia and low muscle attenuation (MA) were defined using published cut-points. All adverse events (AEs) and immune-related AEs (irAEs) were recorded (Common Terminology Criteria For Adverse Event V.4.0).
Eighty-four patients were included in this study (62% male, median age 54 years). At baseline, 24% were sarcopenic and 33% had low MA. On multivariate analysis, sarcopenia and low MA were significantly associated with high-grade AEs (OR=5.34, 95% CI: 1.15-24.88, P=0.033; OR=5.23, 95% CI: 1.41-19.30, P=0.013, respectively), and low MA was associated with high-grade irAEs (OR=3.57, 95% CI: 1.09-11.77, P=0.036). Longitudinal analysis (n=59) revealed significant reductions in skeletal muscle area (SMA), total body fat-free mass, fat mass (all P<0.001) and MA (P=0.030). Mean reduction in SMA was 3.3%/100 days (95% CI: -4.48 to -1.79%, P<0.001). A loss of SMA ⩾7.5%/100 days (highest quartile) was a significant predictor of overall survival in multivariable Cox regression analysis (HR: 2.1, 95% CI: 1.02-4.56, P=0.046).
Patients with sarcopenia and low MA are more likely to experience severe treatment-related toxicity to Ipi. Loss of muscle during treatment was predictive of worse survival. Treatments to increase muscle mass and influence outcome warrant further investigation.
身体组成是药物毒性和治疗结果的重要预测指标。伊匹单抗（Ipi）是一种用于治疗转移性黑色素瘤的单克隆抗体，具有特定的毒性。目前尚无经过验证的可预测Ipi毒性和疗效的生物标志物。此外，Ipi对身体组成的影响尚未明确。
纳入2009年至2015年间接受Ipi治疗的转移性黑色素瘤患者。在基线和Ipi治疗四个周期后，通过计算机断层扫描评估身体组成。采用已发表的切点定义肌肉减少症和低肌肉衰减（MA）。记录所有不良事件（AE）和免疫相关不良事件（irAE）（不良事件通用术语标准第4.0版）。
本研究共纳入84例患者（62%为男性，中位年龄54岁）。基线时，24%的患者存在肌肉减少症，33%的患者MA较低。多变量分析显示，肌肉减少症和低MA与高级别AE显著相关（OR分别为5.34，95%CI：1.15 - 24.88，P = 0.033；OR为5.23，95%CI：1.41 - 19.30，P = 0.013），低MA与高级别irAE相关（OR为3.57，95%CI：1.09 - 11.77，P = 0.036）。纵向分析（n = 59）显示骨骼肌面积（SMA）、全身去脂体重、脂肪量（均P < 0.001）和MA（P = 0.030）均显著降低。SMA平均降低率为3.3%/100天（95%CI：-4.48至-1.79%，P < 0.001）。在多变量Cox回归分析中，SMA损失≥7.5%/100天（最高四分位数）是总生存期的显著预测指标（HR：2.1，95%CI：1.02 - 4.56，P = 0.046）。
存在肌肉减少症和低MA的患者更有可能发生与Ipi治疗相关的严重毒性反应。治疗期间肌肉量的减少预示着生存预后较差。增加肌肉量并影响治疗结果的治疗方法值得进一步研究。
