Madeddu Clelia, Busquets Silvia, Donisi Clelia, Lai Eleonora, Pretta Andrea, López-Soriano Francisco Javier, Argilés Josep Maria, Scartozzi Mario, Macciò Antonio
Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, Department of Medical Sciences and Public Health, University of Cagliari, 09100 Cagliari, Italy.
Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.
Cancers (Basel). 2023 Feb 8;15(4):1076. doi: 10.3390/cancers15041076.
Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia ( = 0.0323), as well as higher miniCASCO-based cachexia severity ( = 0.0428), an mGPS of 2 versus those with a lower mGPS ( = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) ( = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.
基于免疫检查点抑制剂（ICI）的免疫疗法显著提高了晚期非小细胞肺癌（NSCLC）患者的生存率；然而，相当一部分患者并未从这种治疗方法中获益，因此需要预测性生物标志物。越来越多的证据表明，恶病质是一种由癌症相关慢性炎症驱动的复杂综合征，在NSCLC患者中经常出现，它可能会损害免疫反应和ICI疗效。在此，我们开展了一项前瞻性研究，旨在评估恶病质及其相关的营养、代谢和炎症参数变化（通过多维miniCASCO工具评估）对晚期NSCLC患者接受基于ICI的免疫疗法的生存和临床反应（即疾病控制率）的预后和预测作用。我们纳入了74例连续患者。经过多变量回归分析，我们发现白细胞介素-6（IL-6）水平（比值比（OR）=0.9036；95%置信区间（CI）=0.8408 - 0.9711；P = 0.0025）和miniCASCO评分（OR = 0.9768；95%CI = 0.9102 - 0.9999；P = 0.0310）与临床反应呈负相关。至于生存结果，多变量COX回归分析发现，IL-6水平和基于miniCASCO的恶病质严重程度分别显著影响无进展生存期（PFS）（风险比（HR）=1.0388；95%CI = 1.0230 - 1.0548；P < 0.001和HR = 1.2587；95%CI = 1.0850 - 1.4602；P = 0.0024）和总生存期（OS）（HR = 1.0404；95%CI = 1.0221 - 1.0589；P < 0.0001和HR = 2.3834；95%CI = 1.1504 - 4.9378；P = 0.0194）。通过Kaplan-Meier分析比较生存曲线显示，恶病质患者的OS显著低于无恶病质患者（P = 0.0323），基于miniCASCO的恶病质严重程度更高（P = 0.0428），改良格拉斯哥预后评分（mGPS）为2的患者低于mGPS较低的患者（P = 0.0074），IL-6水平较高（>6 ng/mL）的患者低于IL-6水平较低（≤6 ng/mL）的患者（P = 0.0120）。总之，我们的研究支持了这样的证据，即恶病质及其相关的炎症、身体成分和营养参数变化是ICI的关键预后和预测因素。需要进一步开展更大规模的研究来证实这些发现，并探索对抗恶病质以提高免疫治疗疗效的潜在益处。
Zotero 插件