Bigot Frédéric, Castanon Eduardo, Baldini Capucine, Hollebecque Antoine, Carmona Alberto, Postel-Vinay Sophie, Angevin Eric, Armand Jean-Pierre, Ribrag Vincent, Aspeslagh Sandrine, Varga Andrea, Bahleda Rastislav, Menis Jessica, Gazzah Anas, Michot Jean-Marie, Marabelle Aurélien, Soria Jean-Charles, Massard Christophe
University of Paris Sud, Gustave-Roussy Cancer Campus, Drug Development Department, Villejuif, France.
Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, Calle Marqués de los Vélez s/n, Murcia, Spain.
Eur J Cancer. 2017 Oct;84:212-218. doi: 10.1016/j.ejca.2017.07.027. Epub 2017 Aug 18.
Life expectancy evaluation is crucial when selecting patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on three objective variables (number of metastatic sites, lactate dehydrogenase (LDH) and serum albumin) was validated in patients treated with cytotoxics and targeted therapies. We aimed to determine if those factors were applicable to immune-checkpoint therapies (ICTs) in phase I trials and to evaluate new variables that may preclude a better prognosis in patients receiving ICT.
We conducted a retrospective analysis of survival risk factors in a discovery cohort of 155 patients enrolled into ICT phase I trials at our institution. We computed univariate analysis and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in phase I ICT trials was used to prospectively validate this score.
A total of 155 patients (M/F: 83/72; median age 59) receiving an experimental ICT between March 2012 and January 2016 were included in the discovery cohort. An MVA assessing the RMH score variables showed that low albumin (hazard ratio [HR] 1.73, 95% confidence interval [CI] 1.05-2.86) and LDH > upper limit normal (ULN) (HR 1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. Interestingly, neutrophil-to-lymphocyte ratio (NLR) > 6 (HR 1.75, 95% CI 1.04-2.95) was associated with a decrease in OS. The number of metastases was not associated with a poorer outcome for this ICT cohort (HR 0.83, 95% CI 0.51-1.35). A risk score based on the results of the MVA (NLR > 6 = 1; LDH > ULN = 1; albumin < 35 g/l = 1) showed that patients presenting a high score (>1) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0 or 1) (68.9 weeks; 95% CI 50-83.7) (HR 2.9, 95% CI 1.87-4.64). In the validation cohort of 113 patients, again the patients presenting a high score showed an inferior OS (HR 6.3, 95% CI 2.7-14.8).
In ICT phase I trials, traditional prognostic variables included in the RMH score may be suboptimal to determine patient's prognosis. In this context, the NLR is a significant prognostic variable. The Gustave Roussy Immune Score, based on albumin, LDH and NLR, allows a better selection of patients for ICT phase I trials.
在选择可能从I期研究中获益的患者时，预期寿命评估至关重要。基于三个客观变量（转移部位数量、乳酸脱氢酶（LDH）和血清白蛋白）的皇家马斯登医院（RMH）预后评分，已在接受细胞毒性药物和靶向治疗的患者中得到验证。我们旨在确定这些因素是否适用于I期试验中的免疫检查点疗法（ICT），并评估可能预示接受ICT治疗的患者预后较好的新变量。
我们对在我院参加ICT I期试验的155例患者的发现队列中的生存危险因素进行了回顾性分析。我们对人口统计学、临床和生物学数据进行了单因素分析和多因素分析（MVA），以评估它们对总生存期（OS）的预后价值。MVA结果用于构建OS的预后评分。113例参加I期ICT试验的患者的验证队列用于前瞻性验证该评分。
发现队列纳入了2012年3月至2016年1月期间接受实验性ICT治疗的155例患者（男/女：83/72；中位年龄59岁）。评估RMH评分变量的MVA显示，低白蛋白（风险比[HR]1.73，95%置信区间[CI]1.05 - 2.86）和LDH >正常上限（ULN）（HR 1.88，95% CI 1.12 - 3.15）是OS的独立负性预后因素。有趣的是，中性粒细胞与淋巴细胞比值（NLR）> 6（HR 1.75，95% CI 1.04 - 2.95）与OS降低相关。转移灶数量与该ICT队列的较差预后无关（HR 0.83，95% CI 0.51 - 1.35）。基于MVA结果的风险评分（NLR > 6 = 1；LDH > ULN =1；白蛋白< 35 g/l = 1）显示，高评分（>1）的患者与低评分（0或1）的患者相比，OS显著缩短（20.4周；95% CI 5.7 - 35.2）（68.9周；95% CI 50 - 83.7）（HR 2.9，95% CI 1.87 - 4.64）。在113例患者的验证队列中，高评分患者的OS同样较差（HR 6.3，95% CI 2.7 - 14.8）。
在ICT I期试验中，RMH评分中包含的传统预后变量可能不足以确定患者的预后。在此背景下，NLR是一个重要的预后变量。基于白蛋白、LDH和NLR的古斯塔夫·鲁西免疫评分能够更好地为ICT I期试验选择患者。
