Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom.
Division of Pharmacy, University of Manchester, Manchester, United Kingdom.
Clin Lung Cancer. 2018 May;19(3):239-248.e7. doi: 10.1016/j.cllc.2017.12.002. Epub 2017 Dec 11.
There is an unmet need to develop noninvasive biomarkers to stratify patients in drug-radiotherapy trials. In this pilot study we investigated lung cancer radiotherapy response and toxicity blood biomarkers and correlated findings with tumor volume and proliferation imaging.
Blood samples were collected before and during (day 21) radiotherapy. Twenty-six cell-death, hypoxia, angiogenesis, inflammation, proliferation, invasion, and tumor-burden biomarkers were evaluated. Clinical and laboratory data were collected. Univariate analysis was performed on small-cell and non-small-cell lung cancer (NSCLC) whereas multivariate analysis focused on NSCLC.
Blood samples from 78 patients were analyzed. Sixty-one (78.2%) harbored NSCLC, 48 (61.5%) received sequential chemoradiotherapy. Of tested baseline biomarkers, undetectable interleukin (IL)-1b (hazard ratio [HR], 4.02; 95% confidence interval [CI], 2.04-7.93; P < .001) was the only significant survival covariate. Of routinely collected laboratory tests, high baseline neutrophil count was a significant survival covariate (HR, 1.07; 95% CI, 1.02-1.11; P = .017). Baseline IL-1b and neutrophil count were prognostic for survival in a multivariate model. The addition of day-21 cytokeratin-19 antigen modestly improved this model's survival prediction (concordance probability, 0.75-0.78). Chemotherapy (P < .001) and baseline keratinocyte growth factor (P = .019) predicted acute esophagitis, but only chemotherapy remained significant after Bonferroni correction. Baseline angioprotein-1 and hepatocyte growth factor showed a direct correlation with tumor volume whereas changes in vascular cell adhesion molecule 1 showed significant correlations with 18F-fluorothymidine (FLT) positron emission tomography (PET).
Select biomarkers are prognostic after radiotherapy in this lung cancer series. The correlation between circulating biomarkers and 18F-FLT PET is shown, to our knowledge for the first time, highlighting their potential role as imaging surrogates.
开发非侵入性生物标志物来对药物放疗试验中的患者进行分层是未满足的需求。在这项初步研究中，我们研究了肺癌放疗反应和毒性的血液生物标志物，并将这些发现与肿瘤体积和增殖成像相关联。
在放疗前和放疗期间（第 21 天）采集血样。评估了 26 种细胞死亡、缺氧、血管生成、炎症、增殖、侵袭和肿瘤负担的生物标志物。收集了临床和实验室数据。对小细胞肺癌和非小细胞肺癌（NSCLC）进行了单变量分析，而多变量分析则侧重于 NSCLC。
对 78 例患者的血样进行了分析。61 例（78.2%）患有 NSCLC，48 例（61.5%）接受了序贯放化疗。在测试的基线生物标志物中，无法检测到白细胞介素（IL）-1b（风险比 [HR]，4.02；95%置信区间 [CI]，2.04-7.93；P<0.001）是唯一具有显著生存相关性的生物标志物。在常规收集的实验室测试中，高基线中性粒细胞计数是一个显著的生存相关因素（HR，1.07；95%CI，1.02-1.11；P=0.017）。基线 IL-1b 和中性粒细胞计数在多变量模型中对生存具有预后意义。在第 21 天细胞角蛋白 19 抗原的加入略微提高了该模型的生存预测（一致性概率，0.75-0.78）。化疗（P<0.001）和基线角质形成细胞生长因子（P=0.019）预测急性食管炎，但仅化疗在 Bonferroni 校正后仍然具有统计学意义。基线血管生成素-1 和肝细胞生长因子与肿瘤体积呈直接相关，而血管细胞黏附分子 1 的变化与 18F-氟胸腺嘧啶（FLT）正电子发射断层扫描（PET）具有显著相关性。
在这项肺癌系列研究中，放疗后某些生物标志物具有预后意义。我们首次展示了循环生物标志物与 18F-FLT PET 之间的相关性，突出了它们作为成像替代物的潜在作用。
