Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland; Postgraduate School of Molecular Medicine, Medical University of Warsaw, Poland; Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Radiotherapy, N. Copernicus Memorial Regional Specialist Hospital, Lodz, Poland.
Int J Radiat Oncol Biol Phys. 2021 Dec 1;111(5):1237-1249. doi: 10.1016/j.ijrobp.2021.07.008. Epub 2021 Jul 16.
Severe xerostomia is noted in the majority of patients irradiated for oropharyngeal cancer. Extracellular microRNAs (miRNAs) may serve as effective tools allowing prediction of radiation-related toxicity. The aim of this study was to create an efficient prognostic miRNA-based test for severe, patient-rated xerostomia 3 months after primary treatment.
This prospective study enrolled patients with oropharyngeal cancer treated between 2016 and 2018 in 3 centers in Poland. The primary endpoint was severe (grade ≥3) xerostomia as assessed by the European Organisation for Research and Treatment of Cancer H&N-35 questionnaires. Initially, a group of 10 patients with severe xerostomia was randomly selected and matched with a comparative group of 10 patients without severe xerostomia. Samples were collected before radiation therapy, after receiving 20 Gy, and within 24 hours after treatment completion. Quantitative real-time polymerase chain reaction arrays (QIAGEN, Hilden, Germany) were used to quantify expression levels of 752 miRNAs in the serum at all timepoints. The resulting logistic-regression based model was validated in additional 60 patients: 30 with grade >3 xerostomia and 30 without.
Of 152 eligible patients, we successfully recruited 111 patients. Severe xerostomia 3 months after treatment was reported by 63 patients (56.8%). Mean dose delivered to parotid glands was higher in both the exploratory and validation cohort. The model based on miR-185-5p and miR-425-5p expression levels measured before the start of radiation therapy had an area under the curve of 0.96 (95% confidence interval, 0.88-1.00). The model based on the same miRNAs remained robust when parameters were measured after 20 Gy (area under the curve 0.90; 95% confidence interval, 0.75-1.00). These results were confirmed in the validation group. In the validation group, preradiation therapy model application yielded 73.3% sensitivity and 80.0% specificity. In the samples taken after 20 Gy, the same 2 miRNAs yielded 67.7% sensitivity and 72.4% specificity. The model including pretreatment miR-185-5p and miR-425-5p levels together with mean parotid dose yielded 90.0% sensitivity and 80.0% specificity. In the validation cohort, this model yielded 80.6% sensitivity and 55.2% specificity. The model based on miRNA levels measured after 20 Gy and mean parotid dose had 80.0% sensitivity and 100% specificity in the exploratory group. In the validation cohort its performance fell to 71.0% sensitivity and 58.6% specificity.
Serum expression levels of miR-425-5p and miR-185-5p measured before the start of radiation therapy or during therapy (after 20 Gy) had significant prognostic value for the occurrence of severe xerostomia 3 months after treatment completion. The variability explained by miRNAs appears to be, at least partially, independent from that related to the dosimetric data.
在接受头颈部癌症放射治疗的大多数患者中，会出现严重的口干症。细胞外 microRNAs（miRNAs）可能是一种有效的预测工具，可以预测与辐射相关的毒性。本研究的目的是建立一种有效的基于 miRNA 的预后测试方法，用于预测原发性治疗后 3 个月患者严重的、自评的口干症。
本前瞻性研究纳入了 2016 年至 2018 年期间在波兰 3 个中心接受治疗的口咽癌患者。主要终点是采用欧洲癌症研究和治疗组织头颈部 35 问卷评估的严重（等级≥3）口干症。最初，随机选择了 10 例严重口干症患者，并与 10 例无严重口干症患者进行了配对。在放射治疗前、接受 20Gy 后以及治疗完成后 24 小时内采集样本。使用 QIAGEN（德国希尔德斯海姆）的定量实时聚合酶链反应（PCR）微阵列对血清中的 752 种 miRNA 表达水平进行定量分析。基于该模型的逻辑回归分析在另外 60 例患者中得到验证：其中 30 例患者的口干症等级>3，30 例患者的口干症等级为 3 级。
在 152 例符合条件的患者中，我们成功招募了 111 例患者。63 例患者（56.8%）报告治疗后 3 个月出现严重口干症。探索性队列和验证性队列的腮腺平均剂量均较高。基于放射治疗开始前测量的 miR-185-5p 和 miR-425-5p 表达水平的模型，曲线下面积为 0.96（95%置信区间，0.88-1.00）。基于相同 miRNAs 的模型在 20Gy 后测量参数时仍然稳健（曲线下面积为 0.90；95%置信区间，0.75-1.00）。这些结果在验证组中得到了证实。在验证组中，应用放射治疗前模型的敏感性为 73.3%，特异性为 80.0%。在接受 20Gy 治疗后采集的样本中，同样的 2 种 miRNAs 的敏感性为 67.7%，特异性为 72.4%。包括预处理 miR-185-5p 和 miR-425-5p 水平以及腮腺平均剂量的模型，敏感性为 90.0%，特异性为 80.0%。在验证队列中，该模型的敏感性为 80.6%，特异性为 55.2%。基于放射治疗后测量的 miRNA 水平和腮腺平均剂量的模型在探索性队列中具有 80.0%的敏感性和 100%的特异性。在验证队列中，其性能下降至 71.0%的敏感性和 58.6%的特异性。
在放射治疗开始前或治疗期间（20Gy 后）测量的 miR-425-5p 和 miR-185-5p 的血清表达水平对治疗完成后 3 个月严重口干症的发生具有显著的预后价值。miRNA 解释的可变性似乎至少部分独立于与剂量学数据相关的可变性。
