Analysis of Cytokine Expression in Prostate Cancer Patients Undergoing Radiation Therapy: Correlation with Clinicopathological Outcomes

The capacity to diagnose and stage of prostate cancer (PC) is restricted and generally based on pre-treatment assessments such as the prostate-specific antigen (PSA), TNM stages, and the pathologic Gleason score. However, existing pre-treatment assessments cannot be used to predict acute RT-induced toxicity. Therefore, new protein biomarkers are required in RT oncology to improve decision-making, treatment and therapy monitoring for PC patients. This prospective study aimed to assess the magnitude and frequency (increase/decrease) of changes in cytokine expression in patients receiving androgen deprivation therapy (ADT) and intensity-modulated radiotherapy (IMRT) for PC and to link these changes to clinicopathological characteristics and acute genitourinary (GU) and gastrointestinal (GI) toxicity. Principal findings include the following: 1. IHC expression levels of TNF-α, TGF-β1 and IL-6 were significantly reduced with increased Gleason Scores and a significant correlation was only found between TNF-α expression levels and Gleason Scores. 2. A statistically significant correlation was found between the amount of pre-RT plasma levels and the staining intensity of the corresponding prostatic needle-biopsy specimens. 3. Profibrotic cytokine TGF-β1 levels were elevated at the end of RT over baseline. In addition, IL-6 increased after 3 months of completion of RT when compared with baseline and end of RT blood plasma samples. 4. Elevated levels of TNF-α and IL-6 were associated with a higher probability of acute genitourinary and acute gastrointestinal toxicity. 5. The levels of profibrotic TGF-β1 decreased as the severity of acute genitourinary and gastrointestinal increased. This dissertation provides the evidence of the overexpression of cytokines in prostatic needle-biopsy specimens and influence of androgen deprivation therapy (ADT) and radiotherapy (RT) on the changes in cytokine levels in blood plasma before and after curative treatments. In addition, our study also provides evidence of the association of cytokines levels in blood plasma and acute genitourinary (GU) and gastrointestinal (GI) toxicity.

当前前列腺癌（PC）的诊断与分期能力受限，通常依托前列腺特异性抗原（PSA）、TNM分期及病理格里森评分等治疗前评估手段。但现有治疗前评估方法无法预测放射治疗（RT）诱导的急性毒性。因此，放射肿瘤学领域亟需新型蛋白质生物标志物，以改善前列腺癌患者的决策制定、治疗方案及治疗监测。本前瞻性研究旨在评估前列腺癌患者接受雄激素剥夺治疗（ADT）联合调强放射治疗（IMRT）后，细胞因子表达变化的幅度与频率（升高/降低），并将这些变化与临床病理特征及急性泌尿生殖系统（GU）、胃肠道（GI）毒性相关联。主要研究结果如下：1. 随着格里森评分升高，肿瘤坏死因子-α（TNF-α）、转化生长因子-β1（TGF-β1）及白细胞介素-6（IL-6）的免疫组化（IHC）表达水平显著降低，且仅肿瘤坏死因子-α的表达水平与格里森评分存在显著相关性。2. 放射治疗前的血浆细胞因子水平与对应前列腺穿刺活检标本的染色强度呈显著统计学相关性。3. 放射治疗结束时，促纤维化细胞因子转化生长因子-β1（TGF-β1）的水平较基线水平升高。此外，相较于基线及放射治疗结束时的血浆样本，治疗结束3个月后白细胞介素-6（IL-6）的水平有所上升。4. 肿瘤坏死因子-α（TNF-α）与白细胞介素-6（IL-6）的水平升高与急性泌尿生殖系统及急性胃肠道毒性的发生概率增加显著相关。5. 随着急性泌尿生殖系统与胃肠道毒性严重程度加剧，促纤维化细胞因子转化生长因子-β1（TGF-β1）的水平呈下降趋势。本论文为前列腺穿刺活检标本中细胞因子的过表达现象，以及雄激素剥夺治疗（ADT）与放射治疗（RT）对根治性治疗前后血浆细胞因子水平变化的影响提供了证据。此外，本研究还证实了血浆细胞因子水平与急性泌尿生殖系统及胃肠道毒性之间存在关联。