Department of Radiotherapy and Radiation Oncology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
University Medical Center Göttingen, Göttingen, Germany.
BMC Cancer. 2021 Mar 4;21(1):219. doi: 10.1186/s12885-021-07914-5.
The question whether lymphocyte radiosensitivity is representative of patients' response to radiotherapy (RT) remains unsolved. We analyzed lymphocyte cytogenetic damage in patients who were homogeneously treated with preoperative radiochemotherapy (RCT) for rectal cancer within clinical trials. We tested for interindividual variation and consistent radiosensitivity after in-vivo and in-vitro irradiation, analyzed the effect of patients' and RCT characteristics on cytogenetic damage, and tested for correlations with patients' outcome in terms of tumor response, survival and treatment-related toxicity.
The cytokinesis-block micronucleus cytome (CBMNcyt) assay was performed on the peripheral blood lymphocytes (PBLCs) of 134 patients obtained before, during, at the end of RCT, and during the 2-year follow-up. A subset of PBLCs obtained before RCT was irradiated in-vitro with 3 Gy. RCT included 50.4 Gy of pelvic RT with 5-fluorouracil (5-FU) alone (n = 78) or 5-FU plus oxaliplatin (n = 56). The analyzed variables included patients' age, gender, RT characteristics (planning target volume size [PTV size], RT technique), and chemotherapy characteristics (5-FU plasma levels, addition of oxaliplatin). Outcome was analyzed as tumor regression, patient survival, and acute and late toxicity.
Cytogenetic damage increased significantly with the radiation dose and varied substantially between individuals. Women were more sensitive than men; no significant age-dependent differences were observed. There was a significant correlation between the cytogenetic damage after in-vitro irradiation and in-vivo RCT. We found a significant effect of the PTV size on the yields of cytogenetic damage after RCT, while the RT technique had no effect. Neither the addition of oxaliplatin nor the 5-FU levels influenced cytogenetic damage. We found no correlation between patient outcome and the cytogenetic damage.
We found consistent cytogenetic damage in lymphocytes after in-vivo RCT and in-vitro irradiation. Gender was confirmed as a well-known, and the PTV size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation. A consistent level of cytogenetic damage after in-vivo and in-vitro irradiation may indicate the importance of genetic factors for individual radiosensitivity. However, we found no evidence that in-vivo or in-vitro irradiation-induced cytogenetic damage is an adequate biomarker for the response to RCT in rectal cancer patients.
淋巴细胞放射敏感性是否能代表患者对放射治疗（RT）的反应，这个问题仍未解决。我们分析了在临床试验中接受直肠术前放化疗（RCT）的同质治疗的患者的淋巴细胞细胞遗传学损伤。我们检测了体内和体外照射后的个体间变异和一致的放射敏感性，分析了患者和 RCT 特征对细胞遗传学损伤的影响，并检测了与肿瘤反应、生存和治疗相关毒性的患者结局之间的相关性。
对 134 例接受 RCT 前、期间、结束时和 2 年随访期间外周血淋巴细胞（PBLCs）进行胞质分裂阻断微核细胞遗传学（CBMNcyt）分析。在 RCT 前采集的 PBLCs 亚组进行体外照射 3Gy。RCT 包括 50.4Gy 盆腔 RT 联合 5-氟尿嘧啶（5-FU）（n=78）或 5-FU 联合奥沙利铂（n=56）。分析的变量包括患者的年龄、性别、RT 特征（计划靶区体积大小[PTV 大小]、RT 技术）和化疗特征（5-FU 血浆水平、奥沙利铂的添加）。结局分析为肿瘤消退、患者生存以及急性和晚期毒性。
细胞遗传学损伤随辐射剂量显著增加，个体间差异很大。女性比男性更敏感；未观察到年龄依赖性差异。体外照射后和体内 RCT 后的细胞遗传学损伤之间存在显著相关性。我们发现 PTV 大小对 RCT 后细胞遗传学损伤的产率有显著影响，而 RT 技术没有影响。奥沙利铂的添加或 5-FU 水平均不影响细胞遗传学损伤。我们未发现患者结局与细胞遗传学损伤之间存在相关性。
我们发现体内 RCT 和体外照射后淋巴细胞的一致细胞遗传学损伤。性别被确认为一个已知的影响因素，PTV 大小被确定为局部照射后淋巴细胞细胞遗传学损伤的一个不太知名的影响因素。体内和体外照射后一致的细胞遗传学损伤可能表明遗传因素对个体放射敏感性的重要性。然而，我们没有证据表明体内或体外照射诱导的细胞遗传学损伤是直肠癌患者对 RCT 反应的合适生物标志物。
