Abstract
BackgroundThe 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.MethodsThe 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.ResultsCytogenetic 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.ConclusionsWe 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.
Highlights
The question whether lymphocyte radiosensitivity is representative of patients’ response to radiotherapy (RT) remains unsolved
Gender was confirmed as a well-known, and the planning target volume (PTV) size was identified as a less well-known influencing variable on lymphocyte cytogenetic damage after partial-body irradiation
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
Summary
The question whether lymphocyte radiosensitivity is representative of patients’ response to radiotherapy (RT) remains unsolved. The question of whether lymphocyte radiosensitivity is representative of the patients’ response to RT or RCT still remains unsolved. Therapy-induced changes have been analyzed in gene expression studies (e.g., Sonis et al [3]), apoptosis induction (e.g., Ozsahin et al [4]), γ-H2AX techniques [5,6,7], and classical cytogenetics [8,9,10]. None of these approaches have consistently identified radiosensitive patients or are routinely used in the clinic. The suitability of MN yields as biomarkers for the individual radiosensitivity was analyzed in clinical studies; the results remain controversial [10, 15,16,17]
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