Association Between Acute Toxicities Of Chemoradiotherapy And Chromosomal Aberrations In Peripheral Blood Lymphocytes In Esophageal Cancer Patients

Abstract

The purpose of this study was to evaluate the individual radiosensitivity by analyzing the DNA damage response and chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) induced by chemoradiotherapy (CRT) and to predict non-hematologic acute toxicities of CRT in patients with esophageal cancer. Sixteen esophageal cancer patients referred to our institution for definitive CRT were enrolled in this prospective study. Prescribed doses were 60 Gy in 10 patients and 50 Gy in 6 patients. Patients received 2 Gy radiotherapy (RT) five days a week. Cisplatin or Nedaplatin (days 1 and 29) and 5-fluorouracil (days 1–4 and 29–32) were used as chemotherapy. PBLs were obtained during treatment just before and 15 minutes after delivering 2 Gy of RT on the day when the cumulative dose reached 2, 20, 40 and 50/60 Gy. PBLs were also obtained 4 weeks and 6 months after RT from all and thirteen patients, respectively. Dicentric and ring chromosomes in PBLs were counted to evaluate the numbers of CAs. γ-H2AX foci per cell were counted and the increment of γ-H2AX foci by 2 Gy RT was examined to assess DNA double-strand breaks. We assessed the association between these factors and adverse events of CRT evaluated using common terminology criteria for adverse events version 5.0. Paired t-test adjusted by Bonferroni correction and Mann-Whitney U test were used to compare the indices from the same group at different timings and the indices between two groups, respectively. For all analyses, a P value of < 0.05 was considered significant. The mean numbers of CAs per 1,000 cells increased during CRT and decreased after RT: before RT, 13 (range: 0–24); 2 Gy, 50 (31–82); 20 Gy, 442 (218–1,099); 40 Gy: 710 (338–1,333); the last day of RT (50 or 60 Gy), 1,089 (567–2,295); 4 weeks after RT: 1,019 (455–2,063); and 6 months after RT: 646 (269–1,217). The mean numbers of γH2AX foci per cell before RT showed no increase during CRT. The mean increment of γH2AX foci per cell by 2 Gy RT was significantly reduced with accumulation of RT dose: 2Gy, 1.95 (0.57–3.33); 20 Gy, 1.70(0.59–3.17); 40 Gy: 1.01 (0.06–1.88); and the last day of RT (50 or 60 Gy), 0.69 (0.08–2.19), even though the same dose was administered each day. Five patients showed grade 3 toxicities during or after CRT (overreactors: OR), while eleven had grade 2 or less toxicities (non-overreactors: NOR). The numbers of CAs were significantly higher in the OR group than in the NOR group at a cumulative dose of 20 Gy (mean value: 625 vs 355, P = 0.02), 40 Gy (mean value: 903 vs 571, P = 0.04), and the last day of RT (mean value: 1485 vs 869, P = 0.007). The number and increment of γH2AX foci did not show a significant association with acute toxicities. The number of CAs after CRT increased as the cumulative doses increased, while the increment of γ-H2AX foci decreased with an increase in cumulative dose. The number of CAs could be an index for predicting non-hematologic acute toxicities of CRT for esophageal cancer.