Ji Zhu1,2, Anwen Liu3, Xinchen Sun4, Luying Liu5, Yaqun Zhu6, Tao Zhang7, Jianhui Jia8, Shisheng Tan9, Junxin Wu10, Xin Wang11, Juying Zhou12, Jialin Yang13, Chen Zhang14, Hongyan Zhang15, Yuanyuan Zhao16, Gang Cai17, Wei Zhang18, Fan Xia1,2, Juefeng Wan1,2, Hui Zhang1,2, Lijun Shen1,2, SanJun Cai19,2, Zhen Zhang1,2. 1. Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. 2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. 3. Department of Oncology, Second Affiliated Hospital of Nanchang University, Nanchang, China. 4. Department of Radiation Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 5. Department of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences & Zhejiang Cancer Hospital, Hangzhou, China. 6. Department of Radiation Oncology, Second Affiliated Hospital of Soochow University, Suzhou, China. 7. Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. 8. Department of Radiotherapy, Liaoning Cancer Hospital & Institute, China Medical University Cancer Hospital, Shenyang, China. 9. Department of Oncology, Guizhou Provincial People's Hospital, Guiyang, China. 10. Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Fuzhou, China. 11. Department of Abdominal Oncology, West China Hospital Sichuan University, Chengdu, China. 12. Department of Radiation Oncology, First Affiliated Hospital of Soochow University, Suzhou, China. 13. Department of Radiation Oncology, Sichuan Cancer Hospital& Institute, Chengdu, China. 14. Department of Radiation Oncology, HWA MEI Hospital, University of Chinese Academy of Science, Ningbo, China. 15. Department of Radiation Oncology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China. 16. Department of Radiation Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. 17. Department of Radiation Oncology, Ruijin Hospital Shanghai Jiaotong University School of Medicine, Shanghai, China. 18. Department of Biostatistics, School of Public Health, Fudan University, Shanghai, China. 19. Department of Colorectal Cancer, Fudan University Shanghai Cancer Center, Shanghai, China.
Abstract
PURPOSE: Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS: We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively (P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION: Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.
PURPOSE: Differentiating the irinotecan dose on the basis of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype improves the pathologic complete response (pCR) rate. In this study, we further investigated preoperative irinotecan combined with capecitabine-based chemoradiotherapy for locally advanced rectal cancer. PATIENTS AND METHODS: We conducted this randomized, open-label, multicenter, phase III trial in China. Eligible patients with clinical T3-4 and/or N+ rectal adenocarcinoma, UGT1A1 genotype *1*1 or *1*28 were randomly allocated to the control group: pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine; or the experimental group: radiation with capecitabine combined with weekly irinotecan 80 mg/m2 for patients with UGT1A1*1*1 or 65 mg/m2 for patients with UGT1A1*1*28, followed by irinotecan and capecitabine. The primary end point was pCR. This trial was registered with ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT02605265). RESULTS: Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population (n = 178 in both groups). Surgery was performed in 87% and 88% of patients in the control and experimental groups, respectively. The pCR rates were 15% (n = 27 of 178) and 30% (n = 53 of 178) in the control and experimental groups (risk ratio, 1.96; 95% CI, 1.30 to 2.97; P = .001). Four and 6 patients achieved complete clinical response in the control and experimental groups, respectively. Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups, respectively (P < .001). The commonest grade 3-4 toxicities were leukopenia, neutropenia, and diarrhea. The overall surgical complication rate was not significantly different between the two groups (11% v 15%; P < .001). CONCLUSION: Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.
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