Under the guidance of the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) genotype, an increased irinotecan dose in combination with capecitabine-based chemoradiation significantly improved the clinical response rate with acceptable toxicities in Chinese patients with locally advanced rectal cancer. Ji Zhu of the Department of Radiation Oncology, Fudan University Shanghai Cancer Center in Shanghai, China and colleagues investigated whether adding a second drug to neoadjuvant chemoradiation can improve the clinical outcome. They reported the results of the first phase III study to evaluate the use of the UGT1A1 genotype for guiding the irinotecan dose in this setting on 29 October 2020 in the Journal of Clinical Oncology.
The authors explained in the study background that irinotecan has been investigated for its efficacy when combined with neoadjuvant chemoradiation, but there has been concern about its poor tolerability.
Differentiating the irinotecan dose on the basis of the UGT1A1 genotype improves the pathologic complete response (pCR) rate. In this study, the Chinese investigators further explored neoadjuvant irinotecan combined with capecitabine-based chemoradiation for locally advanced rectal cancer and conducted randomised, open-label, multicentre, 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 treated with pelvic radiation of 50 Gy in 25 fractions with concurrent capecitabine, followed by oxaliplatin and capecitabine or the experimental group who received 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 study primary endpoint was pCR.
Of the 360 patients initially enrolled, 356 were evaluated as the modified intention-to-treat population with 178 patients in each group. Surgery was performed in 87% and 88% of patients in the control and experimental groups. The pCR rates were 15% (27 of 178 patients) and 30% (53 of 178 patients) in the control and experimental groups (risk ratio 1.96; 95% confidence interval [CI] 1.30 to 2.97; p = 0.001). Complete clinical response was achieved by 4 and 6 patients in the control and experimental groups.
Grade 3-4 toxicities were recorded in 11 (6%) and 68 (38%) patients in the control and experimental groups (p < 0.001). The commonest grade 3-4 toxicities were leukopenia, neutropenia and diarrhoea.
The overall surgical complication rate was not significantly different between the two groups (11% vs 15%; p < 0.001).
The authors concluded that adding irinotecan guided by UGT1A1 genotype can increase the pCR rate from 15% to 30% compared with capecitabine-based neoadjuvant chemoradiation in Chinese patients. More toxicities were induced by irinotecan, particularly leukopenia, neutropenia and diarrhoea. They speculated that under the guidance of UGT1A1 genotype, an increased dose of irinotecan added to standard chemoradiation might become an improved strategy to achieve a better tumour regression in patients with locally advanced rectal cancer.
Furthermore, the authors commented that ongoing phase III ARISTOTLE study conducted in the United Kingdom was also designed to determine the benefit of irinotecan in neoadjuvant chemoradiation. The main difference between ARISTOTLE and their study is that patients in ARISTOTLE receive a fixed irinotecan dose of 60 mg/m2 per week for four cycles without UGT1A1 genotype–based guidance.
At the ASCO 2020 Annual Meeting, the ARISTOTLE researchers reported that patients in the irinotecan group did not reach a higher pCR rate. The Chinese investigators pressume that the main reason for this was that the irinotecan dose was insufficient. However, there are differences in the genotype prevalence and irinotecan tolerance between White and Asian populations and it is needed to fully consider such differences when assessing the generalisability of the results.
The study was supported by grants from Fudan University Shanghai Cancer Center, National Natural Science Foundation of China and Natural Science Foundation of Shanghai.
Zhu J, Liu A, Sun X, et al. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. JCO; Published online 29 October 2020. DOI: 10.1200/JCO.20.01932.