In a Chinese phase III trial reported in the Journal of Clinical Oncology, Zhu et al found that the addition of irinotecan to neoadjuvant capecitabine chemoradiation (CapIriRT)—with irinotecan dosing guided by UGT1A1 genotype—followed by capecitabine/irinotecan (XELIRI) significantly improved pathologic complete response rate vs capecitabine chemoradiation (CapRT) followed by capecitabine/oxaliplatin (XELOX) in patients with locally advanced rectal cancer.
Study Details
The open-label multicenter trial included 356 patients (modified intent-to-treat population) with clinical T3-4 or N1 rectal adenocarcinoma and UGT1A1 genotype *1*1 or *1*28. Patients were randomly assigned between November 2015 and December 2017 to receive neoadjuvant CapRT followed by XELOX (n = 178) or CapIriRT followed by XELIRI (n = 178). The CapRT group received radiotherapy at 50 Gy/25 fractions with concurrent capecitabine at 825 mg/m2 twice daily 5 days/week, followed 2 weeks after completion of chemoradiation by a cycle of XELOX consisting of capecitabine at 1,000 mg/m2 twice daily on days 1–14 plus oxaliplatin at 130 mg/m2 on day 1. The CapIriRT group received radiotherapy at the same dose with capecitabine at 625 mg/m2 twice daily 5 days/week and weekly irinotecan at 80 mg/m2 in patients with the UGT1A1*1*1 genotype and 65 mg/m2 in those with the UGT1A1*1*28 genotype, followed 2 weeks after completion of chemoradiation by a cycle of XELIRI consisting of capecitabine at 1,000 mg/m2 twice daily on days 1–14 and irinotecan at 200 mg/m2 on day 1. The primary endpoint was pathologic complete response rate in the modified intent-to-treat population.
KEY POINTS
- The addition of irinotecan with dose guided by UGT1A1 genotype to capecitabine chemoradiation was associated with improved pathologic complete response rate.
- Grade 3 or 4 toxicity was more common in patients receiving chemoradiation with capecitabine plus irinotecan.
Pathologic Complete Response Rate
Surgery was performed in 87% of patients in the CapRT group vs 88% of the CapIriRT group. Pathologic complete response was observed in 27 (15%) of 178 patients in the CapRT group vs 53 (30%) of 178 in the CapIriRT group (risk ratio = 1.96, 95% confidence interval [CI] = 1.30–2.97, P = .001). Complete clinical response was observed in four vs six patients. Among patients who underwent surgery, pathologic complete response was achieved in 18% vs 34% (risk ratio = 1.93, 95% CI = 1.28–2.89, P =.001).
Adverse Events
Grade 3 or 4 toxicity occurred in 6% of the CapRT group vs 38% of the CapIriRT group (P < .001), with the most common in the CapIriRT group being leukopenia (25% vs 3%), neutropenia (20% vs 2%), and diarrhea (13% vs 2%). Grade ≥ 3 postoperative complications occurred in 11% vs 15% of patients (P = .268). No deaths within 60 days of surgery were reported.
The investigators concluded: “Adding irinotecan guided by UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.”
Zhen Zhang, MD, of Fudan University Shanghai Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by Fudan University Shanghai Cancer Center, National Natural Science Foundation of China, and Natural Science Foundation of Shanghai. For full disclosures of the study authors, visit ascopubs.org.
