Top Line: Does irinotecan improve pathologic complete response rate (pCR) in locally advanced rectal cancer?

The Study: pCR is an important prognostic factor for patients receiving neoadjuvant fluoropyrimidine-based chemoradiation for rectal cancer. But the outcomes from trials adding second chemotherapy agents have been inconclusive. RTOG 0247 compared oxaliplatin and irinotecan combined with capecitabine and radiation and found that the pCR rate was twice as high (10.4 vs 20.8%) with oxaliplatin. A hypothesis for irinotecan’s underperformance was the required reduction in dose intensity due to toxicity. Recent studies have shown that irinotecan toxicity is associated with the activity of UGT1A1, which is involved in drug inactivation and clearance. In this Chinese trial, 360 patients with locally advanced rectal cancer were randomized to receive capecitabine and 50 Gy in 25 fractions (CapRT) with or without irinotecan (CapIriRT). Importantly, they all had to have one of two UGT1A1 genotypes that are associated with better irinotecan tolerance. Another important note is that these genotypes are more frequent in Asian versus white/western populations. In the CapIriRT arm, capecitabine dose was reduced from 825→ 625 mg/m2 BID, and the irinotecan dose was also adjusted according to UGT1A1 genotype. Over 95% of patients in both arms received >90% of the planned RT and capecitabine dose while 70% in the CapIriRT arm received at least 4 of 5 planned cycles of irinotecan. Both arms received a cycle of consolidation chemotherapy. Irinotecan increased grade 3+ toxicity from 6→ 38%, which were mostly hematologic. However, irinotecan was also associated with a significant increase in the pCR rate from 18→ 34%.

TBL: UGT1A1 genotype may allow more effective dosing of irinotecan and improved pCR among a subset of patients with locally advanced rectal cancer. | Zhu, J Clin Oncol 2020


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