Phase II and gene expression analysis trial of neoadjuvant capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy for locally advanced rectal cancer: Hoosier Oncology Group GI03-53

Purpose

We designed this study in locally advanced rectal cancer to determine the pathological response, toxicity, and disease-free survival (DFS) with induction capecitabine plus irinotecan followed by capecitabine-based chemoradiotherapy (CRT) and analyze the gene expression of enzymes involved in the metabolism of capecitabine and irinotecan for associations with response and toxicity.

Methods

Patients with T3/T4 or node positive rectal cancer were treated with capecitabine 1,000?mg/m² twice daily (BID) days 1?C14, and irinotecan 200?mg/m² on day 1 every 21?days for 2 cycles, followed by capecitabine 825?mg/m² BID days 1?C5 per week with concurrent radiotherapy 50.4?Gy in 28 fractions. Surgical resection occured a median of 7.4?weeks after CRT. Gene expression levels or sequencing were used to analyze carboxylesterase-converting enzymes (CES1, CES2), thymidylate synthase (TS), thymidine phosphorylase (TP), dehydropyrimidine dehydrogenase (DPD), topoisomerase I (TOPO I), and uridine-diphosphate (UDP) glucuronosyl transferase 1A1 in pre- and post-treatment tumor and normal tissue samples.

Results

Twenty-two patients were enrolled, and 18 completed neoadjuvant therapy and underwent R0 resection. Two patients with UGT1A1 7/7 had grade 3 and 4 neutropenic fever and sepsis. Pathological complete response (pCR) occurred in 6 of 18 patients (33?%) and 10 (56?%) had tumor and/or nodal downstaging. The 3-year DFS was 75.5?% (95?% CI, 39.7?C91.8?%). Locoregional control rate was 100?%. We observed higher TP gene expression in pCR patients, but no correlations with toxicity.

Conclusions

This neoadjuvant regimen was safe and demonstrated significant antitumor activity. High TP tumor gene expression was associated with obtaining pCR.