Safety and antitumor activity of arsenic trioxide plus infusional 5-fluorouracil, leucovorin, and irinotecan as second-line chemotherapy for refractory metastatic colorectal cancer: A pilot study from South India.

Abstract

After failing oxaliplatin-based first-line chemotherapy (CT), approximately 4%-21% of patients with metastatic colorectal cancer (mCRC) respond to irinotecan-based second-line treatment. Earlier studies have demonstrated that arsenic trioxide (ATO) can significantly resensitize resistant colon cancer to 5-fluorouracil (5-FU) by downregulating thymidylate synthase (TS). We hypothesized that a combination of ATO with infusional 5-FU, leucovorin, and irinotecan (FOLFIRI) regimen in mCRC patients refractory to first-line FOLFOX/CAPOX could further improve the outcome of second-line CT. Patients were administered ATO 0.15 mg/kg/day on days 1-2 along with FOLFIRI regimen at standard doses every 2 weeks, until disease progression, unacceptable toxicity, or patients' refusal. Responses to CT were reported according to RECIST 1.1. Adverse events were classified based on CTCAE version 4.0. Between September 2016 and July 2017, 17 patients with refractory mCRC were treated with this investigational combination. The median age was 49 years; 13 males and 4 females; ECOG PS 0-1/2, 14/3. The most common site of metastases was liver (n = 11) followed by peritoneum (n = 7) and number of involved metastatic sites 1-2/≥3, 9/8. After 6 cycles of CT, overall response rate and disease control rate were 17.6% and 82.4%, respectively (complete remission = 0, partial remission = 3 patients, stable disease = 11 patients). Median progression-free survival was 5.3 months (95% confidence interval [CI]: 4.3-7.0) and median overall survival was 9 months (95% CI: 7.4-10.5) from the initiation of ATO plus FOLFIRI. The toxicities were as follows: Grade 1/2 toxicity: fatigue (7 patients), constipation (2), and nausea and vomiting (2); Grade 3 toxicity: fatigue (3), neutropenia (2), febrile neutropenia (1), diarrhea (2), and QTc prolongation (1). No patient experienced Grade 4 toxicities. The addition of ATO to FOLFIRI regimen as second-line CT in patients with refractory mCRC offered an encouraging antitumor effect at the cost of manageable toxicity.