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

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.