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- Title
Safety And Antitumor Activity Of Arsenic Trioxide (Ato) Plus Infusional 5-Fu, Leucovorin And Irinotecan (Folfiri) As Second-Line Treatment For Refractory Metastatic Colorectal Cancer: Preliminary Results From A Pilot Study.
- Authors
Lakshmaiah, K. C.; Babu, K. Govind; Dasappa, Lokanatha
- Abstract
Background: After failing oxaliplatin-based first-line chemotherapy (CT), about 4-21% of patients with metastatic colorectal cancer (mCRC) respond to irinotecan-based second-line treatment. Prolonged exposure of colon cancer cells to 5-FU induces resistance, due to increased synthesis of thymidylate synthase (TS). Earlier studies have demonstrated that ATO can significantly re-sensitize resistant colon cancer cells to 5-FU by down regulating TS. Moreover, ATO can also act as a vascular disrupting agent and has synergistic effect with irinotecan on tumor growth delay. We hypothesized that a combination of ATO with FOLFIRI regimen in mCRC patients refractory to first-line FOLFOX, could further improve the outcome of second-line CT. Methods: The inclusion criteria were: age ?18 years; pathologically proven mCRC; ECOG PS ?2; refractory to first-line FOLFOX; not affording for biologic agents due to economic constraint; adequate organ functions and measurable disease according to RECIST 1.1. Major exclusion criteria were: ?2 lines of previous CT for metastatic disease; congestive cardiac failure and evidence of brain metastases. Patients were administered ATO 0.15 mg/kg/day on days 1 to 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 v 4.0. Results: Between October 2016 and May 2017, 13 patients with refractory mCRC were treated with this investigational combination. The median age was 47 years (range, 32-65); 10 males and 3 females; ECOG PS 0-1/2, 12/1; site of primary tumor rectum/ colon, 8/5. Median baseline serum CEA was 78 ng/ml (range, 18- 836). The most common site of metastases was liver (n=7) followed by peritoneum (n=5), lungs (n=3) and non-regional lymph-nodes (n=3); number of involved metastatic sites 1-2/?3, 8/5. After 6 cycles of CT, overall response rate and disease control rate was 23% and 84.6% respectively (CR=0, PR=3 pts, SD=8 pts); approximately 69% of patients experienced a ?50% decline in serum CEA level. At a median follow-up of 5.5 months (range, 4-8), 7 patients had disease progression and kept on best supportive care; 6 patients were still on study drugs; and all 13 patients were alive. Median progressionfree survival was 4.5 months (95%CI 3.8-5.2), from the initiation of ATO plus FOLFIRI. The toxicities were as follows: Grade 1/2 toxicity: fatigue (4 pts.), constipation (1), nausea and vomiting (1). Grade 3 toxicity: fatigue (3), neutropenia (2), diarrhea (2), QTc prolongation (1). No patient experienced grade 4 toxicities. Conclusions: The addition of ATO 0.15 mg/kg/day on days 1 to 2, to standard FOLFIRI regimen as second-line CT in patients with refractory mCRC offers an encouraging anti-tumor effect at the cost of manageable toxicity.
- Subjects
ARSENIC trioxide; COLON cancer; METASTASIS; THYMIDYLATE synthase; FLUOROURACIL; FOLINIC acid
- Publication
Journal of Cancer Research & Therapeutics, 2017, Vol 13, pS21
- ISSN
0973-1482
- Publication type
Article