Use of the combination of raltitrexed (R) and oxaliplatin (O) as a salvage treatment for patients with advanced colorectal cancer (ACRC) refractory to 5-fluorouracil (5-FU) based chemotherapy and with hyperexpression of thymidylate synthase (TS): Final report

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3727 Background: TS is an important target for fluoropyrimidine based TS inhibitors and its hiperexpression has been correlated with resistance to 5-FU, but not necessarily to R, a folate-based TS inhibitor, which appears to be more correlated to FPGS activity (van Triest et al, 1999; Cheradame et al, 1999). O is a novel diaminocyclohexane platinum agent also active in ACRC and obviously not related to TS status. Methods: 21 patients with ACRC not responsive to a first line 5-FU based chemotherapy: 14(67%) to IFL(Saltz) regimen, 4(19%) to 5-FU/LV- (Mayo Clinic) regimen and 3(14%) to capecitabine) and high expression of TS (determined by IHC technique-grades 2+ and 3+) and age less than 70 Y/O, measurable disease, WHO PS 0–2, life expectancy ≥ 2 months, adequate renal and liver functions and informed consent were accrued to receive: T – 3.0 mg/m2 and O – 120mg/m2 every 21 days until progression. Results: Thirteen were male and 8 female; median age: 58(39–67); median PS: 1 (1–2). Number of cycles administered: 98 (median per patient: 4). There were 7 PR (33%), 3 SD(14%) and 11(53%) PD. Clinical benefit based upon weight gain, PSand analgesic consumption was observed in all 7 responders (33%). The median PFS was 6.5 months (1–12) and the median overall SV was 8 months (2–12+). The 1 year SV was 17%. The regimen was well tolerated. WHO grade 4 diarrhea occurred in one patient, grade 3 in 12(12%) cycles; grade 2 vomiting in 10(10%) cycles; grades 3 and 4 neutropenia in 16(16%) cycles; reversible febrile neutropenia in 2 patients: (onedied due to sepsis); grade 3 thrombocitopenia in 6(6%) cycles; anemia grades 2 and 3 in 21(21%) cycles and grade 2 oral mucositis in 3 (3%) of the cycles. Grades 1 and 2 neuropathy was observed in 61% of the cycles. Conclusions: These favorable results suggest that this combination might be effective in the treatment of patients with ACRC with high expression of TS and should be also explored as a first line regimen for this subset of patients with predictable resistance to fluoropyrimidine based chemotherapy. No significant financial relationships to disclose.