Phase I study of weekly oxaliplatin (OXA) + 5-fluorouracil continuous infusion (FU CI) in patients (pts) with advanced colorectal cancer (CRC)

Abstract

3770 Background: A combination of OXA and FU is frequently used as 1st or 2nd line therapy for advanced CRC. Anyway, the optimal schedule for this drugs has not been defined. Methods: To identify the MTD of weekly OXA (60–70-80–90 mg/m2 d1,8,15) in combination with a fixed dose of FU CI (200mg/m2/die d1–21), at least 3 pts were treated at each dose level. Once identified the OXA recommended dose level (RDL), Leucovorin (LV; 20 mg/m2 d1,8,15) was added to the combination. Results: Since April 2000, 39 pts with progressive advanced CRC previously treated with fluoropyrimidines and Irinotecan (IRI) were accrued (males/females: 29/10; median age 67; ECOG PS 0/1/2: 10/24/5). Considering the first 2 cycles of treatment (2 months) no grade III-IV toxicity was observed up to 90 mg/m2/week of OXA (dose level 4). 3/6 pts treated at dose level 4 required a major change in the treatment program due to a dose limiting toxicity (DLT; asthenia, weight loss and unbearable peripheral sensory neuropathy) and OXA 90 mg/m2 + FU 200 mg/m2/die was thus deemed to be the MTD. When LV was added to the RDL (OXA 80 mg/m2 + FU 200 mg/m2/die), 3/5 pts experienced a DLT (gr 3 and gr 4 diarrhoea, neurotoxicity with functional impairment). This was thus defined as the MTD of OXA when combined with FU CI + LV, while OXA 70 mg/m2 + FU 200 mg/m2/die and LV 20 mg/m2 was find as the RDL for this combination (DLT: 0/3 pts) and 11 additional pts was accrued to investigate the tolerance on a larger cohort. Overall, 148 cycles (median number/pts: 3, range 1–9) were delivered corresponding to 438 weeks of chemotherapy (median number/pts: 9, range 2–27). 27/438 (6.2%) weeks of chemotherapy were delayed because of toxicity while 42/438 (9.6%) were delivered at a reduced dose and 6 (1.4%) were omitted. Among 34 pts with measurable disease completing at least one cycle 9 PR, 7 MR, 13 SD and 5 P were obtained. Conclusions: The combination of weekly OXA and FU CI ± LV is feasible and well tolerated. This schedule provided the backbone for a preoperative chemo-radiation regimen that has been developed for locally advanced rectal cancer and for an alternating regimen with weekly IRI and FU CI in pts with metastatic CRC. No significant financial relationships to disclose.