A randomized phase II study to compare oxaliplatin plus 5-fluorouracil and leucovorin (FOLFOX4) versus oxaliplatin plus raltitrexed (TOMOX) as first-line chemotherapy for advanced colorectal cancer

Patients were ≥18 years with advanced, histologically or cytologically confirmed, non-resectable metastatic CRC with bi-dimensionally measurable disease, life expectancy ≥3 months, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, adequate bone marrow (platelet count ≥100,000/L, neutrophil count ≥2,000 cells/L, and hemoglobin level ≥9.0 mg/dL), renal [serum creatinine concentration <1.25× upper limit of normal (ULN) and creatinine clearance (CrCl) >65 mL/min] and hepatic (serum bilirubin level ≤1.5× ULN, aspartate amino transferase and alanine amino transferase ≤2.5× ULN, and alkaline phosphatase ≤5× ULN) function. Exclusion criteria included previous chemotherapy for advanced disease (or adjuvant chemotherapy ≤6 months before enrollment), treatment with an experimental drug within 4 weeks of inclusion, uncontrolled intercurrent disease, bone metastases as the only manifestation of the disease, any malignancy within 5 years of study entry (except for adequately treated non-melanoma skin cancer or in-situ cervical carcinoma) and grade ≥2 peripheral neuropathy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC) version 2.0. Pretreatment assessments included complete medical history, physical examination, performance status, complete blood count, serum chemistry, electrocardiogram, and baseline measurement of tumor size based on tomography scans (CT). The study was carried out in compliance with the Declaration of Helsinki, Good Clinical Practice Guidelines, and all applicable local regulatory requirements. Signed informed consent was obtained from all patients.

In this phase II, multicenter, open-label study, patients were randomized centrally in a 1:1 ratio to receive FOLFOX4 or TOMOX. Randomization was carried out using a four patient block randomization system at each study site, centrally administrated. FOLFOX4 was administered as previously described [8]: leucovorin 200 mg/m², bolus 5-FU 400 mg/m² plus 22-h continuous infusion of 5-FU 600 mg/m² days 1–2, and oxaliplatino 85 mg/m² day 1, every 2 weeks. Patients in the TOMOX group received raltitrexed 3 mg/m² as a 15-min infusion, followed 45 min later by oxaliplatin 130 mg/m² as a 2-h infusion, on day 1 of 3-week cycles. Raltitrexed dose and administration schedules were adjusted according to CrCl on day 1 of each cycle (CrCl >65 mL/min: 100 % of planned dose every 3 weeks; CrCl = 55–65 mL/min: 75 % of planned dose every 4 weeks; CrCl = 25–54 mL/min: 50 % of planned dose every 4 weeks). If raltitrexed administration was delayed, administration of oxaliplatin was also delayed.

Tolerability was evaluated at baseline and before each cycle. All toxicities graded according to the NCI-CTC version 2.0 except peripheral neuropathy that was evaluated according with the Sanofi classification. Dose adjustments and administration delays were evaluated based on the each patient’s most severe toxicity. In FOLFOX4 group, bolus and continuous infusion 5-FU was reduced to 300 and 500 mg/m², respectively, if neutropenia, thrombocytopenia, diarrhea, stomatitis, or other toxicities grade (G) 3–4 occurred. Oxaliplatin was reduced to 65 mg/m² in case of paresthesias associated with pain or functional less lasted during 7–14 days, and it was stopped if longer. In the TOMOX regimen, in case of neutropenia or thrombocytopenia G3 or G4, raltitrexed was reduced to 75 or 50 %, respectively, and oxaliplatin was administered at 100 mg/m². Regarding non-hematological toxicities, in case of diarrhea, or stomatitis G2, G3 or G4 raltitrexed was reduced at 75, 50 % or omitted, respectively. Oxaliplatin was reduced to 100 mg/m² in case of paresthesias associated with pain or functional less lasted during 7–14 days, and was stopped if longer.

In both groups, treatment was continued until progressive disease (PD), death, withdrawal of informed consent, or unacceptable toxicity. In patients who achieved a complete response, treatment was continued for a maximum of 6 months with or without oxaliplatin, depending on degree of cumulative neurotoxicity. Prophylactic anti-emetics were administered according to normal clinical practice. Routine use of a granulocyte colony-stimulating factor was not allowed.

QoL was assessed every 6 weeks using the short form-36 (SF-36) questionnaire.

The primary objective of the study was to demonstrate the non-inferiority of TOMOX when compared with FOLFOX4 in terms of Objective Response Rate (ORR). To avoid bias, response was evaluated according to RECIST every 3 months, regardless of the number of cycles administrated. The secondary objectives included OS, PFS, response duration, tolerability and QoL. OS and PFS were assessed from date of randomization until progression (PD), death or last follow-up. Response duration was defined as date of first response until PD, death or last follow-up.

Determination of sample size was based on the primary endpoint. Based on previously published data, the ORR for both regimens was expected to be ~50 %. The study was designed to detect a 12 % as a maximum difference for non-inferiority in ORR between the two arms, using α of 0.05 and a β of 0.20. To achieve this, the number of patients required was 430 (215 per group). Intergroup comparisons of ORR ±95 % confidence intervals (CI) were conducted using a normal asymptotic one-sided Z test for proportions (non-inferiority) on independent samples. Univariate analyses of OS and PFS were conducted according to Kaplan–Meier estimates [26]. Comparisons between survival distributions were made by Cox proportional hazards model regressions, hazard ratios (HR) and 95 % CI [27]. Statistical significance was defined as p ≤ 0.05. The limit for non-inferiority was established in 12 % applied to the HR 95 % CI limits.