The Value of Oxaliplatin in Combination with Continuous infusion ± Bolus 5-Fluorouracil and Levo-Folinic Acid in Metastatic Colorectal Cancer Progressing after 5FU-Based Chemotherapy: A Giscad (Italian Group for the Study of Digestive Tract) Cancer Phase II Trial

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Abstract
Aims and background: The phase II trial was designed to evaluate the activity of combined oxaliplatin (L-OHP), continuous infusion (CI) ± bolus 5-fluorouracil (5FU) and levo-folinic acid (IFA) in patients with metastatic colorectal cancer progressing after one or more lines of 5FU-based chemotherapy. Patients and methods: We designed two contemporary studies: in the former we enrolled patients previously treated with 1 line of chemotherapy, and in the latter, patients previously treated with 2, 3 and 4 lines. Seventy-six consecutive patients were enrolled: 45 received L-OHP (85 mg/m2 iv 2 h on day 1) + I-FA (100 mg/m2 iv 2 h on days 1 and 2) + 5FU iv bolus (400 mg/m2 days 1 and 2) + 5FU (600 mg/m2 CI 22 h days 1 and 2 (FOLFOX 4); 31 received L-OHP (100 mg/m2 iv 2 h on day 1) + I-FA (250 mg/m2 iv 2 h on days 1 and 2), followed by 5FU (1500 mg/m2 CI 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression and/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disease [SD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. Results: Forty-five patients in 2nd line (22 FOLFOX 4, 23 FOLFOX 2), 23 (17 FOLFOX 4, 6 FOLFOX 2) in 3rd, 4 in 4th and 1 in 5th line were assessable; 3 were lost to follow-up. In 15 patients (11 FOLFOX 4, 4 FOLFOX 2), disease involved the liver only. A total of 533 courses were administered with a range of 1-14 in FOLFOX4 and 1-12 in FOLFOX2; dose intensity was 92.85%, and the total dose of the administered L-OHP was 98.29%. As a 2nd line treatment, FOLFOX 4 achieved TGC in 72.8% of the patients (PR, 18.2%; SD, 54.6%), with a median TTP of 6 months and a median OS of 7 months, whereas in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3rd line treatment, FOLFOX 4 produced TGC in 41.1% of patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median OS of 7+ months, whereas FOLFOX 2 obtained respective values of 50% (PR 16.7%, SD 33.3%), 7 and 9 months. As a 4th line of treatment, TGC was achieved in 2 patients (1 PR, 1 SD); the patient in 5th line therapy obtained a SD. With “de Gramont” as the first-line regimen, patients assessable were 24 in FOLFOX 4 and 18 in FOLFOX 2. In the former population, TGC was 70.8% (PR 37.5%, SD 33.3%), with a TTP of 6 months and OS of 10 months, whereas with FOLFOX2 these values were 61.1% (PR 5.6%, SD 55.5), 5 and 7 months. In patients with liver involvement only, FOLFOX 4 obtained TGC in 63.6% of cases (with a TTP of 7 months and OS of 6+ months), FOLFOX 2 in 100% (with a TTP of 9.5 months and OS of 13.5+ months). Both schedules exhibited an acceptable toxicity: neurologic, hematologic and hepatic grade 3 side effects occurred in a limited number of patients, with a higher frequency in the FOLFOX 2 group. Conclusions: Treatment with L-OHP, CI ± bolus 5FU and I-FA was well tolerated. The activity in terms of TGC was interesting and comparable with results reported in the literature for the standard treatment for 2nd line, i.e. irinotecan alone. Treatment was effective in 2nd line and in patients previously treated with more than two chemotherapy lines; in particular, treatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we could not define from the study the better regime.

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