The value of oxaliplatin in combination with continuous infusion +/- bolus5-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

Aims and background: The phase II trial was designed to evaluate the activi ty of combined oxaliplatin (L-OHP), continuous infusion (CI) +/- bolus 5-fl uorouracil (5FU) and levo-folinic acid (IFA) in patients with metastatic co lorectal cancer progressing after one or more lines of 5FU-based chemothera py. Patients and methods: We designed two contemporary studies: in the former w e 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/m(2) iv 2 h on day 1) + I-FA (100 mg/m(2) iv 2 h on days 1 and 2)+ 5FU iv bolus (400 mg/m (2) days 1 and 2)+ 5FU (600 mg/m(2) CI 22 h days 1 and 2 (FOLFOX 4); 31 rec eived L-OHP (100 mg/m(2) iv 2 h on day 1) + I-FA (250 mg/m(2) iv 2 h on day s 1 and 2), followed by 5FU (1500 mg/m(2) CI 24 h days 1 and 2 (FOLFOX 2). The treatment was recycled every 2 weeks and continued until progression an d/or unacceptable toxicity or patient preference. The primary end point was activity (tumor growth control [TGC]: partial response [PR] + stable disea se ESD]); the secondary end points were time to progression (TTP), overall survival (OS) and toxicity. Results: Forty-five patients in 2(nd) line (22 FOLFOX 4, 23 FOLFOX 2), 23 ( 17 FOLFOX 4, 6 FOLFOX 2) in 3(rd), 4 in 4(th) and 1 in 5(th) line were asse ssable; 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 2(nd) li ne 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, wherea s in the FOLFOX 2 group these figures were 78.3% (PR 21.8%, SD 56.5%), and 5 and 9 months. As a 3(rd) line treatment, FOLFOX 4 produced TGC in 41.1% o f patients (PR 23.5%, SD 17.6%), with a median TTP of 5 months and median O S of 7 + months, whereas FOLFOX 2 obtained respective values of 50% (PR 16. 7%, SD 33.3%), 7 and 9 months. As a 4(th) line of treatment, TGC was achiev ed in 2 patients (1 PR, 1 SD); the patient in 5(th) 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 w ith FOLFOX 4 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 ca ses (with a TTP of I 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 acce ptable toxicity: neurologic, hematologic and hepatic grade 3 side effects o ccurred in a limited number of patients, with a higher frequency in the FOL FOX 2 group. Conclusions: Treatment with L-OHP, Cl +/- bolus 5FU and I-FA was well toler ated. The activity in terms of TGC was interesting and comparable with resu lts reported in the literature for the standard treatment for 2(nd) line, i .e. irinotecan alone. Treatment was effective in 2(nd) line and in patients previously treated with more than two chemotherapy lines; in particular, t reatment was active in patients with hepatic disease only. Although the two schedules seemed to achieve the same benefit with the same tolerance, we c ould not define from the study the better regime.