729 High dose 5FU biomodulation by high dose leucovorin and individual 5FU dose adjustment in metastatic colorectal cancer. A multicentric prospective study of 130 patients

Extrahematopoietic toxic side effects limit 5FU dose intensification. In a previous study with 5FU dose escalation, a pharmacokinetic follow up led us to define a therapeutic index. 5FU plasma level range: 2.5 to 3.5 mg/I (AUC: 20 to 28 mgxh/1 (Proc. AACR 92). Study a phase II prospective study was carried out from 05/1991 to 12/1992. Weekly 8 hour infusion high dose 5FU were potentiated by 400 mg/m 2 leucovorin. The initial dose of 5FU, 1300 mg/m 2 , was adapted weekly, according to a 5FU plasma levels fo up (HPLC) to obtain the optimal therapeutic range previously determined. The therapeutic efficiency was evaluated after 2 months in the optimal range. Results 130 patients (pts); no prior chemotherapy or only adjuvant chemotherapy (18 pts); mean age 62 (27−75); initial P.S.: 0 (28%); 1 (26%); 2 (36%); 3 (3%). Metastatic sites:liver (71%); lung (20%); lymphnodes (8%); other (11%); local recurrence (17%); measurable disease (89%). Toxicity for the whole treatment (mean: 9 months (mo); diarrhea (39%) (4 grade III; handfoot syndrome (30%) (4 grade III); mucositis (4%); WH.O. grade toxicity: I (22%);II (25%); III (3%); IV (0%). PS. after 2 months: improved for 50% pts. Response rates CR (17%); PR (39%); minor + stable disease (29%); progression (15%); mean duration of response (15.5 mo). Overall survival and disease free survival at 1 year (68.5%, 53%); at 2 years (38%, 18%); median survival: 15 mo; mean disease free survival: 11 mo. Pharmacokinetics Study 5FU dose necessary to obtain therapeutic levels: at 3 months (3 g, s.e. 68, 0.9 g to 4.5 g), at 6 mo (3.5 g, s.e. 450, 1 g to 7 g). Five pts were immediately in a highly toxic zone. Time necessary to obtain the therapeutic levels was predictive for the quality of the response (CRvsPR + ST: 3 vs 6 courses). Variations of 5FU metabolism were observed during the treatment leading to a 5FU plasma levels decrease or increase. They required a 5FU dose adjustment to maintain the optitnal 5FU levels to prevent tumor escape or acute toxicity. Discussion we have started a multicenter phase III trial comparing a constant dose of 5FU and an individual 5FU dose adjustment to prove the benefit of a pharmacokinetics follow up.