Double Modulation of 5-Fluorouracil by Trimetrexate and Leucovorin in Patients With Advanced Colorectal Carcinoma

Abstract

The purpose of this report is to evaluate the efficacy and toxicity (Tx) of a double modulation of 5-fluorouracil (5-FU) by trimetrexate (TMTX) and leucovorin (LV) in patients with advanced recurrent (inoperable) or metastatic colorectal cancer (ACC). Between December 1997 and August 2000, 36 patients were entered in this phase II study. Median age was 61 years, and 18 patients (50%) were female. Median performance status was 0 (range: 0-1), whereas primary tumor location was colon in 21 patients (58%) and rectum in 15 patients (42%). The number of metastatic sites was 1:29 patients (81%); 2:6 patients (17%) and 3:1 patient (3%). Hepatic involvement was observed in 33 patients (92%). Treatment consisted of TMTX 110 mg/m2 IV over 1 hour at hour (H) 0; LV 50 mg/m2 IV over 2 hours IV infusion starting at H 18; and 5-FU 900 mg/m2 IV bolus at H 20. LV (rescue) 15 mg/m2 orally was administered every 6 hours (total 6 doses) beginning at H 24. Cycles were repeated every 2 weeks until progressive disease (PD) or severe Tx. Thirty-four patients are assessable for response (R) (two patients refused further treatment after the first course of therapy), whereas all patients were assessable for Tx. Complete response: 1 patient (3%); partial response: 4 patients (12%), with an overall objective response rate of 15% (95% CI, 1%-25%); no change: 12 patients (35%); and progressive disease: 17 patients (50%). The median time to treatment failure was 4 months and median survival was 11 months. Tx was within acceptable limits. The dose-limiting side effect was mucositis. Eight episodes of grade II or III stomatitis were observed and were responsible for dosage modifications of TMTX and 5-FU. Leukopenia was observed in 16 patients (44%); neutropenia was registered in 19 patients (53%); anemia was seen in 18 patients (50%); emesis in 22 patients (61%); and dermatitis in 3 patients (8%). There were no therapy-related deaths. The double modulation of 5-FU by TMTX and LV showed modest antitumoral activity with mild to moderate Tx.

From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates

“…In a phase I study the combination of TMTX and 5FU with leucovorin produced a 20% response rate in previously treated patients with gastroin- testinal malignancies, the majority of which were colorectal [132]. These observations led to phase II combinations studies in which response rates of 15-42% were obtained with the combination in patients with previously untreated colorectal cancer [127][128][129], and later to 2 randomized trials in which 5FU leucovorin was compared with TMTX, 5FU and leucovorin (Table 6) [133,134]. These trials had disappointing outcomes.…”

What’s the news about antimetabolites in oncology?

“…1), cinq essais cliniques sont enregistré s aux É tats-Unis et en Amé rique du Sud, dans le traitement de l'osté osarcome, du cancer du cô lon, du cancer du pancré as et dans les leucé mies, mais plus aucune inclusion n'est ré alisé e. D'autres associations seraient plus efficaces, en deuxiè me ou troisiè me ligne, que l'association trimé trexate-capé citabine dans le traitement du cancer colorectal [14]. La double modulation du 5-FU par trimé trexate et LV n'entraîne qu'une modeste activité antitumorale [12]. Avec le composé OSI-7904L, nouvel inhibiteur liposomal de la TS, cinq essais cliniques ont é té ouverts.…”

Antimetabolites and cancer: emerging data with a focus on antifolates

“…Recently, a doublet scheme, in combination with 5-FU, achieved 30% response rates in metastatic colon cancer [18].…”