A dose-finding study of raltitrexed (tomudex) with cisplatin and epirubicin in advanced gastro-oesophageal adenocarcinoma

The standard treatment for advanced gastro-oesophageal cancer in the UK is epirubicin, cisplatin and continuous infusion 5-fluoruracil by an indwellin g central venous catheter (ECF), which has significant morbidity. Raltitrex ed (tomudex), a specific inhibitor of thymidylate synthase with a long plas ma terminal half-life (50-100 h) has activity in gastro-intestinal tract ma lignancy. To reduce the Hickman line-associated morbidity of ECF; we have c onducted a dose-finding study of tomudex combined with epirubicin and cispl atin, Twenty-four patients (22 males, two female), median age 63 years (ran ge 21-75), ECOG performance status less than or equal to 2 with histologica lly proven, unresectable or metastatic gastric (14 patients), gastro-oesoph ageal junction (nine patients) or oesophageal (one patient) adenocarcinoma received treatment with 3-weekly cisplatin 60 mg m(-2), epirubicin 50 mg m( -2) and tomudex at doses of 2 mg m(-2), 2.5 mg m(-2) or 3 mg m(-2) in succe ssive cohorts. Six patients were treated per dose level with no intra-patie nt dose escalation. Dose escalation occurred after six patients had complet ed at least one cycle of chemotherapy at the previous dose level. After def ining the maximum tolerated dose a further six patients were treated at the preceding dose level to assess toxicity at the proposed phase II dose. A t otal of 102 cycles (50% completed 6 cycles) were administered. The dose-lim iting toxicities are neutropenia and diarrhoea occurring in 2/6 patients at the 3 mg m(-2) dose level. Of those patients evaluable for response, there were eight partial and one complete response (overall response rate 38%). The median survival was 9.9 months. ECT is an active regimen in oesophagoga stric adenocarcinoma. The recommended dose of tomudex for further study in combination with epirubicin and cisplatin is 2.5 mg m(-2). (C) 2000 Cancer Research Campaign.