title: A dose-finding study of raltitrexed (tomudex) with cisplatin and epirubicin in advanced gastro-oesophageal adenocarcinoma.
abstract: The standard treatment for advanced gastro-oesophageal cancer in the UK is epirubicin, cisplatin and continuous infusion 5-fluoruracil by an indwelling central venous catheter (ECF), which has significant morbidity. Raltitrexed (tomudex), a specific inhibitor of thymidylate synthase with a long plasma terminal half-life (50-100 h) has activity in gastro-intestinal tract malignancy. To reduce the Hickman line-associated morbidity of ECF; we have conducted a dose-finding study of tomudex combined with epirubicin and cisplatin. Twenty-four patients (22 males, two female), median age 63 years (range 21-75), ECOG performance status < or =2 with histologically proven, unresectable or metastatic gastric (14 patients), gastro-oesophageal 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 successive cohorts. Six patients were treated per dose level with no intra-patient dose escalation. Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level. After defining 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 total of 102 cycles (50% completed 6 cycles) were administered. The dose-limiting 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 oesophagogastric adenocarcinoma. The recommended dose of tomudex for further study in combination with epirubicin and cisplatin is 2.5 mg m(-2).
authors.affiliation: CRC Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Glasgow, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Eatock
authors.forename: D A
authors.initials: DA
authors.lastname: Anthony
authors.forename: M
authors.initials: M
authors.lastname: El-Abassi
authors.forename: P
authors.initials: P
authors.lastname: Wilson
authors.forename: J
authors.initials: J
authors.lastname: Paul
authors.forename: M
authors.initials: M
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Soukop
authors.forename: T R
authors.initials: TR
authors.lastname: Evans
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines / Q000008:administration & dosage*; D013274:Stomach Neoplasms / Q000188:drug therapy*; D013876:Thiophenes / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D013876:Thiophenes; D015251:Epirubicin; C068874:raltitrexed; D002945:Cisplatin