No abstract

Gastric adenocarcinoma has a poor prognosis, accounting for 10 000 deaths per year in the UK. Although its incidence is declining, it remains the second most common tumour world-wide and the fourth commonest cancer in Europe. At presentation around 30% of patients have metastatic disease and a further 30% have locally advanced disease penetrating the serosal surface of the stomach or directly invading adjacent organs. With locally advanced disease, curative surgery is only possible in a minority of patients and recurrent disease affects 80% of patients within 5 years of potentially curative surgery. Therefore the prognosis remains poor with an overall survival of around 20% at 5 years (Allum et al, 1989).Combination chemotherapy results in a significant survival advantage in patients with advanced gastric cancer compared with best supportive care in randomized clinical trials. High response rates may be obtained with the use of protracted venous infusional 5-fluorouracil (5-FU), cisplatin and epirubicin -the ECF regimen (Findlay et al, 1994). In an initial study with this regimen, an overall response rate of 71% and a complete response rate of 12% were observed. These encouraging results have been confirmed in two subsequent studies, with overall response rates of around 60% and with complete responses occurring in around 10% of patients (Highley et al, 1994;Zaniboni et al, 1995). In a multi-centre randomized study, ECF resulted in significantly better response rate (45%) and median survival (8.9 months), with significantly less toxicity compared to the FAMtx regimen (Webb et al, 1997). Consequently the ECF regimen is considered the treatment of choice for advanced adenocarcinoma of the oesophagus and stomach by many clinicians in the UK.This regimen, however, requires protracted venous infusion of 5-FU through a Hickman catheter, which is associated with significant morbidity. The most common problems encountered are thrombosis and sepsis requiring line removal in up to 15% of patients (Webb et al, 1997). Consequently, replacing the continuous infusion of 5-FU by a drug with a related mechanism of action would overcome the need for inserting a Hickman catheter and its associated morbidity. As inhibition of thymidylate synthase (TS) is an important mechanism of action of infusional 5-FU, one such strategy is to combine epirubicin and cisplatin with a specific TS inhibitor. TS catalyses the reductive methylation of deoxyuridylate (dUMP) to thymidylate (TMP), the rate-limiting step in the synthesis of deoxythmidine triphosphate (TTP). TTP is the only nucleotide specifically required for DNA synthesis and has been postulated as an ideal target for anticancer drugs.Raltitrexed (tomudex) is a quinazolone-based, water-soluble anti-folate, which is extensively and efficiently poly-glutamated. The poly-glutamates are 100 times more potent inhibitors of TS than the parent drug and are retained intra-cellularly allowing a A dose-finding study of raltitrexed (tomudex) with cisplatin and epirubicin in advanced gastro-oesoph...