Etoposide, doxorubicin and cisplatin (EAP) treatment in advanced gastric carcinoma: a multicentre study of the Italian Trials in Medical Oncology (I.T.M.O.) Group

Bajetta, Emilio; Bartolomeo, Maria Di; Braud, Filippo de; Bozzetti, Federico; Bochicchio, Anna Maria; Comella, Pasquale; Fagnani, Daniele; Farina, G.; Ferroni, C.; Franchi, R.; Gebbia, Vittorio; Ianniello, Giovanni Pietro; Iirillo, A.; Pinotti, Graziella; Schieppati, G.; Ucci, G.; Visini, M.; Zaniboni, Alberto; Buzzoni, Roberto; Casartelli, C.; Nelli, Patrizia

doi:10.1016/0959-8049(94)90527-4

Cited by 11 publications

(7 citation statements)

References 22 publications

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“…Nonetheless, this combination is clearly active in patients with advanced gastro-oesophageal cancer with an overall response rate of 38% in a limited number of evaluable patients. Whilst this is lower than the phase II response rates initially obtained with infusional 5-FU in combination with epirubicin and cisplatin (Findlay et al, 1994;Zaniboni et al, 1995), it is similar to that obtained with other platinum-containing regimens (Elliott et al, 1990;Sparano et al, 1990;Lacave et al, 1991;Cervantes et al, 1993;Bajetta et al, 1994Bajetta et al, , 1998Taal et al, 1994;Kondo et al, 1996;Cheng et al, 1998) or with ECF in randomized studies (Webb et al, 1997). The median survival of 9.9 months compares with 8.9 months obtained with ECF and between 7 and 11 months with other cisplatin-based therapies (Lacave et al, 1991;Cervantes et al, 1993;Bajetta et al, 1999Bajetta et al, , 1998Kondo et al, 1996;Cheng et al, 1998).…”

Section: Discussionsupporting

confidence: 56%

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et al. 2000

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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...

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Section: Discussionsupporting

confidence: 56%

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et al. 2000

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“…PolvchemotheraDVinadvanced aastriccancer 1153 Our previous study confirmed that the EAP regimen was active in inducing objective responses (RR, 37%: CR, 12%), but grade 3-4 myelosuppression was reported in about 30% of the patients (Bajetta et al, 1994). However, although the study demonstrated the feasibility of the schedule, side-effects such as myelosuppression occurred more frequently as the number of cycles increased or when the patients were in poor condition, thus meaning that the treatment had to be delayed or reduced.…”

Section: Discussionmentioning

confidence: 61%

“…On the basis of this experience, we consider that the EAP regimen is feasible in an outpatient setting when administered to patients with an ambulatory performance status (Bajetta et al, 1994). However, the length of the treatment (8 days every 3-4 weeks) proved to be a drawback, and so it has been found useful to modify the schedule.…”

mentioning

confidence: 99%

FEP regimen (epidoxorubicin, etoposide and cisplatin) in advanced gastric cancer, with or without low-dose GM-CSF: an Italian Trial in Medical Oncology (ITMO) study

et al. 1998

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Summary The new regimens developed over the last few years have led to an improvement in the treatment of advanced gastric cancer, and our previous experience confirmed the fact that the combination of etoposide, doxorubicin and cisplatin (EAP regimen) is an active treatment that leads to interesting complete remission rates. The primary end point of the present multicentre, randomized, parallel-group phase 11 study was to determine the activity of the simplified 2-day EAP schedule in patients with locally advanced or metastatic gastric cancer, and to verify whether the addition of low doses of granulocyte-macrophage colony-stimulating factor (GM-CSF) made it possible to increase dose intensity.Of the 62 enrolled patients, 30 were randomized to receive epirubicin 35 mg m-2, etoposide 120 mg m-2 and cisplatin 45 mg m-2 (FEP) on days 1 and 2 every 28 days and 32 to receive the same schedule plus subcutaneous GM-CSF (molgramostin) 150 ,ug day-1 on days 5-14 every 21 days. The patients were stratified by age and the number of disease sites. The characteristics of the patients were well balanced between the two groups. The objective response rate of the patients as a whole was 34% (21 out of 62; 95% confidence interval 22-46), with only one complete remission. The median response duration was 4.5 months (range 1-24 months). The median time to treatment failure was 5 months (range 1-14 months), without any difference between the two groups. The median survival of the patients as a whole was 9 months. Full doses were administered in 92% and 94% of the cycles in the control and GM-CSF arms respectively. The average dose intensity calculated for all drugs was 0.96% in the control and 1.27% in the GM-CSF group. CTC-NCI grade 3-4 neutropenia was reported in 39% vs 45% of patients, thrombocytopenia in 11% vs 35% (P = 0.020) and anaemia in 7% vs 35% (P = 0.014). The FEP combination is as active (OR: 34%) in the treatment of patients with advanced gastric cancer as the EAP regimen, although it leads to fewer complete remissions. The patients randomized to receive low-dose GM-CSF achieved a significantly higher dose intensity than controls (P = 0.0001).Keywords: polychemotherapy; gastric cancer; growth factor Although the incidence of gastric cancer seems to have declined regularly in Western countries over the last decade, it is still one of the leading causes of death worldwide (Moller et al, 1990). Furthermore, given that many of the patients are diagnosed when the disease is unsuitable for curative surgery, there is a pressing need to develop better systemic therapies in adjuvant, neoadjuvant and metastatic settings (Macdonald et al, 1992).The development of new chemotherapeutic regimens for the treatment of advanced gastric cancer, including cisplatin (CDDP), and anthracycine, or fluorouracil and high-dose methotrexate (EAP, FAMTX, ECF), has led to objective responses (OR) in 30-40% of the patients, with a complete remission (CR) rate of 10-15% (Wils et al, 1986;Preusser et al, 1989;Findlay et al, 1994;Rougier et al, 199...

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“…However, response rates of 15-52% in eight other studies with at least 25 evaluable patients give the impression that EAP is an active combination in the treatment of advanced gastric cancer [5][6][7][8][18][19][20][21]. On the other hand, a high rate of hematologic toxicity with an associated average 5.1% mortality rate was observed in almost all trials [5][6][7][8]15,17,[19][20][21] other than those reported by Preusser et al [4], Wilke et al [16], and Rath et al [18].…”

Section: Discussionmentioning

confidence: 88%