Feasibility of sequential therapy with FOLFIRI followed by docetaxel/cisplatin in patients with radically resected gastric adenocarcinoma: a randomized phase III trial.
Di Bartolomeo M, Buzzoni R, Mariani L et al.
Oncology, 2007, epub ahead of print
Over the last 20 years, there have been few improvements in adjuvant treatment after radical resection of gastric cancers. Only one large trial has reported the benefit of adjuvant chemo-radiotherapy but this increase in efficacy was only demonstrated for stage III cancer after D0/1 dissection (Intergroup 0116 Gastric Surgical Adjuvant Trial ).
Chemo-radiotherapy is not easy to administer and in many centres it is offered only to a selected population of patients: those at high risk of recurrence with a good nutritional status and the ability to tolerate it. Regarding adjuvant chemotherapy, no large study before the recent report on S1 efficacy  has shown positive results and therefore there is no clear recommendation for its use. The most recent reports using platinum-based adjuvant chemotherapies failed to demonstrate that the use of more intensive chemotherapy significantly improve disease-free survival (DFS) and overall survival (OS) of patients after resection of stage 2/3 gastric cancer. In 2005, we reported the results of a Phase III study  showing that one cycle of 5-fluorouracil (5FU) followed by four cycles of monthly 5FU/cisplatin in 260 patients only marginally improves the OS (44.6% versus 34.9% at 7 years; P=0.06) and more significantly the recurrence-free survival (RFS) [hazard ratio (HR), 0.70; P=0.032]. Recently, the negative results of a Phase III trial using four cycles of the cisplatin, epirubicin, leucovorin and 5FU (PELF) combination have been reported . With inclusion of 258 patients and a median follow-up of 72.8 months, they reported no improvement in OS (HR, 0.90) or DFS (HR, 0.92).
This study conducted by Di Bartolomeo et al. is of interest because it has explored a sequential adjuvant treatment using most of the known active drugs in advanced gastric cancer: four cycles of 5FU, leucovorin and irinotecan (FOLFIRI) followed by three cycles of cisplatin and docetaxel. They compared this sequential adjuvant chemotherapy to monotherapy using mitomycin C (four cycles at the initial dose of 10 mg/[m.sup.2] subsequently reduced to 8 mg/[m.sup.2] after 13 patients) and reported interesting but preliminary data on the tolerance and efficacy of the sequential regimen. The tolerance was good (76% of the patients completed the planned treatment) and there was some evidence of efficacy with a higher DFS at 3 years (67.4% versus 50.2%; P=0.045) and a non-significant increase in OS (73.5% versus 62.4%). However, the validity of this approach cannot be established by this study for the following reasons: (1) it is an unplanned analysis with a short follow-up (median 29 months) which has been conducted before reaching the 403 events as required according to the statistical plan; (2) the population is unbalanced between the two arms, especially with respect to the number of gastric cardia cancers which have a poorer prognosis; (3) no information is provided on the delay between surgery and the initiation of the treatment; (4) there is no information available on the nutritional status of the patients and its relationship with the tolerance and the results of treatment; (5) mitomycin C is not accepted as a suitable control arm by most European centres because of its toxicity which may artificially favour the 'experimental' arm. This, in fact, may be the case in this study where 13 out 81 patients in the control arm (arm B) received a high dose of mitomycin C and experienced a high toxicity and poor compliance. Thus, the conclusion from this study can only be that a further confirmatory study would be of major interest. Indeed a large Italian study has been launched using a combination of 5FU and leucovorin as the control arm, which is 'more acceptable' from a scientific point of view.
One interesting point raised by this study is the potential value of DFS as a surrogate endpoint in studies on adjuvant treatment in gastric cancer, which may save time (and lives) for patients (as in colon cancer where DFS is predictive of OS). In this study the difference in DFS was significant but did not translate into an OS advantage as in our study . The reason for this may be a lack of power; it is hoped that this problem will be addressed by the ongoing GASTRIC project which is the largest meta-analysis ever conducted in gastric cancer. Data from more than 3000 individuals have been collected so far and the aim is to collect data from more than 4000 individuals before the end of 2008.
The main drawback of adjuvant chemotherapy is the fact that many patients in the post-operative period are unable to receive any adjuvant treatment because of complications or poor nutritional status, and it is estimated that only half of patients are able to receive an adjuvant treatment 6-8 weeks after surgical excision of gastric cancer. Therefore, the future place of adjuvant chemotherapy beside the development of pre-operative (neoadjuvant) or peri-operative chemotherapy in gastric cancer is unclear. The main advantages of neoadjuvant chemotherapies are that more than 90% of patients are able to receive a pre-operative chemotherapy and may achieve better chances for R0 resection and higher survival rates. Two randomised trials have demonstrated that peri-operative chemotherapy has a positive impact on OS and DFS, and is considered a valid option. It has therefore become a new standard in some countries.
Results from the UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial (503 patients undergoing surgery for gastric cancer) have shown that three pre-operative cycles and three post-operative cycles of epirubicin, cisplatin and continuous intravenous 5FU (ECF) resulted in a significant downstaging of tumours, better OS (HR for death, 0.75; 95% confidence interval, 0.53-0.93) and a better progression-free survival (HR, 0.66) for the group receiving neoadjuvant chemotherapy . A French trial (224 patients undergoing surgery for oesophageal, oesophagogastric junction or gastric adenocarcinomas, randomly assigned between peri-operative chemotherapy and surgery alone) has similarly demonstrated that three cycles of pre-operative and three cycles of post-operative 5FU/cisplatin combination significantly improves the R0 resection rate, DFS and OS (HR for death, 0.69) . As for adjuvant trials in these two studies [5,6], only about half of the patients were able to restart the chemotherapy after the surgical resection, underlining the difficulty of administering adjuvant chemotherapy in gastric cancer. Therefore the therapeutic effect of these peri-operative chemotherapy regimens seems to be due mainly to the pre-operative part of the chemotherapy.
Thus the study by Di Bartolomeo et al., reporting favourable results with their sequential regimen in the adjuvant setting, may support the idea of testing it as neoadjuvant treatment in advanced gastric cancer because its use in the pre-operative rather than the post-operative setting may perhaps provide benefit to more patients.
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