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Annals of Oncology Advance Access originally published online on November 17, 2005
Annals of Oncology 2006 17(2):262-269; doi:10.1093/annonc/mdj077
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© 2005 European Society for Medical Oncology

Randomized phase III trials of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer. A combined analysis of the EORTC GI Group and the ICCG

D. Nitti1,*, J. Wils2, J. Guimaraes Dos Santos3, G. Fountzilas4, P. F. Conte5, C. Sava6, A. Tres7, R. C. Coombes8, D. Crivellari9, A. Marchet1, E. Sanchez3, J. M. Bliss10, J. Homewood10, M. L. Couvreur11, E. Hall10, B. Baron11, E. Woods8, M. Emson8, E. Van Cutsem12 and M. Lise1

1 Università di Padova, Clinica Chirurgica II, Padova, Italy; 2 Laurentius Hospital, Roermond, The Netherlands; 3 Instituto Portugues de Oncologia, Porto, Portugal; 4 Aristotle University of Thessaloniki, Macedonia, Greece; 5 University Hospital, Modena, Italy; 6 Regional Hospital, Treviso, Italy; 7 Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain; 8 Charing Cross Hospital, and International Collaborative Cancer Group (ICCG), Imperial College London, UK; 9 Centro di Riferimento Oncologico, Aviano, Italy; 10 Clinical Trials and Statistics Unit, Institute of Cancer Research, Sutton, UK; 11 European Organization for Research and Treatment of Cancer (EORTC), Data Center, Brussels, Belgium; 12 University Hospital Gasthuisberg, Leuven, Belgium

* Correspondence to: Prof. D. Nitti, Clinica Chirurgica II, Via Giustiniani 2, Padova, I-35128, Italy; Tel: +39-049-8212073/8212055, Fax: +39-049-651891; E-mail: donato.nitti{at}unipd.it


   Abstract
Top
 Abstract
introduction
 patients and methods
 results
 discussion
 appendix
 References
 
Background: In patients who underwent radical resection for gastric cancer, we investigate the relative efficacy of combined 5-fluorouracil + adriamycin or epirubicin and methotrexate with leucovorin rescue (FAMTX or FEMTX) compared with a control arm.

Patients and methods: This report is a prospective combined analysis of two randomized clinical trials conducted on patients who underwent radical resection for histologically proven adenocarcinoma of the stomach or esophago-gastric junction. Three hundred and ninety-seven untreated patients, 206 from 23 European Organization for Research and Treatment of Cancer (EORTC) institutions and 191 from 16 International Collaborative Cancer Group (ICCG) institutions, were randomized. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan–Meier method and the treatments were compared for these end-points by means of the log-rank test, retrospectively stratified by trial.

Results: In a planned combined analysis of the two trials, no significant differences were found between the treatment and control arms for either DFS (hazards ratio: 0.98, P = 0.87) or OS (hazards ratio: 0.98, P = 0.86). The 5-year OS was 43% in the treatment arm and 44% in the control arm and the 5-year DFS was 41% and 42%, respectively.

Conclusion: Neither FAMTX nor FEMTX can be advocated as adjuvant treatment in patients who undergo resection for gastric cancer.

Key words: adjuvant chemotherapy, FAMTX, FEMTX, gastric cancer


   introduction
Top
 Abstract
 introduction
patients and methods
 results
 discussion
 appendix
 References
 
Surgery remains the primary treatment modality for patients with gastric cancer. In Europe and the United States, the average 5-year survival rate after radical surgery is 30–40%; most patients die from locoregional recurrences and/or distant metastases. In studies in Western countries [1Go, 2Go] and in Asia [3Go], more than 50% of patients have lymph node metastases at the time of resection, and are therefore at high risk of relapse. For several decades attempts have been made with chemotherapy to improve upon the low rate of cure following surgery in patients with advanced gastric cancer.

In the late 1980s, in a prospective phase III multicentre trial conducted by the EORTC Gastro Intestinal (GI) Group, 213 patients with metastatic gastric cancer were randomized to receive sequential high-dose FAMTX or FAM. FAMTX-treated patients were found to have a significantly greater response rate (41% versus 9%; P < 0.0001) and overall survival than FAM patients (median 42 weeks versus 29 weeks; P = 0.004) [4Go]. These promising findings prompted the EORTC GI Group to design an adjuvant-randomized clinical trial to investigate the efficacy of FAMTX with leucovorin rescue versus no treatment, which was still considered standard practice for patients with radically resected gastric cancer. At that time, the ICCG was also investigating 5-FU+ epirubicin (E) + MTX with leucovorin rescue (FEMTX) versus surgery only. After 7 years of recruitment, an Independent Data Monitoring Committee (ICDM) appointed for both studies recommended that both trials should be closed due to poor accrual and that the data obtained should be considered jointly in a prospective meta-analysis. The results of the analysis of these studies are reported in the present paper.


   patients and methods
Top
 Abstract
 introduction
 patients and methods
results
 discussion
 appendix
 References
 
patients
Inclusion criteria for both trials included: age <71 years; adenocarcinoma of the stomach or esophago-gastric junction treated with curative resection with macroscopically negative resection margins; pathological stage Ib, II, IIIa, IIIB and IV (only M0) according to the UICC staging system (1987); WBC ≥ 4.0 x 109/l; platelets ≥100 x 109/l; adequate renal and hepatic function; plasma albumin ≥35 g/l; no evidence of metastasis; Karnofsky score >70 (i.e. WHO performance status 0–2); patient's condition good enough for chemotherapy to be given within 4 weeks of resection; patient's fully informed consent.

treatment
The surgical procedure recommended for the primary tumour was subtotal gastrectomy, for lower third tumours, and total gastrectomy, for middle and upper tumours. For tumours of the esophago-gastric junction, an esophago-gastric resection was preferred, an abdomino-thoracic route being used whenever possible. D2 lymphadenectomy was required in the EORTC trial. On an ‘ad hoc’ form, the surgeon specified the anatomical location of the lymph nodes removed. The patients were screened for admission to the study from 10 to 28 days after surgery and, if randomized to the treatment arm, chemotherapy was started within 4 weeks of surgery.

FAMTX trial patients received six cycles (4 weeks each): day 1 methotrexate 1.5 g/m2, 30 min i.v., followed by 5-FU 1.5 g/m2, 30 min i.v. + leucovorin rescue 15 mg/m2 every 6 h (oral or i.v.) on days 2, 3 and 4 (12 doses) + adriamycin 30 mg/m2 i.v. on day 15.

FEMTX trial patients received six cycles (4 weeks each) with the above 5-FU regimen + methotrexate + leucovorin rescue 30 mg/m2 every 6 h (oral or i.v.) on days 2 and 3 (eight doses) + epirubicin 70 mg/m2 i.v. on day 15.

Acute toxicity was graded according to the WHO scale (1979). Appropriate dose adjustments were made if haematological and/or non-haematological toxicity was found.

follow-up
Follow-up controls (performed every 29 days for the first 6 months, every 6 months until the end of the 5th year and yearly thereafter) consisted of a physical examination, complete blood count, liver and renal function tests, plasma-albumin test, chest radiography, liver echography or liver CAT alternately, and barium meal test or gastroscopy alternately. Biopsy of local or distant metastases was performed whenever possible. Typical nodules on liver echography, CAT scan or chest radiography, or lytic areas of damage on skeletal X-ray are acceptable as metastases without histological confirmation if they reflect a definitive change with respect to baseline studies.

statistical considerations
For the EORTC trial, randomization was achieved by minimization with stratification according to institution, pathological stage (IB versus II versus IIIA versus IIIB) and tumour location (esophago-gastric junction versus stomach); at ICCG trial, patients were randomized according to permuted blocks within strata defined by institution and pathological stage (IB/II versus IIIA/IIIB/IV).

In both the multicentre trials, the primary endpoint was OS. Secondary endpoints were treatment toxicity and DFS. OS was defined as the interval from the date of randomization to the date of death. DFS was the interval from the date of randomization to the date of recurrence or death, whichever occurred first.

The ICCG trial was designed to detect a 15% improvement in 5-year OS (from 45 to 60%) at a 5% two-sided significance level with 90% power. The original sample size planned was 480 (230 patients per arm plus dropouts), in order to observe the 218 events (deaths) required to test the hypothesis.

The EORTC trial was designed to detect a 10% improvement in 3-year OS (from 50 to 60%) at a 5% two-sided significance level with 80% power. The original sample size planned was 760 (380 patients per arm) in order to observe the 344 deaths required to test the hypothesis.

Both OS and DFS were estimated using the Kaplan–Meier method. Considering both trials together, the treatments were compared for these endpoints by means of the log-rank test, and retrospectively stratified by trial. Analysis used the intent to treat principle, i.e. all randomized patients were included and analysed in the treatment group assigned at randomization. Formal statistical tests were not performed separately for each trial due to the lack of power in both the studies.

Independent Data Monitoring Committee (IDMC)
Due to the low accrual in both trials, after 7 years of recruitment a common IDMC was convened to review these studies. The trials were considered sufficiently similar to be pooled for analysis. In June 1996, based on a joint analysis of the ICCG and EORTC trials, the IDMC advised the investigators to increase the accrual rate of the studies. However, during the subsequent 18 months, only 65 further patients were randomized. On meeting again in March 1998, the IDMC concluded that patient accrual had declined to such a point that both trials should be closed.

Given the objectives and hypotheses in both trials, and considering the longer follow-up period required for the patients already randomized, it was decided that, combined, these studies could still provide valuable findings. The IDMC therefore recommended a joint analysis when a total of 218 deaths were reported across both trials.


   results
Top
 Abstract
 introduction
 patients and methods
 results
discussion
 appendix
 References
 
patient accrual and characteristics
From July 1990 to March 1998, a total of 397 patients were randomized: 191 by 16 ICCG institutions and 206 by 23 EORTC institutions (the FAMTX trial opened in February 1991). Eight patients were ineligible (inadequate surgery, 1; locally advanced disease, 2; metastatic disease, 5). The numbers of patients randomized for each trial are reported in Figure 1.


Figure 1
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  		Figure 1. Numbers of patients randomized in EORTC FAMTX and ICCG FEMTX trials.

 
Table 1 reports the age, sex and primary tumour sites. The types of surgical procedure performed are shown in Table 2. There were important differences between the two trials for extent of surgery. In the EORTC trial, in which a D2 dissection was recommended, 87% of patients underwent this procedure. The median number of lymph nodes removed was 13 in the ICCG, and 20 in the EORTC trial. Tumour characteristics were similar in both trials, but the ICCG study included a greater number of patients with infiltrated resection margins and patients with advanced (stage IV) disease (Table 3). Within each trial, patient characteristics, surgery type and pathology data were well balanced across the two treatment groups.


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  		Table 1. Patients' characteristics and primary tumour sites

 

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  		Table 2. Surgical procedures

 

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  		Table 3. Pathology data

 
treatment
Table 4 shows the number of chemotherapy cycles administered.


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  		Table 4. Treatment administered

 
FAMTX.
Eight (8%) of 103 patients randomized to chemotherapy received no treatment. Five patients refused, one had postoperative complications, one was erroneously considered as randomized in the control arm; for another patient, no reason was given for this omission. Of the 103 patients, 76 (74%) received the six planned cycles of treatment. One patient randomized to the control arm was considered randomized to the treatment arm and received four cycles of FAMTX.

FEMTX.
Ten (11%) of 91 patients randomized to chemotherapy did not start treatment. Three refused treatment, one was treated as a control, three had distant metastases discovered after randomization, one patient had a second primary tumour found after randomization and two patients preferred to undergo alternative chemotherapy. In a further two cases, no data were available. Of the 91 patients, 55 (60%) received the six cycles of treatment.

Table 5 shows the rate of grade 3–4 toxicity, which was mainly haematological. In each trial there were two deaths from toxicity. The causes of death from toxicity were: renal failure and sepsis (one patient), sepsis (one patient) in the FAMTX trial, and cerebral stroke (one patient), renal failure and sepsis (one patient) in the FEMTX trial. FAMTX and FEMTX treatment, respectively, incurred 29% and 52% grade 3 alopecia, 29% and 25% grade 3–4 leucopenia, 32% and 4% grade 3–4 neutropenia and 12% and 14% grade 3–4 nausea and vomiting.


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  		Table 5. Grade 3–4 toxicity in patients receiving chemotherapy

 
efficacy
In the EORTC trial, with a median follow-up of 6.6 years, 50/103 (49%) of the patients in the control group and 40/103 (39%) in the treated group had local or distant disease recurrence (Table 6). At a median follow-up of 6.4 years, the incidence of recurrence in the ICCG trial was 54% in the control group and 50% in the treated group. However, on taking into account both recurrences and deaths, the Kaplan–Meier DFS curves for the EORTC and ICCG trials did not indicate any difference between findings from treated patients and those from controls. In the EORTC trial, the hazards ratio (HR) for DFS was 0.90 [95% confidence interval (CI): 0.54–1.26] with a 5-year DFS of 51% (95% CI: 41–60%) in the FAMTX arm and 50% (95% CI: 40–59%) in the control arm. In the ICCG trial, the HR for DFS was 1.04 (95% CI: 0.68–1.40) with a 5-year DFS of 29% (95% CI: 19–39%) in the FEMTX arm and 34% (95% CI: 24–44%) in the control arm.


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  		Table 6. Survival and first disease progression status

 
On considering first relapse, distant recurrences were found to be more frequent than local recurrences: 69 patients (33%) versus 29 (14%), respectively, in the EORTC study and 96 patients (50%) versus 25 (14%), respectively, in the ICCG study. On considering all patients from both trials, it was found that 14% developed concurrent local and distant progression. Sites of local and distant disease progression are listed in Table 6.

In the EORTC trial, 49/103 (48%) of control group patients and 54/103 (52%) of FAMTX patients were alive at the time of analysis. In the ICCG trial, 36/100 (36%) control patients and 28/91 (31%) FEMTX patients were alive. Eighty-five per cent of deaths were due to malignant disease.

Kaplan–Meier OS curves for the EORTC and ICCG trials did not show any difference between treated patients and controls. In the EORTC trial, the HR for OS was 0.89 (95% CI: 0.51–1.31) with a 5-year OS of 52% (95% CI: 42–62%) in the FAMTX arm and 51% (95% CI: 41–61%) in the control arm. In the ICCG trial, the HR for OS was 1.05 (95% CI: 0.69–1.41) with a 5-year OS of 33% (95% CI: 23–42%) in the FEMTX arm and 36% (95% CI: 26–45%) in the control arm.

Figures 2 and 3 show the results of the combined analysis for OS and DFS, respectively, in all patients from both trials. No significant difference was found between the arms for DFS (HR: 0.98, 95% CI: 0.72–1.24, P = 0.87) and OS (HR: 0.98, 95% CI: 0.72–1.24, P = 0.86). Five-year DFS was 41% (95% CI: 34–48%) in the treatment arm and 42% (95% CI: 35–49%) in the control arm, and 5-year OS was 43% (95% CI: 36–50%) in the treatment arm and 44% (95% CI: 36–51%) in the control arm.


Figure 2
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  		Figure 2. Overall survival and disease-free survival in combined analysis of EORTC and ICCG trial.

 

Figure 3
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  		Figure 3. Forest plot of overall survival and disease-free survival in the combined analysis of EORTC and ICCG trial.

 

   discussion
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
appendix
 References
 
In the combined analysis of the EORTC FAMTX and ICCG FEMTX trial findings, no significant differences for DFS or OS were found between patients with gastric cancer treated with FAMTX or FEMTX after radical resection and patients who underwent surgery alone. However, even this pooled analysis lacks the statistical power required to detect absolute differences of the order of 10%. The analyses made were based on all randomized patients. Eight patients were not eligible and 14 other patients did not start chemotherapy for various reasons. Six patients, who had been allocated to the control arm, received chemotherapy. This accounted for 7% of all patients (28/397), but a sensitivity analysis carried out excluding these patients did not show changes in the results (data not shown).

Furthermore, 74% of patients enrolled in the EORTC trial, and 60% of those enrolled in the ICCG trial, received all six cycles of treatment. Most patients who discontinued treatment stopped due to toxicity or because they refused to continue for all six cycles. In both trials, grade 3–4 toxicity was reported in 30% of patients, leading to dose reductions in >50% of cases. These results suggest that the toxicity of these regimens should be taken seriously into account in the future. The potential high toxicity incurred by FAMTX/FEMTX treatments was one of the reasons for the slow and declining accrual of patients and the final closure of the studies. Others contributory factors were the complexity of the regimen, and the knowledge that ECF has advantages over FAMTX treatment [5Go].

The overall 5-year survival was 43%: 51% in the EORTC trial and 34% in the ICCG trial. An analysis of the surgical procedures used in the two trials showed differences between extent of surgery. In the EORTC trial, which called for D2 dissection, 89% of patients underwent this procedure. The median number of lymph nodes removed was 13 in the ICCG study, whereas in 74% of EORTC trial patients, 13 or more nodes were removed (median number 23 and 18 in control and chemotherapy arms, respectively). Although a formal comparison of the extent of surgery in the separate trials cannot be made, it is tempting to suggest that the more radical surgery performed in the EORTC study may have resulted in a better survival than the less radical surgery performed in the ICCG trial. However, any claims that extended lymphadenectomy (D2) is beneficial are controversial because of findings made in two trials conducted in Europe to compare outcome following D1 and D2 lymphadenectomy [6Go, 7Go]. Both studies reported a significant increase in mortality and morbidity rates and longer mean hospital stays following D2 lymphadenectomy, without finding that it provided benefit in terms of overall and disease-free survival. Although these results are not supported by findings made by other institutions in Europe and the USA dedicated to gastric surgery [1Go, 8Go–10Go], D1 lymph node dissection is still widely performed in Western countries and it was recently reported that, in the USA, D2 dissection is performed in only 4–7% of cases [11Go]. Finally, after a prolonged follow-up, the D2 arm of the Dutch randomized study has now shown a trend for overall survival benefit, this difference being significant with respect to the subgroup of N+ patients [12Go].

Following ‘second-generation’ combined chemotherapy regimens (e.g. 5-FU with etoposide or cisplatin) developed in the 1980s with a high activity in locally advanced and metastatic disease [13Go], similar regimens have been proposed in the adjuvant setting. A French trial with FUP (infusional 5-FU for 5 days + cisplatin) included 260 eligible patients and reported a 5-year OS of 45.6% and 41.9% (P = 0.22) for the treatment and control arms, respectively [14Go]. An adjuvant chemotherapy trial of EAP (etoposide, adriamycin, cisplatin) versus 5-FU/LV, reported from Italy on 274 patients, was associated with 5-year survival of 52% in the treatment arm and 48% in the control arm (HR: 0.93, 95% CI 0.65–1.34) [15Go]. In another Italian trial [16Go], on 258 patients with stage Ib–IV (M0) gastric cancer, the PELF (cisplatin, epirubicin, leucoverin, 5-FU) regimen reduced the mortality rate by 9%, although this reduction was not significant (HR = 0.91; 95% CI 0.64–1.28). In an Intergroup/SWOG study, radiotherapy plus 5-FU/leucovorin was investigated in patients who underwent resection for gastric cancer [17Go]. Although chemotherapy plus radiotherapy was followed by a significant survival benefit, 54% of the patients had less than D1 lymphadenectomy and no more than 10% underwent D2 lymphadenectomy; it has been claimed that the poor standard of surgery in this study contributed heavily to the results obtained [11Go]. In most European series, survival data reported in patients who undergo combined treatment are no better than those in patients who undergo optimal surgery (more than D1 resection) alone.

In the last 10 years, five meta-analyses have evaluated the role of adjuvant chemotherapy for gastric cancer [18Go–22Go]. All suggest that a slight survival benefit is provided by adjuvant chemotherapy, but the findings are mainly generated by a few small studies from Spain [23Go] while all large multicentre trials conducted have reported no benefit. In these trials, as found in the present study, series have not been large enough to reveal smaller differences, in the order of 5–10%. Findings from larger clinical trials are needed to demonstrate such small differences. An ongoing Italian clinical trial on sequential treatment with CPT11 + 5FU/LV + taxotere + CDDP versus 5FU/LV regimen plans to enrol 1200 patients in order to verify a minimum progression-free survival advantage (at 3 years) of 5–10%.

Preoperative chemotherapy may be a better approach. Results of the UK ‘MAGIC’ trial, comparing preoperative and postoperative epirubicin + cisplatin + 5-FU (ECF) with surgery alone, have recently been presented [24Go]: 5-year survival rates for the perioperative chemotherapy group and the surgery alone group were 36% and 23%, respectively (P = 0.009). Progression-free survival was also significantly prolonged (P =0.0001). Unfortunately, however, surgery was not well defined. OS in the surgery alone arm was only 23% at 5 years which is inferior to the outcome of European trials discussed above and also to survival in the present study. In 1999, the Swiss Group for Clinical Cancer Research initiated a phase III trial of preoperative versus postoperative chemotherapy with taxotere + cisplatin + 5-FU in patients with locally advanced resectable gastric carcinoma. The outcome from this study is awaited with interest.

In conclusion, no significant benefit has been observed following postoperative second-generation polychemotherapy. There is now a need for findings from new clinical trials using the preoperative or postoperative administration of potentially more effective drugs (irinotecan, taxanes) probably in combination with radiotherapy to be compared with those following optimal surgery alone. This type of study should be performed by inter-group consortium (e.g. PETACC) uniting national groups with a view to accruing a sufficient number of patients.


   appendix
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 appendix
References
 
The following centres and their investigators participated in the EORTC study:

Instituto Portugues de Oncologia, Centro do Porto, Portugal (J. Guimaraes Dos Santos, 55 patients); Clinica Chirurgica II, Università di Padova, Padova, Italy (M. Lise, D. Nitti, 45 patients); Ospedale Civile di Treviso, Treviso Italy (C. Sava, 35 patients); Centro di Riferimento Oncologico, Aviano, Italy (D. Crivellari, 13 patients); Ospedale Civile di Padova, Padova, Italy (A. Fornasiero, 10 patients); Ospedale Civile di Castelfranco Veneto, Castelfranco Veneto, Italy (P. Manente, eight patients); Bethesda Krankenhaus, Essen, Germany (F. Roelofsen, six patients); Clinica Chirurgica III, Università di Padova, Padova, Italy (E. Ancona, six patients); Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland (S. Leyvraz, five patients); Laurentius Ziekenhuis, Roermond, The Netherlands (J. Wils, four patients); Institut Gustave Roussy, Vellejuif, France (Ph. Rougier, three patients); Institut Jules Bordet, Brussels, Belgium (H. Bleiberg, two patients); Akademisch Ziekenhuis VUB, Brussels, Belgium (J. De Greve, two patients); Hôpital Guillaume & Rene Laennec, Nantes, France (H. Lacroix, two patients); Università di Firenze, Policlinico di Careggi, Firenze, Italy (F. Tonelli, two patients); Maaslandziekenhuis, Sittard, The Netherlands (F. L. G. Erdkamp, one patient); Hopital Universitaire Brugmann, Brussels, Belgium (M. Buset, one patient); Centre Antoine Lacassagne, Nece, France (M. Namer, one patient); Centre Eugene Marquis, Rennes, France (J. L. Raoul, one patient); CHRU de Caen, Caen, France (M. Gignoux, one patient); Atrium Medisch Centrum, Heerlen, The Netherlands (M. Pannebakker, one patient); Maria Sklodowska-Curie Cancer Center–Institute of Oncology, Warsaw, Poland (K. G. Jeziorski, one patient); Ospedale Civile di Belluno, Belluno, Italy (F. Favretti, one patient).

The following centres and their investigators participated in the ICCG study:

AHEPA Hospital, Aristotle University of Thessaloniki, Macedonia, Greece (G. Fountzilas, 45 patients); Ospedale S. Chiara, Pisa, Italy (P. F. Conte, 39 patients); Hospital Clinico Universitario Lozano Blesa, Zaragoza, Spain (A. Tres, 20 patients); Institut Catala del la Salut, Hospital Badalona, Spain (A. Abad, 17 patients); Centre Hospitalier René Dubos, Pontoise, France (F. Morvan, 14 patients); Saint-Savvas Anticancer Hospital, Athens, Greece (P. Vassilpoulos, 13 patients); Ospedale L. Pierantoni, Forlí, Italy (D. Amadori, 10 patients); Franziskus Hospital, Bielefeld, Germany (H. J. Weh, six patients); Comprehensive Cancer Centre (IKL), Limburg, Netherlands (J. Wils, five patients), Instituto Portugese de Oncologia, Oporto, Portugal (E. Pinto Ferreira, five patients); Charing Cross Hospital, London, UK (R. C. Coombes, four patients); Institute National de la Salud, Madrid, Spain (H. Cortes Funes, three patients); Fundacion Instituto Valenciano De Oncolgia, Valencia, Spain (C. Fernandes Martos, three patients); University Hospital Gasthuisberg, Leuven, Belgium (E. Van Cutsem, three patients); Antwerp Belgium (Wassenar, three patients); Hospital St Louis, Paris, France (M. Marty, one patient).


   Acknowledgements
 
The authors would like to thank the patients who participated in both trials and the investigators and staff at all centres involved (listed in Appendix).

This publication was supported by grants numbers 5U10 CA11488-21 through 5U10 CA11488-28 from the National Cancer Institute (Bethesda, MD, USA) to the EORTC. The ICCG Data Centre receives funding from Pharmacia (now Pfizer) and is supported by Cancer Research UK. The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute, Pfizer or Cancer Research UK.

Received for publication June 6, 2005. Revision received October 5, 2005. Accepted for publication October 11, 2005.


   References
Top
 Abstract
 introduction
 patients and methods
 results
 discussion
 appendix
 References
 
1. Siewert JR, Bottcher K, Stein HJ et al. Relevant prognostic factors in gastric cancer. Ten-year results of the German gastric cancer study. Ann Surg 1998; 228: 449–461.[CrossRef][ISI][Medline]

2. Wanebo HJ, Kennedy BJ, Winchester DP et al. Gastric carcinoma: does lymph node dissection alter the survival? J Am Coll Surg 1996; 183: 616–624.[ISI][Medline]

3. Kim JP, Lee JH, Kim SJ et al. Clinicopathologic characteristics and prognostic factors in 10783 patients with gastric cancer. Gastric Cancer 1998; 1: 125–133.[CrossRef][Medline]

4. Wils JA, Klein HO, Wagener DJ et al. Sequential high-dose methotrexate and fluorouracil combined with doxorubicin—a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer, Gastrointestinal Tract Cooperative Group. J Clin Oncol 1991; 9: 827–831.[Abstract]

5. Webb A, Cunningham D, Scarffe JH et al. Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophago-gastric cancer. J Clin Oncol 1997; 15: 261–267.[Abstract/Free Full Text]

6. Bonenkamp JJ, Hermans J, Sasako M et al. Extended lymph-node dissection for gastric cancer. N Engl J Med 1999; 340: 908–914.[Abstract/Free Full Text]

7. Cuschieri A, Weeden S, Fielding J et al. Patient survival after D1 and D2 resections for gastric cancer. Long term results of the MRC randomized surgical trial. Br J Cancer 1999; 79: 1522–1530.[CrossRef][ISI][Medline]

8. Lise M, Nitti D, Marchet A et al. Prognostic factors in resectable gastric cancer: results of EORTC Study No. 40813 on FAM adjuvant chemotherapy. Ann Surg Oncol 1995; 2: 495–501.[Abstract]

9. Brennan MF. Lymph node dissection for gastric cancer. New Engl J Med 1999; 340: 956–958.[Free Full Text]

10. Sasako M. Risk factors for surgical treatment in the Dutch Gastric Cancer Trial. Br J Surg 1997; 84: 1567–1571.[CrossRef][ISI][Medline]

11. Hundahl SA, Macdonald JS, Benedetti J, Fitzsimmons T for the Southwest Oncology Group and the Gastric Intergroup. Surgical treatment variation in a prospective, randomized trial of chemoradiotherapy in gastric cancer: the effect of undertreatment. Ann Surg Oncol 2002; 9: 278–286.[Abstract/Free Full Text]

12. Hartgrink HH, van de Velde CJH, Putter H et al. Extended lymph node dissection for gastric cancer: who may benefit? Final results of the randomized Dutch Gastric Cancer Group Trial. J Clin Oncol 2004; 22: 2069–2077.[Abstract/Free Full Text]

13. Wils J. The treatment of advanced gastric cancer. Semin Oncol 1996; 23: 397–406.[ISI][Medline]

14. Bouche O, Ychou M, Burtin P et al. Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801). Ann Oncol 2005; 16: 1488–1497.[Abstract/Free Full Text]

15. Bajetta E, Buzzoni R, Mariani L et al. Adjuvant chemotherapy in gastric cancer: 5-year results of a randomized study by the Italian Trials in Medical Oncology (ITMO) Group. Ann Oncol 2002; 13: 299–307.[Abstract/Free Full Text]

16. Di Costanzo F, Gasperoni S, Manzione L et al. Postoperative chemotherapy (CT) in resected gastric cancer (GC): follow-up (FUP) vs PELF. Results of an Italian intergroup (GOIRC & GISCAD) study. Proc Am Soc Clin Oncol 2003; 22: 296a. (Abstr).

17. Macdonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–730.[Abstract/Free Full Text]

18. Hermans J, Bonenkamp JJ, Boon MC et al. Adjuvant therapy after curative resection for gastric cancer: meta-analysis of randomized trials. J Clin Oncol 1994; 11: 1441–1447.

19. Earle CC, Maroun JA. Adjuvant chemotherapy after resection for gastric cancer in non-Asian patients: revisiting a meta-analysis of randomised trials. Eur J Cancer 1999; 35: 1059–1064.[CrossRef][ISI][Medline]

20. Mari E, Floriani I, Tinazzi A et al. Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published trials: Study of the GISCAD. Ann Oncol 2000; 11: 837–843.[Abstract/Free Full Text]

21. Panzini I, Gianni L, Fattori PP et al. Adjuvant chemotherapy in gastric cancer: a meta-analysis of randomized trials and a comparison with previous meta-analysis. Tumori 2002; 88: 21–27.[ISI][Medline]

22. Hu JK, Chen ZX, Zhou ZG et al. Intravenous chemotherapy for resected gastric cancer: meta-analysis of randomized controlled trials. World J Gastroenterol 2002; 8: 1023–1028.[ISI][Medline]

23. Estape J, Grau JJ, Alcobendas F et al. Mitomycin C as an adjuvant treatment to resected gastric cancer. Ann Surg 1991; 213: 219–221.[ISI][Medline]

24. Cunningham D, Allum W, Stenning S. Perioperative chemotherapy in operable gastric and lower esophageal cancer: Final results of a randomized, controlled trial (the MAGIC trial ISRCTN 93793971). Proc Am Soc Clin Oncol 2005; 23: 308s (Abstr).


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