0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Review |

Benefit of Adjuvant Chemotherapy for Resectable Gastric Cancer:  A Meta-analysis FREE

The GASTRIC (Global Advanced/Adjuvant Stomach Tumor Research International Collaboration) Group*
[+] Author Affiliations

*The GASTRIC Group Writing Committee:Xavier Paoletti, PhD, Institut National du Cancer, Boulogne, France;Koji Oba, MSc, EBM Research Center, Kyoto University, Kyoto, Japan;Tomasz Burzykowski, PhD, Hasselt University, Diepenbeek, Belgium;Stefan Michiels, PhD, Institut Gustave-Roussy, Villejuif, France;Yasuo Ohashi, PhD, University of Tokyo, Tokyo, Japan;Jean-Pierre Pignon, MD, PhD, Institut Gustave-Roussy, Villejuif;Philippe Rougier, MD, PhD, University Hospital Ambroise Paré (AP-HP), Boulogne;Junichi Sakamoto, MD, PhD, Nagoya University, Aichi, Japan;Daniel Sargent, PhD, Mayo Clinic, Rochester, Minnesota;Mitsuru Sasako, MD, PhD, Hyogo College of Medicine, Hyogo, Japan;Eric Van Cutsem, MD, PhD, Digestive Oncology Unit, University Hospital Gasthuisberf, Leuven, Belgium; andMarc Buyse, ScD, International Drug Development Institute, Louvain-la-Neuve, Belgium.


JAMA. 2010;303(17):1729-1737. doi:10.1001/jama.2010.534.
Text Size: A A A
Published online

Context Despite potentially curative resection of stomach cancer, 50% to 90% of patients die of disease relapse. Numerous randomized clinical trials (RCTs) have compared surgery alone with adjuvant chemotherapy, but definitive evidence is lacking.

Objectives To perform an individual patient-level meta-analysis of all RCTs to quantify the potential benefit of chemotherapy after complete resection over surgery alone in terms of overall survival and disease-free survival, and to further study the role of regimens, including monochemotherapy; combined chemotherapy with fluorouracil derivatives, mitomycin C, and other therapies but no anthracyclines; combined chemotherapy with fluorouracil derivatives, mitomycin C, and anthracyclines; and other treatments.

Data Sources Data from all RCTs comparing adjuvant chemotherapy with surgery alone in patients with resectable gastric cancer. We searched MEDLINE (up to 2009), the Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry, and published proceedings from major oncologic and gastrointestinal cancer meetings.

Study Selection All RCTs closed to patient recruitment before 2004 were eligible. Trials testing radiotherapy; neoadjuvant, perioperative, or intraperitoneal chemotherapy; or immunotherapy were excluded. Thirty-one eligible trials (6390 patients) were identified.

Data Extraction As of 2010, individual patient data were available from 17 trials (3838 patients representing 60% of the targeted data) with a median follow-up exceeding 7 years.

Results There were 1000 deaths among 1924 patients assigned to chemotherapy groups and 1067 deaths among 1857 patients assigned to surgery-only groups. Adjuvant chemotherapy was associated with a statistically significant benefit in terms of overall survival (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.76-0.90; P < .001) and disease-free survival (HR, 0.82; 95% CI, 0.75-0.90; P < .001). There was no significant heterogeneity for overall survival across RCTs (P = .52) or the 4 regimen groups (P = .13). Five-year overall survival increased from 49.6% to 55.3% with chemotherapy.

Conclusion Among the RCTs included, postoperative adjuvant chemotherapy based on fluorouracil regimens was associated with reduced risk of death in gastric cancer compared with surgery alone.

Figures in this Article

Although epidemiological studies describe a reduction in recent years in gastric cancer incidence, gastric cancer is a common and highly fatal disease, with current 5-year survival rates less than 20%.1 Surgery for disease at an early stage can usually be performed with curative intent, but the 5-year survival rate is disappointing.2,3 Over the last 3 decades, numerous phase 3 studies including a surgery-only group have been reported, but definitive evidence of the efficacy of adjuvant chemotherapy is lacking. Recently, the large-scale Japanese phase 3 trial by the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) group4 reported the superiority of S-1 as an adjuvant chemotherapy over surgery alone after D2 lymph node dissection. Its applicability outside of East Asia is uncertain, and the First-Line Advanced Gastric Cancer Study (FLAGS) in advanced disease5 that compared cisplatin and S-1 vs cisplatin and fluoropyridines in non-Asian countries was negative. Therefore, standard management following curative surgery is heterogeneous throughout the world.

No patient-level meta-analyses have been carried out to date. Based on published results, recent meta-analyses610 indicated that adjuvant chemotherapy produces a small survival benefit, if any, in patients with resected gastric carcinoma (eTable 1) but did not recommend adjuvant chemotherapy as routine therapy. Since then, several additional trials have been conducted in this setting. Overall, the results of some of these trials were promising but inconsistent when all trials were considered. Therefore, it was deemed important to assess the benefit of adjuvant chemotherapy quantitatively through an exhaustive meta-analysis based on individual patient data from all relevant trials.

Data from all published randomized trials comparing adjuvant chemotherapy with surgery alone for resectable gastric cancers were sought electronically. The strategy filter for computerized bibliographic searches of MEDLINE (1970 to 2009) is described in the eMethods). No restriction on language of publication was considered. The Cochrane Central Register of Controlled Trials, the National Institutes of Health trial registry (ClinicalTrials.gov), and proceedings books from major oncologic and gastrointestinal cancer meetings were also examined for published results. To ensure that all relevant trials were included, researchers with expertise in the area were queried for the existence of unpublished trials. Four groups of regimens were specified in the protocol: trials investigating (1) monochemotherapy agents; (2) fluorouracil, mitomycin C, and other therapies without anthracyclines; (3) fluorouracil, mitomycin C, and anthracyclines; and (4) other polychemotherapy regimens.

Study Selection and Data Extraction

Trials were eligible if they were randomized, they ended patient recruitment before 2004, and they compared any adjuvant therapy after curative resection vs surgery alone. Trials investigating immunotherapy or neoadjuvant or perioperative chemotherapy were excluded. Likewise, trials with radiotherapy or intraperitoneal chemotherapy were not in the scope of our research.

The following data were requested for all individual patients: center, randomization date, date of last follow-up (or date of death), survival status, cause of death, relapse status, type and date of relapse if any, TNM stage, overall stage grouping system, performance status (World Health Organization or Karnofsky index), and age at entry. Because the International Union Against Cancer modified the staging system in 1997, stages measured with the old system were expressed according to the new classification. Updated survival status and date of last follow-up were requested from the trialists. Data for patients excluded from the analysis after randomization were obtained whenever possible.

Overall survival (OS) was defined as the time from randomization to death from any cause or to the last follow-up that was used as a date of censoring. Disease-free survival (DFS) was the time to relapse, second cancer, or death from any cause, whichever came first. Detailed information on the type of relapse was not always available. All data were centrally reanalyzed and checked for inconsistencies. In particular, diagnostic tools for randomization quality were systematically applied.11

Statistical Methods

Time-related end points (OS and DFS) were analyzed through log-rank tests, with trial as stratification factor. We used a fixed-effects model and the inverse variance method where the weight of each trial was proportional to the variance of the observed minus expected number of events.12 Heterogeneity between trials and groups of trials (eg, defined by different chemotherapy regimens) was tested using χ2 statistics13 and measured with the I2 statistic.14 Forest plots were used to display hazard ratios (HRs) within individual trials and overall. Within each trial, HRs were estimated without adjusting for any covariates. When a statistically significant effect was detected, the increase in survival probabilities or absolute benefit at 5 or 10 years after randomization was computed based on the estimates of the survival curves. Estimates of the survival curves used the actuarial approach adjusted for trial proposed by the Early Breast Cancer Trialists' Collaborative Group,15 yielding a representation consistent with the main log-rank analyses stratified by trial. Their interpretations are similar to the Kaplan-Meier curves.

The hypothesis of proportional hazards was explored graphically and tested by using the Grambsch and Therneau test16 with linear residual relation and by including a time-dependent covariate in a stratified Cox model. We further investigated the hazard functions through time in each group under study. Median follow-up was estimated using the reversed Kaplan-Meier function.17 All patients were included in the analyses as randomly assigned based on an intention-to-treat principle, whether or not they were analyzed in the trial publication. In cases where survival data were missing, those patients were excluded from the analysis.

As a sensitivity analysis we investigated the overall treatment effect in all the identified trials, pooling individual patient data with summary statistics extracted from the publication.18 We also analyzed these summary statistics separately. In addition, we investigated heterogeneity among the regions where the trials were conducted (Europe, Asia, and the United States). All P values were 2-sided at the 5% level, and confidence intervals (CIs) had 2-sided probability coverage of 95%. SAS version 9.1 (SAS Institute, Cary, North Carolina) was used with macros developed at the European Organization for Research and Treatment of Cancer Data Center (Brussels, Belgium) for meta-analysis and at Institut Gustave-Roussy (Villejuif, France) for survival curves. Hazard functions were plotted with Stata version 9.2 (StataCorp, College Station, Texas). All the results were discussed during 4 large international investigators' meetings organized in different countries.

Thirty-one trials that had randomized 6390 patients were identified (Figure 1). We obtained individual data for 3838 patients included in 17 trials (Table). This represents 60% of the targeted data. Corresponding authors of the eligible trials were contacted at least 5 times each between January 2007 and February 2010. Data were not obtained for 2552 patients in 14 trials because of no reply or a refusal to share data from the principal investigator3539 or because data were lost or inaccessible.4048 One trial21 compared surgery alone against 2 investigational groups with fluorouracil or ftorafur. Both groups were pooled. Central randomization was reported in 14 trials (with block stratification for 8 and minimization for 6). All trials were open without blinding procedures. No trials were found to have major inconsistencies in the randomization procedure, and no difference in follow-up could be detected between the 2 groups.

Place holder to copy figure label and caption
Figure 1. Study Flowchart
Graphic Jump Location
Table Graphic Jump LocationTable. List of the Included Randomized Trials
Patient Characteristics

The characteristics of the 3838 randomly assigned patients are listed by group (eTable 2) and chemotherapy regimen (eTable 3). There were no major differences in patient characteristics between treatment groups. The eTables also show summary statistics on the clinical outcomes of interest: median OS and median DFS. Fifty-seven patients (1.5%) with missing survival data were excluded from analyses (date of randomization, last status, and last date were missing for 25, 8, and 49 patients, respectively). They were balanced between the 2 groups (28 patients with chemotherapy vs 29 patients with surgery only). We identified 361 patients and 103 deaths with a last date after the publication date of the related trial.

Any Adjuvant Chemotherapy vs Surgery Alone

Median follow-up for OS was slightly different between the 2 groups (7 years; range, 0.1-28.2 years in the surgery-only group vs 7.2 years; range, 0.1-30.3 years; P < .001), during which 1067 patients in the surgery-only group and 1000 patients in the chemotherapy group died. Figure 2 shows the HRs for OS in the individual trials and overall. There was a significant benefit from any chemotherapy compared with surgery alone, with an overall HR of death equal to 0.82 (95% CI, 0.76-0.90; P < .001), corresponding to an overall 18% reduction of the hazard with chemotherapy. The estimated median OS was 4.9 years (95% CI, 4.4-5.5) in the surgery-only group vs 7.8 years (95% CI, 6.5-8.7) in the group receiving adjuvant chemotherapy. Absolute benefits were 5.8% at 5 years (from 49.6% to 55.3%) and 7.4% at 10 years (from 37.5% to 44.9%) (Figure 3). No significant heterogeneity (variability of trial-specific HRs) was apparent across the set of trials (P = .52). Globally, there were no time trends in the treatment effect according to the year of last inclusion (P = .82). Similarly, no significant heterogeneity was detected across the 3 continents (P = .27) (eFigure 1).

Place holder to copy figure label and caption
Figure 2. Individual Trial and Overall Hazard Ratio for Overall Survival When Comparing Any Adjuvant Chemotherapy vs Surgery Alone
Graphic Jump Location

The inverse of the variance of observed events minus expected events measures the weight of each trial in the analysis. P values are from P-for-effect modification testing for heterogeneity within or across the groups of regimens. The sizes of data markers are proportional to the number of deaths in the trials. CI indicates confidence interval; HR, hazard ratio.

Place holder to copy figure label and caption
Figure 3. Overall Survival Estimate After Any Chemotherapy or Surgery Alone Truncated at 10 Years
Graphic Jump Location

The estimates of the survival curves use an actuarial approach as described in the Methods.

As a sensitivity analysis, we combined summary statistics extracted from unavailable trials with the collected individual patient data for a total of 5866 patients and 28 trials. For 3 trials,43,44,47 no summary statistics could be extracted from the report. Neither the general conclusions nor the magnitude of the observed treatment effect (HR, 0.82; 95% CI, 0.77-0.88; P < .001) were modified (eFigure 2). Analysis of the 11 trials with available summary resulted in an HR of 0.81 (95% CI, 0.73-0.91; P < .001). No significant heterogeneity was detected (P = .11).

Disease-free survival was available on a subset of 14 trials with a total number of 3297 patients from the 21 trials that collected this information, representing 78% of the targeted number of patients. On this subpopulation, we observed an HR of death of 0.85 (95% CI, 0.77-0.93), consistent with the estimate on the full database. Hazard ratios for DFS in individual trials and overall are shown in Figure 4. Adjuvant chemotherapy improved DFS compared with surgery alone with an overall HR of 0.82 (95% CI, 0.75-0.90; P < .001). The absolute benefit at 5 years was 5.3%, from 48.7% to 54.0% (eFigure 3). There was no indication of heterogeneity between trials in treatment effect (P = .57).

Place holder to copy figure label and caption
Figure 4. Individual Trial and Overall Hazard Ratio for Disease-Free Survival When Comparing Any Adjuvant Chemotherapy vs Surgery Alone
Graphic Jump Location

The inverse of variance of observed events minus expected events measures the weight of each trial in the analysis. P values are from P-for-effect modification testing for heterogeneity within or across the groups of regimens. The sizes of the data markers are proportional to the number of events. CI indicates confidence interval; HR, hazard ratio.

Analysis of Groups of Regimens

An interaction test between the type of regimen (monochemotherapy; fluorouracil and mitomycin C with anthracyclines; fluorouracil, mitomycin C, and others without anthracyclines; other polychemotherapy) and the treatment effect on OS and on DFS were not significant (P = .13 for both). In the sensitivity analysis, interaction was of borderline significance for OS (P = .05). We further explored these 4 groups. Survival curves are provided as supplementary material (eFigures 4 through 7).

Monochemotherapies. The 2 medium-sized trials19,20 (1 European, 1 Japanese) included a total of 324 patients of whom 317 patients were eligible for the meta-analysis with OS data. They showed a statistically significant benefit of adjuvant monochemotherapy over surgery alone (HR, 0.60; 95% CI, 0.42-0.84; P = .03), with 5-year survival rates of 53.9% for the surgery-only group vs 71.4% for the chemotherapy group. This rate was much higher than in the whole meta-analysis, suggesting that these patients had a good baseline prognosis. Disease-free survival was not collected in 1 of the 2 trials and hence not analyzed.

Polychemotherapies: Fluorouracil + Mitomycin C + Others Without Anthracyclines. Three Japanese trials with 1053 patients total used combined chemotherapy including fluorouracil derivatives, mitomycin C, and others without anthracyclines.2123 Overall, a statistically significant benefit for OS was observed (HR, 0.74; 95% CI, 0.58-0.95; P = .03), with 5-year survival rates of 76.6% for the surgery-only group vs 82.8% for the chemotherapy group. A similar effect on DFS was observed in the 2 more recent studies (HR, 0.69; 95% CI, 0.48-0.98) with 5-year DFS rates of 84.2% for the surgery-only group vs 88.2% for the chemotherapy group.

Polychemotherapies: Fluorouracil + Mitomycin C + Anthracyclines. Five trials (4 European, 1 US) using combined chemotherapy including anthracyclines had 1013 patients total and 1000 patients with OS data.2428 Overall, a statistically significant hazard reduction was observed for OS (HR, 0.82; 95% CI, 0.71-0.96; P = .01). The 5-year survival rate increased from 31.9% to 39.3%, and heterogeneity was not detected (P = .52). The HR for DFS was estimated from 4 trials. The risk of relapse or second primary cancer or death was also statistically significantly reduced (HR, 0.80; 95% CI, 0.69-0.94; P = .006) with 5-year DFS rates of 31.9% for the surgery-only group vs 39% for the chemotherapy group.

Polychemotherapies: Group “Other” vs Surgery Alone. For 1411 of 1448 patients in 7 trials for whom survival data were available,2934 we did not detect a significant effect of adjuvant regimens vs surgery alone (HR, 0.89; 95% CI, 0.78-1.02; P = .09). The 5-year survival rate was 41.5%. Heterogeneity was not detected (P = .51) even though 1 trial29 that used fluorouracil and semustine showed a significant treatment effect. Five-year DFS was 41.9% for the surgery-only group vs 44.5% for the chemotherapy group, and a marginally significant effect of treatment on DFS was observed (HR, 0.88; 95% CI, 0.78-1.0; P = .05), which was mainly driven by the positive study29; in a sensitivity analysis excluding this trial, the DFS effect was not significant (HR, 0.91; 95% CI, 0.79-1.04; P = .18).

Proportionality of the Hazard Functions

Plots of survival curves for all chemotherapy regimens combined or in each regimen group suggested nonproportional hazard functions, as illustrated by late separation of the survival function estimates. Nonproportional hazards were not detected using the Grambsch and Therneau test (P = .35). When a time-dependent model was fitted on the full data set with a cut-point at 2 years, treatment effect before and after 2 years was significantly different (P < .001). Point estimates of the HR by 2-year intervals showed a regular decrease from 0.91 in the first 2 years from randomization to 0.75 between 2 and 4 years and 0.62 beyond 4 years. After 8 years, the number of events became too small to provide meaningful estimates. Because these cut-points were derived from the data, they should be considered with caution. Hazard functions showed that the rate of death reached a peak at 18 months and steadily decreased thereafter to reach a plateau at about 5 years (eFigure 8).

Adjuvant chemotherapy without radiation for gastric cancer has recently become the standard of care in Japan after the publication of the results of the ACTS-GS trial reporting on S-14 but not in Europe or the United States. Numerous randomized phase 2 and phase 3 trials have produced conflicting results. However, many of these trials had limited sample sizes, making it difficult to draw definitive conclusions. Based on the individual data of 3838 patients from 17 different trials with a median follow-up longer than 7 years, the largest patient-level meta-analysis performed so far, we showed a modest but statistically significant benefit associated with adjuvant chemotherapy after curative resection of gastric cancers. The mortality hazard was reduced by about 18% and an absolute improvement of about 6% in OS was observed after 5 years. This improvement was maintained at 10 years. An 18% reduction in the risk of relapse, second primary, or death was also observed. This treatment benefit was maintained in 3 of the 4 investigated groups of fluorouracil-based regimens, with reductions in the risk of death ranging from 20% to 40% (nonstatistically significant heterogeneity). Only 1 trial19 that enrolled 134 patients investigated a non–fluoropyrimidines-based regimen. Sensitivity analysis excluding this trial led to the same results. The absence of interaction with the class of regimen and with the region as well as the long follow-up is reassuring. Patient-level meta-analyses are the most reliable means to provide an exhaustive and unbiased summary of the available evidence on a clinical question of interest and complete large well-conducted trials (such as those that are currently done).

Postoperative chemotherapy is not the only adjuvant treatment for gastric cancer. In 2001, results of a trial that randomized between surgery and surgery with chemoradiotherapy showed an absolute increase in median survival of 9 months.49 Thereafter, chemoradiation therapy has gained popularity and has been increasingly used as a standard of care, especially in the United States, even though the optimal chemotherapy regimen has not been identified yet. Several trials are currently being conducted to explore this issue, but their results will not be available until 2011. Similarly, neoadjuvant trials have shown the benefit of starting the chemotherapy treatment as early as possible.5052 Although the short-term results of delayed surgery are being debated,53 neoadjuvant treatment, which can be administered to more patients than postoperative chemotherapy, has gained acceptance in western countries.

We could only collect about two-thirds of all data available from randomized trials in early gastric cancer, which is disappointing in view of the intensive efforts made at repeatedly contacting the principal investigators of the trials. However, for all but 3 trials with unavailable individual patient data, we could extract summary statistics from the published articles. Our results remained unchanged when these summary statistics were included in the calculations. Combining unverified published summary statistics with carefully checked individual patient data is not a satisfactory way of estimating an unbiased overall treatment effect, but it provides a way of assessing the robustness of a meta-analysis with respect to unavailable trials.

The optimal design of future adjuvant gastric cancer clinical trials, particularly the choice of an adequate control group, is a delicate issue. It is beyond the scope of our meta-analysis to identify the optimal regimen; however, based on our data, chemotherapy seems justified as a control group. Fluoropyrimidines-based regimens, in particular the oral forms (uracil plus tegafur and recently S-1 monotherapy) that have been shown to be better tolerated,8 seem reasonable treatment options, although their applicability outside East Asian countries remains uncertain. This raises the question of why fluoropyrimidines (intravenous fluorouracil or oral tegafur) appear to have activity in the adjuvant setting for gastric cancer as well as in colon cancer even though their efficacy is disappointing for the treatment of advanced disease.

In conclusion, this patient-level meta-analysis shows that adjuvant fluorouracil-based chemotherapy, even in monotherapy, is associated with improvement in overall survival (HR, 0.82) and is recommended for patients who have not received perioperative treatments after complete resection of their gastric cancer. Future reports based on data being collected will explore prognostic factors and the surrogacy of disease-free survival for overall survival in this population.

Corresponding Author: Xavier Paoletti, PhD, Institut National du Cancer, Direction de la Recherche, 52 Avenue Morizet, 92510 Boulogne Cedex, France (xpaoletti@institutcancer.fr).

Author Contributions: Dr Paoletti had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Paoletti and Oba contributed equally to this work.

Study concept and design: Paoletti, Oba, Burzykowski, Michiels, Ohashi, Pignon, Rougier, Sakamoto, Sasako, Buyse.

Acquisition of data: Paoletti, Oba, Ohashi, Sakamoto, Sargent, Sasako, Van Cutsem, Buyse.

Analysis and interpretation of data: Paoletti, Oba, Burzykowski, Michiels, Pignon, Rougier, Sargent, Van Cutsem, Buyse.

Drafting of the manuscript: Paoletti, Oba, Burzykowski, Sasako, Buyse.

Critical revision of the manuscript for important intellectual content: Paoletti, Oba, Burzykowski, Michiels, Ohashi, Pignon, Rougier, Sakamoto, Sargent, Van Cutsem, Buyse.

Statistical analysis: Paoletti, Oba, Burzykowski, Michiels, Pignon, Sargent, Buyse.

Obtained funding: Oba, Ohashi.

Administrative, technical, or material support: Paoletti, Oba, Sakamoto, Sargent.

Study supervision: Paoletti, Ohashi, Rougier, Sasako, Van Cutsem, Buyse.

Financial Disclosures: None reported.

Funding/Support: This project was partially funded by the Japan Clinical Research Support Unit (J-CRSU), the Epidemiological and Clinical Research Information Network (ECRIN), and the Institut National du Cancer (INCa), France.

Role of the Sponsor: The project was initiated under the auspice of the INCa, who served as a sponsor. The INCa did not participate in the design of the study. It participated in the conduct of the study by centralizing all the databases and by providing administrative and data management support. The sponsor did not participate in the analysis and interpretation of the data, which were solely the responsibility of the writing committee. The sponsor had no role in the preparation, review, or approval of the manuscript.

The GASTRIC Investigators:Secretariat: Marc Buyse, Stefan Michiels, Koji Oba, Xavier Paoletti, Philippe Rougier, Seiichiro Yamamoto, Kenichi Yoshimura; Steering Committee: Yung-Jue Bang (Seoul National University College of Medicine, Seoul, Korea); Harry Bleiberg (Brussels, Belgium); Tomasz Burzykowski (Hasselt University, Diepenbeek, Belgium); Marc Buyse (International Drug Development Institute, Louvain-la-Neuve, Belgium); Catherine Delbaldo (University Hospital Henri Mondore, AP-HP, Créteil, France); Stefan Michiels (Institut Gustave-Roussy, Villejuif, France); Satoshi Morita (Yokohama City University, Kanagawa, Japan); Yasuo Ohashi (University of Tokyo, Tokyo, Japan); Xavier Paoletti (Institut National du Cancer, Boulogne, France); Jean-Pierre Pignon (Institut Gustave-Roussy); Carmelo Pozzo (Catholic University of the Sacred Heart, Rome, Italia); Philippe Rougier (University Hospital Ambroise Paré [AP-HP], Boulogne); Junichi Sakamoto (Nagoya University, Aichi, Japan); Daniel Sargent (Mayo Clinic, Rochester, Minnesota); Mitsuru Sasako (Hyogo College of Medicine, Hyogo, Japan); Eric Van Cutsem (Digestive Oncology Unit, University Hospital Gasthuisberf, Leuven, Belgium); Collaborators Who Supplied Individual Patient Data: Steven Alberts (Mayo Clinic); Emilio Bajetta (Department of Medical Oncology, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy); Jacqueline Benedetti (SWOG Statistical Center, Seattle, Washington); Franck Bonnetain, FFCD (Dijon, France); Olivier Bouche (Department of Gastro-Intestinal Oncology, University Hospital Robert Debré, Reims, France); R. Charles Coombes (Medical Oncology Unit, Charing Cross Hospital, London, United Kingdom); Maria Di Bartolomeo (Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori); Juan J. Grau (Department of Oncology, Institut Clinic de Malalties Hemato-Oncologiques of Hospital Clinic, University of Barcelona, Barcelona, Spain); Juan C. Garcia-Valdecasas (Department of Oncology, Institut Clinic de Malalties Hemato-Oncologiques of Hospital Clinic, University of Barcelona); Josep Fuster (Department of Oncology, Institut Clinic de Malalties Hemato-Oncologiques of Hospital Clinic, University of Barcelona); James E. Krook (Mayo Clinic); Florian Lordick (National Center for Tumor Diseases, Department of Medical Oncology, University of Heidelberg, Heidelberg, Germany); Mario Lise (Department of Oncological and Surgical Sciences, University of Padua, Padua, Italy); John S. Macdonald (St Vincent's Cancer Center, New York, New York); Pierre Michel (Department of Gastro-Intestinal Oncology, Charles-Nicolle University Hospital, Rouen, France); Toshifusa Nakajima (Cancer Institute Hospital, Tokyo, Japan); Atsushi Nashimoto (Niigata Cancer Center Hospital, Niigata, Japan); Garth D. Nelson (Mayo Clinic); Donato Nitti (Department of Oncological and Surgical Sciences, University of Padua); Tadeusz Popiela (Department of Surgery, Jagiellonian University Medical College, Krakow, Poland); Philippe Rougier (University Hospital Ambroise Paré); Nicolas Tsavaris (Laiko University Hospital, Athens, Greece).

Disclaimer: The conclusions may not reflect the views of the INCa.

Additional Contributions: The GASTRIC Group thanks all patients who took part in the trials and contributed to this research. The meta-analysis would not have been possible without their participation or without active participation of the collaborating institutions that provided their trial data (ECOG, EORTC, FFCD, GITSG, ICCG, ITMO, JCOG, NCCTG, SWOG, Hospital Clinic Villarroel of Barcelona, Metaxa Cancer Hospital, Jagiellonian of Pireus University, Medical College of Krakow). We thank the EMMES Corporation, Rockville, Maryland, for extracting the GITSG data. Caroline Tournoux-Facon, MD, and Elise Seringe, MD (INCa, France), helped in the project management, and Frédéric Agnola (INCa, France) helped in data management. They did not receive compensation. We are indebted to Sanofi-Aventis for funding 3 investigator meetings.

Crew KD, Neugut AI. Epidemiology of gastric cancer.  World J Gastroenterol. 2006;12(3):354-362
PubMed
Stewart BW, ed, Kleihues P, edWorld Cancer Report. Lyon, France: International Agency on Research for Cancer; 2003
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer.  Lancet. 2009;374(9688):477-490
PubMed   |  Link to Article
Sakuramoto S, Sasako M, Yamaguchi T,  et al; ACTS-GC Group.  Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.  N Engl J Med. 2007;357(18):1810-1820
PubMed   |  Link to Article
Ajani JA, Rodriguez W, Bodoky G,  et al.  Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial.  J Clin Oncol. 2010;28(9):1547-1553
PubMed   |  Link to Article
Liu TS, Wang Y, Chen SY, Sun YH. An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.  Eur J Surg Oncol. 2008;34(11):1208-1216
PubMed   |  Link to Article
Zhao SL, Fang JY. The role of postoperative adjuvant chemotherapy following curative resection for gastric cancer: a meta-analysis.  Cancer Invest. 2008;26(3):317-325
PubMed   |  Link to Article
Oba K, Morita S, Tsuburaya A, Kodera Y, Kobayashi M, Sakamoto J. Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in Japan.  J Chemother. 2006;18(3):311-317
PubMed
Janunger KG, Hafström L, Glimelius B. Chemotherapy in gastric cancer: a review and updated meta-analysis.  Eur J Surg. 2002;168(11):597-608
PubMed   |  Link to Article
Mari E, Floriani I, Tinazzi A,  et al.  Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials: a study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente).  Ann Oncol. 2000;11(7):837-843
PubMed   |  Link to Article
Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using updated individual patient data: Cochrane Working Group.  Stat Med. 1995;14(19):2057-2079
PubMed   |  Link to Article
Pignon JP, Hill C. Meta-analyses of randomised clinical trials in oncology.  Lancet Oncol. 2001;2(8):475-482
PubMed   |  Link to Article
Cochran WG. The combination of estimates from different experiments.  Biometrics. 1954;10:101-129
Link to Article
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Early Breast Cancer Trialists' Collaborative Group.  Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women.  Lancet. 1992;339(8784):1-15
PubMed
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals.  Biometrika. 1994;81(3):515-526
Link to Article
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time.  Control Clin Trials. 1996;17(4):343-346
PubMed   |  Link to Article
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.  Stat Med. 1998;17(24):2815-2834
PubMed   |  Link to Article
Grau JJ, Estape J, Alcobendas F, Pera C, Daniels M, Terés J. Positive results of adjuvant mitomycin-C in resected gastric cancer: a randomised trial on 134 patients.  Eur J Cancer. 1993;29A(3):340-342
PubMed   |  Link to Article
Nakajima T, Kinoshita T, Nashimoto A,  et al; National Surgical Adjuvant Study of Gastric Cancer Group.  Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer.  Br J Surg. 2007;94(12):1468-1476
PubMed   |  Link to Article
Nakajima T, Takahashi T, Takagi K, Kuno K, Kajitani T. Comparison of 5-fluorouracil with ftorafur in adjuvant chemotherapies with combined inductive and maintenance therapies for gastric cancer.  J Clin Oncol. 1984;2(12):1366-1371
PubMed
Nakajima T, Nashimoto A, Kitamura M,  et al; Gastric Cancer Surgical Study Group.  Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial.  Lancet. 1999;354(9175):273-277
PubMed   |  Link to Article
Nashimoto A, Nakajima T, Furukawa H,  et al; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group.  Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1.  J Clin Oncol. 2003;21(12):2282-2287
PubMed   |  Link to Article
Coombes RC, Schein PS, Chilvers CE,  et al; International Collaborative Cancer Group.  A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer.  J Clin Oncol. 1990;8(8):1362-1369
PubMed
Lise M, Nitti D, Marchet A,  et al.  Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.  J Clin Oncol. 1995;13(11):2757-2763
PubMed
Macdonald JS, Fleming TR, Peterson RF,  et al.  Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: a Southwest Oncology Group study.  Ann Surg Oncol. 1995;2(6):488-494
PubMed   |  Link to Article
Tsavaris N, Tentas K, Kosmidis P,  et al.  A randomized trial comparing adjuvant fluorouracil, epirubicin, and mitomycin with no treatment in operable gastric cancer.  Chemotherapy. 1996;42(3):220-226
PubMed   |  Link to Article
Popiela T, Kulig J, Czupryna A, Szczepanik AM, Zembala M. Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer.  Gastric Cancer. 2004;7(4):240-245
PubMed   |  Link to Article
Douglass HO, Stablein DM.The Gastrointestinal Tumor Study Group.  Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer.  Cancer. 1982;49(6):1116-1122
PubMed   |  Link to Article
Engstrom PF, Lavin PT, Douglass HO Jr, Brunner KW. Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients: Eastern Cooperative Oncology Group study (EST 3275).  Cancer. 1985;55(9):1868-1873
PubMed   |  Link to Article
Krook JE, O’Connell MJ, Wieand HS,  et al.  A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer.  Cancer. 1991;67(10):2454-2458
PubMed   |  Link to Article
Bajetta E, Buzzoni R, Mariani L,  et al.  Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group.  Ann Oncol. 2002;13(2):299-307
PubMed   |  Link to Article
Bouché O, Ychou M, Burtin P,  et al; Fédération Francophone de Cancérologie Digestive Group.  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(9):1488-1497
PubMed   |  Link to Article
Nitti D, Wils J, Dos Santos JG,  et al; EORTC GI Group; ICCG.  Randomized phase III trial of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI group and the ICCG.  Ann Oncol. 2006;17(2):262-269
PubMed   |  Link to Article
Chou FF, Sheen-Chen SM, Liu PP, Chen FC. Adjuvant chemotherapy for resectable gastric cancer: a preliminary report.  J Surg Oncol. 1994;57(4):239-242
PubMed   |  Link to Article
Allum WH, Hallissey MT, Kelly KA. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial.  Lancet. 1989;1(8638):571-574
PubMed   |  Link to Article
Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up.  Lancet. 1994;343(8909):1309-1312
PubMed   |  Link to Article
Di Costanzo F, Gasperoni S, Manzione L,  et al; Italian Oncology Group for Cancer Research.  Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.  J Natl Cancer Inst. 2008;100(6):388-398
PubMed   |  Link to Article
De Vita F, Giuliani F, Orditura M,  et al; Gruppo Oncologico Italia Meridionale.  Adjuvant chemotherapy with epirubicin, leucovorin, fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study).  Ann Oncol. 2007;18(8):1354-1358
PubMed   |  Link to Article
Jakesz R, Dittrich C, Funovics J,  et al.  The effect of adjuvant chemotherapy in gastric carcinoma is dependent on tumor histology: 5-year results of a prospective randomized trial.  Recent Results Cancer Res. 1988;110:44-51
PubMed
Cirera L, Balil A, Batiste-Alentorn E,  et al.  Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.  J Clin Oncol. 1999;17(12):3810-3815
PubMed
Fujii M, Sakabe T, Wakabayashi K,  et al.  The optimal period for orally administered fluoropyrimidines as an adjuvant chemotherapy for gastric cancer: a pilot study using 5-FU tablets compared with surgical operation alone [in Japanese].  Gan To Kagaku Ryoho. 1994;21(8):1199-1208
PubMed
Carrato A, Diaz-Rubio E, Medrano J,  et al.  Phase III trial of surgery versus adjuvant chemotherapy with mitomycin C (MMC) and tegafur plus uracil (UFT), starting within the first week after surgery, for gastric adenocarcinoma [meeting abstract].  Proc Am Soc Clin Oncol. 1995;14:468
Huguier M, Destroyes H, Baschet C, Le Henand F, Bernard PF. Gastric carcinoma treated by chemotherapy after resection: a controlled study.  Am J Surg. 1980;139(2):197-199
PubMed   |  Link to Article
Schlag P, Schreml W, Gaus W,  et al.  Adjuvant 5-fluorouracil and BCNU chemotherapy in gastric cancer: 3-year results.  Recent Results Cancer Res. 1982;80:277-283
PubMed
Neri B, de Leonardis V, Romano S,  et al.  Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multi-centre randomised study.  Br J Cancer. 1996;73(4):549-552
PubMed   |  Link to Article
Chipponi J, Huguier M, Pezet D,  et al.  Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer.  Am J Surg. 2004;187(3):440-445
PubMed   |  Link to Article
Bonfanti G, Gennari L, Bozzetti F,  et al; The Italian Gastrointestinal Tumor Study Group.  Adjuvant treatments following curative resection for gastric cancer.  Br J Surg. 1988;75(11):1100-1104
PubMed   |  Link to Article
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(10):725-730
PubMed   |  Link to Article
Cunningham D, Allum WH, Stenning SP,  et al; MAGIC Trial Participants.  Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.  N Engl J Med. 2006;355(1):11-20
PubMed   |  Link to Article
Boige V, Pignon JP, Saint-Aubert B,  et al.  Final results of a randomized trial comparing preoperative 5-fluorouracil/cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial.  J Clin Oncol. 2007;25:(suppl 18)  4510
Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J.Australasian Gastro-Intestinal Trials Group.  Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis.  Lancet Oncol. 2007;8(3):226-234
PubMed   |  Link to Article
D’Ugo D, Rausei S, Biondi A, Persiani R. Preoperative treatment and surgery in gastric cancer: friends or foes?  Lancet Oncol. 2009;10(2):191-195
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1. Study Flowchart
Graphic Jump Location
Place holder to copy figure label and caption
Figure 2. Individual Trial and Overall Hazard Ratio for Overall Survival When Comparing Any Adjuvant Chemotherapy vs Surgery Alone
Graphic Jump Location

The inverse of the variance of observed events minus expected events measures the weight of each trial in the analysis. P values are from P-for-effect modification testing for heterogeneity within or across the groups of regimens. The sizes of data markers are proportional to the number of deaths in the trials. CI indicates confidence interval; HR, hazard ratio.

Place holder to copy figure label and caption
Figure 3. Overall Survival Estimate After Any Chemotherapy or Surgery Alone Truncated at 10 Years
Graphic Jump Location

The estimates of the survival curves use an actuarial approach as described in the Methods.

Place holder to copy figure label and caption
Figure 4. Individual Trial and Overall Hazard Ratio for Disease-Free Survival When Comparing Any Adjuvant Chemotherapy vs Surgery Alone
Graphic Jump Location

The inverse of variance of observed events minus expected events measures the weight of each trial in the analysis. P values are from P-for-effect modification testing for heterogeneity within or across the groups of regimens. The sizes of the data markers are proportional to the number of events. CI indicates confidence interval; HR, hazard ratio.

Tables

Table Graphic Jump LocationTable. List of the Included Randomized Trials

References

Crew KD, Neugut AI. Epidemiology of gastric cancer.  World J Gastroenterol. 2006;12(3):354-362
PubMed
Stewart BW, ed, Kleihues P, edWorld Cancer Report. Lyon, France: International Agency on Research for Cancer; 2003
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer.  Lancet. 2009;374(9688):477-490
PubMed   |  Link to Article
Sakuramoto S, Sasako M, Yamaguchi T,  et al; ACTS-GC Group.  Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine.  N Engl J Med. 2007;357(18):1810-1820
PubMed   |  Link to Article
Ajani JA, Rodriguez W, Bodoky G,  et al.  Multicenter phase III comparison of cisplatin/S-1 with cisplatin/infusional fluorouracil in advanced gastric or gastroesophageal adenocarcinoma study: the FLAGS trial.  J Clin Oncol. 2010;28(9):1547-1553
PubMed   |  Link to Article
Liu TS, Wang Y, Chen SY, Sun YH. An updated meta-analysis of adjuvant chemotherapy after curative resection for gastric cancer.  Eur J Surg Oncol. 2008;34(11):1208-1216
PubMed   |  Link to Article
Zhao SL, Fang JY. The role of postoperative adjuvant chemotherapy following curative resection for gastric cancer: a meta-analysis.  Cancer Invest. 2008;26(3):317-325
PubMed   |  Link to Article
Oba K, Morita S, Tsuburaya A, Kodera Y, Kobayashi M, Sakamoto J. Efficacy of adjuvant chemotherapy using oral fluorinated pyrimidines for curatively resected gastric cancer: a meta-analysis of centrally randomized controlled clinical trials in Japan.  J Chemother. 2006;18(3):311-317
PubMed
Janunger KG, Hafström L, Glimelius B. Chemotherapy in gastric cancer: a review and updated meta-analysis.  Eur J Surg. 2002;168(11):597-608
PubMed   |  Link to Article
Mari E, Floriani I, Tinazzi A,  et al.  Efficacy of adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis of published randomised trials: a study of the GISCAD (Gruppo Italiano per lo Studio dei Carcinomi dell’Apparato Digerente).  Ann Oncol. 2000;11(7):837-843
PubMed   |  Link to Article
Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using updated individual patient data: Cochrane Working Group.  Stat Med. 1995;14(19):2057-2079
PubMed   |  Link to Article
Pignon JP, Hill C. Meta-analyses of randomised clinical trials in oncology.  Lancet Oncol. 2001;2(8):475-482
PubMed   |  Link to Article
Cochran WG. The combination of estimates from different experiments.  Biometrics. 1954;10:101-129
Link to Article
Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses.  BMJ. 2003;327(7414):557-560
PubMed   |  Link to Article
Early Breast Cancer Trialists' Collaborative Group.  Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women.  Lancet. 1992;339(8784):1-15
PubMed
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals.  Biometrika. 1994;81(3):515-526
Link to Article
Schemper M, Smith TL. A note on quantifying follow-up in studies of failure time.  Control Clin Trials. 1996;17(4):343-346
PubMed   |  Link to Article
Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints.  Stat Med. 1998;17(24):2815-2834
PubMed   |  Link to Article
Grau JJ, Estape J, Alcobendas F, Pera C, Daniels M, Terés J. Positive results of adjuvant mitomycin-C in resected gastric cancer: a randomised trial on 134 patients.  Eur J Cancer. 1993;29A(3):340-342
PubMed   |  Link to Article
Nakajima T, Kinoshita T, Nashimoto A,  et al; National Surgical Adjuvant Study of Gastric Cancer Group.  Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer.  Br J Surg. 2007;94(12):1468-1476
PubMed   |  Link to Article
Nakajima T, Takahashi T, Takagi K, Kuno K, Kajitani T. Comparison of 5-fluorouracil with ftorafur in adjuvant chemotherapies with combined inductive and maintenance therapies for gastric cancer.  J Clin Oncol. 1984;2(12):1366-1371
PubMed
Nakajima T, Nashimoto A, Kitamura M,  et al; Gastric Cancer Surgical Study Group.  Adjuvant mitomycin and fluorouracil followed by oral uracil plus tegafur in serosa-negative gastric cancer: a randomised trial.  Lancet. 1999;354(9175):273-277
PubMed   |  Link to Article
Nashimoto A, Nakajima T, Furukawa H,  et al; Gastric Cancer Surgical Study Group, Japan Clinical Oncology Group.  Randomized trial of adjuvant chemotherapy with mitomycin, fluorouracil, and cytosine arabinoside followed by oral fluorouracil in serosa-negative gastric cancer: Japan Clinical Oncology Group 9206-1.  J Clin Oncol. 2003;21(12):2282-2287
PubMed   |  Link to Article
Coombes RC, Schein PS, Chilvers CE,  et al; International Collaborative Cancer Group.  A randomized trial comparing adjuvant fluorouracil, doxorubicin, and mitomycin with no treatment in operable gastric cancer.  J Clin Oncol. 1990;8(8):1362-1369
PubMed
Lise M, Nitti D, Marchet A,  et al.  Final results of a phase III clinical trial of adjuvant chemotherapy with the modified fluorouracil, doxorubicin, and mitomycin regimen in resectable gastric cancer.  J Clin Oncol. 1995;13(11):2757-2763
PubMed
Macdonald JS, Fleming TR, Peterson RF,  et al.  Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: a Southwest Oncology Group study.  Ann Surg Oncol. 1995;2(6):488-494
PubMed   |  Link to Article
Tsavaris N, Tentas K, Kosmidis P,  et al.  A randomized trial comparing adjuvant fluorouracil, epirubicin, and mitomycin with no treatment in operable gastric cancer.  Chemotherapy. 1996;42(3):220-226
PubMed   |  Link to Article
Popiela T, Kulig J, Czupryna A, Szczepanik AM, Zembala M. Efficiency of adjuvant immunochemotherapy following curative resection in patients with locally advanced gastric cancer.  Gastric Cancer. 2004;7(4):240-245
PubMed   |  Link to Article
Douglass HO, Stablein DM.The Gastrointestinal Tumor Study Group.  Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer.  Cancer. 1982;49(6):1116-1122
PubMed   |  Link to Article
Engstrom PF, Lavin PT, Douglass HO Jr, Brunner KW. Postoperative adjuvant 5-fluorouracil plus methyl-CCNU therapy for gastric cancer patients: Eastern Cooperative Oncology Group study (EST 3275).  Cancer. 1985;55(9):1868-1873
PubMed   |  Link to Article
Krook JE, O’Connell MJ, Wieand HS,  et al.  A prospective, randomized evaluation of intensive-course 5-fluorouracil plus doxorubicin as surgical adjuvant chemotherapy for resected gastric cancer.  Cancer. 1991;67(10):2454-2458
PubMed   |  Link to Article
Bajetta E, Buzzoni R, Mariani L,  et al.  Adjuvant chemotherapy in gastric cancer: 5-year results of a randomised study by the Italian Trials in Medical Oncology (ITMO) Group.  Ann Oncol. 2002;13(2):299-307
PubMed   |  Link to Article
Bouché O, Ychou M, Burtin P,  et al; Fédération Francophone de Cancérologie Digestive Group.  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(9):1488-1497
PubMed   |  Link to Article
Nitti D, Wils J, Dos Santos JG,  et al; EORTC GI Group; ICCG.  Randomized phase III trial of adjuvant FAMTX or FEMTX compared with surgery alone in resected gastric cancer: a combined analysis of the EORTC GI group and the ICCG.  Ann Oncol. 2006;17(2):262-269
PubMed   |  Link to Article
Chou FF, Sheen-Chen SM, Liu PP, Chen FC. Adjuvant chemotherapy for resectable gastric cancer: a preliminary report.  J Surg Oncol. 1994;57(4):239-242
PubMed   |  Link to Article
Allum WH, Hallissey MT, Kelly KA. Adjuvant chemotherapy in operable gastric cancer: 5 year follow-up of first British Stomach Cancer Group trial.  Lancet. 1989;1(8638):571-574
PubMed   |  Link to Article
Hallissey MT, Dunn JA, Ward LC, Allum WH. The second British Stomach Cancer Group trial of adjuvant radiotherapy or chemotherapy in resectable gastric cancer: five-year follow-up.  Lancet. 1994;343(8909):1309-1312
PubMed   |  Link to Article
Di Costanzo F, Gasperoni S, Manzione L,  et al; Italian Oncology Group for Cancer Research.  Adjuvant chemotherapy in completely resected gastric cancer: a randomized phase III trial conducted by GOIRC.  J Natl Cancer Inst. 2008;100(6):388-398
PubMed   |  Link to Article
De Vita F, Giuliani F, Orditura M,  et al; Gruppo Oncologico Italia Meridionale.  Adjuvant chemotherapy with epirubicin, leucovorin, fluorouracil and etoposide regimen in resected gastric cancer patients: a randomized phase III trial by the Gruppo Oncologico Italia Meridionale (GOIM 9602 Study).  Ann Oncol. 2007;18(8):1354-1358
PubMed   |  Link to Article
Jakesz R, Dittrich C, Funovics J,  et al.  The effect of adjuvant chemotherapy in gastric carcinoma is dependent on tumor histology: 5-year results of a prospective randomized trial.  Recent Results Cancer Res. 1988;110:44-51
PubMed
Cirera L, Balil A, Batiste-Alentorn E,  et al.  Randomized clinical trial of adjuvant mitomycin plus tegafur in patients with resected stage III gastric cancer.  J Clin Oncol. 1999;17(12):3810-3815
PubMed
Fujii M, Sakabe T, Wakabayashi K,  et al.  The optimal period for orally administered fluoropyrimidines as an adjuvant chemotherapy for gastric cancer: a pilot study using 5-FU tablets compared with surgical operation alone [in Japanese].  Gan To Kagaku Ryoho. 1994;21(8):1199-1208
PubMed
Carrato A, Diaz-Rubio E, Medrano J,  et al.  Phase III trial of surgery versus adjuvant chemotherapy with mitomycin C (MMC) and tegafur plus uracil (UFT), starting within the first week after surgery, for gastric adenocarcinoma [meeting abstract].  Proc Am Soc Clin Oncol. 1995;14:468
Huguier M, Destroyes H, Baschet C, Le Henand F, Bernard PF. Gastric carcinoma treated by chemotherapy after resection: a controlled study.  Am J Surg. 1980;139(2):197-199
PubMed   |  Link to Article
Schlag P, Schreml W, Gaus W,  et al.  Adjuvant 5-fluorouracil and BCNU chemotherapy in gastric cancer: 3-year results.  Recent Results Cancer Res. 1982;80:277-283
PubMed
Neri B, de Leonardis V, Romano S,  et al.  Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multi-centre randomised study.  Br J Cancer. 1996;73(4):549-552
PubMed   |  Link to Article
Chipponi J, Huguier M, Pezet D,  et al.  Randomized trial of adjuvant chemotherapy after curative resection for gastric cancer.  Am J Surg. 2004;187(3):440-445
PubMed   |  Link to Article
Bonfanti G, Gennari L, Bozzetti F,  et al; The Italian Gastrointestinal Tumor Study Group.  Adjuvant treatments following curative resection for gastric cancer.  Br J Surg. 1988;75(11):1100-1104
PubMed   |  Link to Article
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(10):725-730
PubMed   |  Link to Article
Cunningham D, Allum WH, Stenning SP,  et al; MAGIC Trial Participants.  Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.  N Engl J Med. 2006;355(1):11-20
PubMed   |  Link to Article
Boige V, Pignon JP, Saint-Aubert B,  et al.  Final results of a randomized trial comparing preoperative 5-fluorouracil/cisplatin to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial.  J Clin Oncol. 2007;25:(suppl 18)  4510
Gebski V, Burmeister B, Smithers BM, Foo K, Zalcberg J, Simes J.Australasian Gastro-Intestinal Trials Group.  Survival benefits from neoadjuvant chemoradiotherapy or chemotherapy in oesophageal carcinoma: a meta-analysis.  Lancet Oncol. 2007;8(3):226-234
PubMed   |  Link to Article
D’Ugo D, Rausei S, Biondi A, Persiani R. Preoperative treatment and surgery in gastric cancer: friends or foes?  Lancet Oncol. 2009;10(2):191-195
PubMed   |  Link to Article

Letters

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.

Multimedia

Data Supplement
Supplemental Content

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 169

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
Related Collections
PubMed Articles