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Chemotherapy in Advanced Gastric Cancer: A Systematic Review and Meta-Analysis Based on Aggregate Data

Anna D. Wagner, Wilfried Grothe, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig

From the First Department of Medicine, Coordinating Centre for Clinical Trials, Department of Medicine IV, and Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany; and Mayo Clinic College of Medicine, Rochester, MN

Address reprint requests to Anna D. Wagner, MD, First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str 40, 06120 Halle/Saale, Germany; e-mail: anna-dorothea.wagner{at}gmx.de

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: This systematic review and meta-analysis were performed to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer.

METHODS: Randomized phase II and III clinical trials on first-line chemotherapy in advanced gastric cancer were identified by electronic searches of Medline, Embase, the Cochrane Controlled Trials Register, and Cancerlit; hand searches of relevant abstract books and reference lists; and contact to experts. Meta-analysis was performed using the fixed-effect model. Overall survival, reported as hazard ratio (HR) with 95% CI, was the primary outcome measure.

RESULTS: Analysis of chemotherapy versus best supportive care (HR = 0.39; 95% CI, 0.28 to 0.52) and combination versus single agent, mainly fluorouracil (FU) -based chemotherapy (HR = 0.83; 95% CI = 0.74 to 0.93) showed significant overall survival benefits in favor of chemotherapy and combination chemotherapy, respectively. In addition, comparisons of FU/cisplatin-containing regimens with versus without anthracyclines (HR = 0.77; 95% CI, 0.62 to 0.95) and FU/anthracycline-containing combinations with versus without cisplatin (HR = 0.83; 95% CI, 0.76 to 0.91) both demonstrated a significant survival benefit for the three-drug combination. Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly FU/cisplatin) resulted in a nonsignificant survival benefit in favor of the irinotecan-containing regimens (HR = 0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination.

CONCLUSION: Best survival results are achieved with three-drug regimens containing FU, an anthracycline, and cisplatin. Among these, regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Despite a sharp decline of its incidence during the second half of the 20th century, gastric cancer remains the second leading cause of cancer mortality in the world.¹ Infection with Helicobacter pylori, atrophic gastritis, intestinal metaplasia, and dysplasia have been identified as important steps in the pathogenesis of gastric adenocarcinoma,² whereas Barrett's esophagus and dysplasia are associated with the development of esophageal adenocarcinoma.³ The incidence of this cancer in white males increased more than 3.5-fold between 1974 and 1994 in the United States, which is more than that of any other malignancy. Similar observations have been made in other Western countries.^4,5 Because it is difficult to determine whether these cancers are gastroesophageal junction tumors or distal esophageal malignancies, they are usually treated in the same manner in clinical trials for advanced disease.

In the Western world, most gastric cancer patients are diagnosed when the tumor is inoperable. For these patients, systemic chemotherapy is the main treatment option. Although a large number of chemotherapy regimens have been tested in randomized studies, there is no internationally accepted standard of care, and uncertainty remains regarding the choice of the regimen. Therefore, we performed a systematic review and meta-analysis of randomized phase II and III treatment trials to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer.

	METHODS

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We conducted this systematic review on the basis of a peer-reviewed, published protocol in accordance with the guidelines of the Cochrane Collaboration.⁶

Study Selection
Trials were identified by electronic searches in the Cochrane Controlled Trials Register, Medline, Embase, and Cancerlit. The search strategy included the medical subject headings of "stomach neoplasms," "drug therapy," "chemotherapy," "antineoplastic agents combined," and "palliative care" and free text searches. No language limits were applied. Initial searches were performed in February 2003, with updates in February 2004 and February 2005. In addition, we contacted drug manufacturers, asked experts in the field, and performed manual searches in reference lists and conference proceedings of United European Gastroenterology Week (1993 to 2004), Digestive Disease Week (1981 to 2004), European Society for Medical Oncology (1978 to 2004), European Cancer Conference (1981 to 2004), and American Society for Clinical Oncology (1981 to 2005). Selection criteria were as follows: study design: randomized, controlled trials; participants: patients with histologically confirmed, advanced, recurrent, or metastasized adenocarcinoma of the stomach or gastroesophageal junction; and interventions: systemic intravenous chemotherapy and/or best supportive care (BSC).

Authors were contacted to obtain any missing information. Abstracts or unpublished data were included if sufficient information was available and if final results were confirmed by contacting the first author. Cross-over studies were excluded because they dilute differences between study arms. Study selection, data extraction, and data entry were performed by two authors independently. Differences were resolved by consensus with a third author.

Statistical Methods
Overall survival was the primary outcome measure. Hazard ratios (HRs) and 95% CIs as relevant effect measures were estimated directly or indirectly from the given data.⁷ The fixed-effect model was used for meta-analysis. To assess statistical heterogeneity between studies, the Cochran Q test was performed, with a predefined significance threshold of 0.1. The methodologic quality of all eligible studies was assessed according to a predefined quality score⁸ using the Cochrane Collaboration software (RevMan version 4.2.2; http://www.cochrane.org). This quality score was used as the basis for sensitivity analysis. Funnel plots were used to assess publication bias. Details of statistical analyses and trial selection have been described elsewhere.⁸ Here, results for overall survival as the primary outcome measure, toxicity, and, where available, quality of life are reported. Comparisons of chemotherapy versus BSC and combination versus single-agent chemotherapy were prespecified in advance in the protocol for the review process.

In addition, eligible studies comparing different combination chemotherapy regimens were classified into subcategories depending on whether they contained fluorouracil (FU), an anthracycline, or cisplatin. Because a rational decision on which comparisons of different combination chemotherapy regimens were to be tested had to take into account the availability and eligibility of relevant studies, it was impossible to define these comparisons before starting the review process. As a consensus among the reviewers, the following two comparisons of chemotherapy regimens widely used in clinical practice and serving as reference arms in ongoing trials were selected after review of the eligible studies: FU/cisplatin/anthracycline combinations versus FU/cisplatin combinations without anthracyclines; and FU/cisplatin/anthracycline combinations versus FU/anthracycline combinations without cisplatin. The comparison of irinotecan-containing versus nonirinotecan-containing combinations was added in 2005.

	RESULTS

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We identified 158 references through electronic searches and 55 references by manual searches and contact with experts. After exclusion of duplicate publications, 194 unique references remained for further evaluation. Among these, 27 studies were eligible for analysis of the five comparisons specified earlier. Trials including gastric and esophageal or gastric and pancreatic cancer patients were included if sufficient information for the subgroup of patients with gastric cancer patients was available. Because trials differed in how toxicity was reported (eg, per number of patients or per number of cycles), only the percentage of toxic deaths could be used for summarizing results across different studies.

Chemotherapy Versus BSC
Three eligible studies^9-11 including 184 patients were included in this meta-analysis (Fig 1). All three studies used combination chemotherapy. The overall HR of 0.39 (95% CI, 0.28 to 0.52) in favor of the chemotherapy arms demonstrates a convincing benefit in overall survival over BSC alone, which translates to a benefit in weighted mean average survival of approximately 6 months. Heterogeneity was nonsignificant (P = .19). However, two of these three studies had substantial methodologic limitations. Murad et al⁹ interrupted random assignment in the middle of the study because of "strong evidence of benefit for the treated patients." The study by Pyrhönen et al¹⁰ was terminated early because of slow accrual and "a conspicuous difference in survival." A sensitivity analysis according to the quality score including only studies with adequate allocation concealment^10,11 changes the overall HR to 0.49 (95% CI, 0.36 to 0.67), but the result retains statistical significance. An additional study,¹² which was excluded from the analysis because of cross over, provided important insights about the quality of life of patients in the chemotherapy and BSC arms. The average proportion of the total survival time with a high quality of life was significantly higher in the group of patients randomly assigned to chemotherapy compared with the BSC group (69% v 47%, respectively; P < .05).

View larger version (8K): [in this window] [in a new window]   Fig 1. Effect of chemotherapy versus best supportive care (BSC) on overall survival. Hazard ratios were analyzed with the fixed-effect model (reproduced with permission8).

View larger version (15K): [in this window] [in a new window]   Fig 2. Effect of combination versus single-agent chemotherapy on overall survival. Hazard ratios were analyzed with the fixed-effect model.

View larger version (8K): [in this window] [in a new window]   Fig 3. Effect of fluorouracil (FU)/cisplatin (P)/anthracycline combinations versus FU/cisplatin combinations (without anthracyclines). Hazard ratios were analyzed with the fixed-effect model (reproduced with permission8). KRGCGC, Kyoto Research Group for Chemotherapy of Gastric Cancer.

View larger version (11K): [in this window] [in a new window]   Fig 4. Effect of fluorouracil (FU)/cisplatin (P)/anthracycline combinations versus FU/anthracycline combinations (without cisplatin). Hazard ratios were analyzed with the fixed-effect model (reproduced with permission8). GITSG, Gastrointestinal Tumor Study Group.

Irinotecan-Containing Versus Nonirinotecan-Containing Combinations
Three trials including 536 patients^17,35,36 were summarized in this meta-analysis. Only the combination chemotherapy arms of the study by Bouché et al¹⁷ were eligible and, therefore, included for this analysis. The resulting HR for overall survival of 0.88 (95% CI, 0.73 to 1.06; Fig 5) in favor of the irinotecan-containing regimens translates into a benefit in pooled median survival time of approximately 1 month for the irinotecan-containing regimens. Heterogeneity was nonsignificant (P = .83). Rates of treatment-related deaths were 0.7% in the irinotecan-containing arm versus 2.6% in the nonirinotecan-containing arm (exact Mantel-Haenszel OR = 0.275; P = .166²⁴). In two of three studies included in this comparison, irinotecan/FU combinations were compared against cisplatin/FU. The analysis was performed on ITT in all three studies.

View larger version (8K): [in this window] [in a new window]   Fig 5. Effect of irinotecan-containing versus nonirinotecan-containing regimens. Hazard ratios were analyzed with the fixed-effect model.

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
This systematic review revealed major findings for two questions of ongoing debate. First, is combination therapy better than single-agent chemotherapy? Although the use of combination chemotherapy is accepted as standard of care in Europe and the United States, this issue is a matter of discussion in Japan. In this controversy, the findings of our review provide important information. Nine of 11 individual studies relevant for this comparison did not demonstrate a significant benefit in overall survival for the combination chemotherapy arms. However, our meta-analysis demonstrates a small but statistically significant and consistent advantage of approximately 1 month in pooled median survival time for combination chemotherapy, which, in view of the short overall survival of these patients, we consider as clinically relevant. Nevertheless, because this survival benefit is achieved at the expense of increased toxicity and has to be balanced against it, this might be regarded as controversial. The impact of chemotherapy-related toxicity on the patients' quality of life has been insufficiently studied. However, the combination chemotherapy regimens in this comparison probably have not achieved optimal survival results because most of them included only FU/anthracycline but not FU/anthracycline/platinum combinations.

Thus, the second question should ask which of the combination chemotherapy regimens is best. The survival advantage of the three-drug combination of FU/anthracyclines and cisplatin compared with regimens containing either FU and cisplatin without anthracyclines or FU and anthracyclines without cisplatin is comparable to the difference in survival between combination and single-agent chemotherapy. Again, only a few of the individual studies for these comparisons generated conclusive results, and the power of the meta-analysis was necessary to demonstrate statistically significant and clinically relevant differences of 1 and 2 months in pooled median survival time between the two- and three-drug combinations.

Among the three-drug combinations, the difference in the percentage of treatment-related deaths is likely to be attributed to the administration of FU as bolus in PELF versus continuous infusion in ECF. It confirms an unacceptably high rate of toxic deaths for FU when administered as bolus in combination chemotherapy regimens as recently observed in colorectal cancer.³⁷ Our findings support the results of the studies by Webb et al³³and Ross et al²⁷ as well as a recently published review,³⁸ which have proposed ECF as standard of care.

The limitations of these studies still need attention. The patients included may not be characteristic of the overall population of patients with gastric cancer because they were generally younger.³⁹ Furthermore, patients with comorbidities such as renal or cardiac disease, which preclude the use of anthracyclines and/or cisplatin, were excluded. For this reason, these findings may apply only to younger patients with adequate general health. Whether FU/anthracycline/cisplatin-containing combination chemotherapy is equally beneficial in populations such as the elderly and those suffering from comorbid conditions remains unknown. A disadvantage of infusional FU in the ECF regimen is the inconvenience associated with portable pumps for continuous infusion. The question of whether continuous-infusion FU might be replaced by an oral FU prodrug is the subject of an ongoing investigation. According to a recently reported interim analysis,⁴⁰ replacement of continuous-infusion FU by capecitabine does not impair efficiency. However, the final results are required to provide a definitive answer to this question.

Four recently published, randomized studies^17,35,36,41 included chemotherapy combinations of infusional FU and irinotecan, which has proven efficacy in colorectal cancer and supposed activity against gastric cancer.⁴² According to our meta-analysis, irinotecan-containing regimens exhibit a benefit in survival of approximately 1 month and a lower rate of treatment-related deaths over the reference regimen, which was FU and cisplatin in two of three studies. Although these differences were statistically nonsignificant, we do not consider them as clinically irrelevant. Furthermore, rates of renal, hematologic, and neurologic toxicity were generally lower for the irinotecan-containing regimens, whereas the rate of diarrhea was increased. The overall number of patients who discontinued treatment as a result of toxicity was less than half in patients treated with irinotecan compared with patients not treated with irinotecan (10% v 21.5%, respectively) in the largest of these studies.³⁶ Thus, irinotecan/FU seems to be an appropriate alternative to FU and cisplatin, with a more favorable toxicity profile, but has never been compared against a three-drug combination.

In addition to irinotecan, combinations of docetaxel with either cisplatin alone⁴³ or cisplatin/FU (DCF)^44,45 have been evaluated in advanced gastric cancer recently. At present, final results are available from only one trial.⁴⁴ The small survival advantage for DCF compared with cisplatin and FU observed in this randomized phase III study, although statistically significant (median survival, 9.2 v 8.6 months, respectively; P = .02), seems to be of questionable clinical relevance in the light of a considerably increased toxicity, especially in patients older than 65 years of age. Again, DCF or infusional FU and irinotecan have never been compared against ECF. For this reason, there is reasonable doubt about whether they truly represent therapeutic advances over an established three-drug regimen, which demonstrated a survival advantage in our meta-analysis over the reference treatment in these trials, FU and cisplatin. However, results of other ongoing studies need to be awaited to draw definitive conclusions.

Therefore, at present, combinations of infusional FU/cisplatin, infusional FU/irinotecan, and infusional FU and an anthracycline or single-agent chemotherapy with FU, depending on the performance status and comorbidities of the individual patient, are reasonable alternatives for patients in whom the three-drug combination is considered inappropriate. Because of relevant rates of neutropenia, neutropenic infection, and diarrhea, DCF can be recommended as an alternative treatment option only to younger patients with adequate general health.

Another major unresolved issue is the impact of second- and third-line chemotherapy on overall survival. Patients with colorectal cancer who receive fluoropyrimidines as well as irinotecan and oxaliplatin seem to have a survival benefit over patients in whom one or the other of these drugs is omitted.⁴⁶ Because the number of active drugs against gastric cancer is increasing, it will be important to learn if a similar approach might be beneficial for gastric cancer patients as well, although the biology of gastric cancer is clearly different.

Irrespective of the positive impact of any presently available chemotherapy, the prognosis of patients with advanced gastric cancer remains desperate, with a median survival of only 7 to 10 months in most of the larger clinical studies. Although the benefit of treatment quo ad vitam may be greater in a few individual patients, appropriate treatment measures should consider the principles of palliative care. The WHO has defined palliative care⁴⁷ as "an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness." Thus, in addition to survival, quality of life and quality-adjusted survival should be prominent therapeutic objectives. Further research is required to evaluate the balance between relief of tumor-associated symptoms and treatment-associated toxicity of novel therapy regimens from the patient's perspective.⁸

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Anna D. Wagner, Wilfried Grothe, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig Collection and assembly of data: Anna D. Wagner, Wilfried Grothe Data analysis and interpretation: Anna D. Wagner, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig Manuscript writing: Anna D. Wagner, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig Final approval of manuscript: Anna D. Wagner, Wilfried Grothe, Johannes Haerting, Gerhard Kleber, Axel Grothey, Wolfgang E. Fleig

 

	ACKNOWLEDGMENTS

 
We thank Shino Yuo for translations of Japanese studies, Y. Shimada for providing important insights on the Japanese view of the subject, all authors who provided unpublished data, and J. Abbruzzese, D. Cunningham, and B. Glimelius for helpful comments.

	NOTES

 
Support for the Coordinating Centre for Clinical Trials, Halle, Germany by the German Ministry of Education and Research Grant No. BMBF/FKZ: 01GH0105 KKS, Halle, Germany.

Presented in part at the 6th International Gastric Cancer Congress, Yokohama, Japan, May 4-7, 2005; and the 13th European Cancer Conference, Paris, France, October 30-November 3, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted November 22, 2005; accepted March 8, 2006.

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