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In Reply

Department of Internal Medicine II, University Hospital, Friedrich-Schiller-University Jena, Jena, Germany

Wolfgang E. Fleig

University of Leipzig Hospitals and Clinics, Leipzig, Germany

Johannes Haerting

Institute of Medical Epidemiology, Biostatistics and Informatics, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany

We greatly appreciate the opportunity to address the points Dr Ajani has raised in response to our meta-analysis recently published in the Journal of Clinical Oncology.¹ He adds yet another variation to the longstanding theme of—meta-analysis versus the one large randomized clinical trial—² a debate that encounters believers and nonbelievers of meta-analyses rather than simple, critical interpreters of data.

It appears that we must have touched a sensitive point to elicit such emotions. Dr Ajani has spent most of his response in convincing us of the necessity for and the advantages of large prospective clinical trials holding a Philippika that addresses the community of clinical researchers dealing with advanced gastric cancer, including himself. Most serious clinical scientists will agree with many of the issues he raised on this topic within his letter. Meticulously designed and conducted prospective clinical trials of adequate sample size with overall survival as the primary end point are the clue to improved survival and quality of life of our patients with gastric cancer, and, similarly, nobody would question the importance of translational research in promoting our understanding of the mechanisms of disease and of the action of novel agents for treatment.

Nevertheless, the actual clinical and scientific reality reflects substantial uncertainty about the role of the various drug combinations around. Why do we need a systematic review and meta-analysis, and what is the clinical place of anthracyclines in advanced gastric cancer in 2006? Retrospective by definition, systematic reviews and meta-analyses will neither take us to the dark ages, nor do they intend to define novel standards of care. However, they do provide important information complimentary to clinical trials, which is particularly relevant in situations where data from individual clinical trials are inconclusive or lacking and where assumptions rather than conclusions guide decision making, such as on the role of anthracyclines in chemotherapy for advanced gastric cancer. In such a situation of uncertainty, a systematic review and meta-analysis may serve as a rational approach for the identification of the reference treatment for future clinical trials, a crucially weak point in many fields of clinical oncology. Of course, one would prefer to perform a meta-analysis based on individual patient data. However, this is not feasible for this subject as relevant studies have been published over a period of 20 years and individual patient data are impossible to obtain for many of them. Unfortunately, several important methodological details have escaped Dr Ajani's attention in his global criticism of this work.

Firstly, while it remains obscure how he has identified substantial publication bias in our meta-analysis, we would like to remind Dr Ajani that we have definitively made all reasonable efforts to avoid just this. In our search strategy, which was defined prospectively and published in advance in a peer-reviewed protocol in the Cochrane Library,³ we avoided any language limits and included vigorous searches for published, unpublished, and incompletely published trials, such as searches in conference proceedings and contact with experts, including Dr Ajani himself, as well as to drug manufacturers. Thus, trials were identified prospectively and funnel plots were performed, which showed no evidence of publication bias. As a result, we managed to identify somewhat more than a handful (ie, a total of 194) of randomized trials on chemotherapy in advanced gastric cancer. Among these, 27 were relevant for our comparisons. The reasons for noneligibility of each of the other trials are specified in the Cochrane Library.⁴

Secondly, the methodological quality of all trials included in our meta-analysis was meticulously evaluated according to a quality score defined in advance. The impact of trials with a lower methodological quality on the overall result of the meta-analysis was addressed by sensitivity analyses prespecified in the protocol of the review and described in the article. We explicitly reported that exclusion of such studies did not alter the results.

Thirdly, not affecting our appreciation for his acknowledged statistician, Dr Ajani's assumption that the inclusion of reference 25⁵ substantially skewed the results in our Figure 3 is incorrect. The relative weight of each study entered into a meta-analysis depends on the number of included patients. Due to its small sample size, the relative weight of this particular trial in the meta-analysis is 8.15%. Exclusion of this trial would have changed the hazard ratio from 0.77 to 0.79 (95% CI, 0.63 to 0.99). We agree that the overall number of patients included in this meta-analysis is relatively small compared with other meta-analyses, but this reflects the scenario of published evidence in the field. Even more then, one should consider evidence from at least a few well-conducted trials as superior to any assumption.

We agree with Dr Ajani that prospective clinical trials would be desirable to further elucidate the role of anthracyclines in gastric cancer. Although not including an anthracycline-free treatment arm, the recently presented REAL-2 trial⁶ provides further information to this question and, in our view, might have set a new standard of care. With 1,000 patients recruited for this largest randomized trial on chemotherapy in advanced gastric cancer up to date, epirubicin, oxaliplatin, and capecitabine (EOX) achieved an excellent median overall survival of 11.2 months. Should this regimen now become a global standard of care? Dr Ajani correctly states that treatment decisions in different parts of the world may depend on issues other than the results of clinical trials. Nevertheless, the results of this trial will influence clinical practice and research, wherever chemotherapy for advanced gastric cancer is an issue. In the light of this trial, is epirubicin plus cisplatin and fluorouracil versus cisplatin and fluorouracil still a major question in 2006? Since the relative contribution of anthracyclines might be altered if cisplatin is exchanged by oxaliplatin and fluorouracil by capecitabine as in the EOX regimen, shouldn't we follow Dr Ajani's notion to focus our energies to evaluate newer drugs and consider a trial comparing capecitabine/oxaliplatin with EOX?

Although one should not reply to questions with another question, Figure 1 —in an admittedly unscientific comparison—depicts the median survivals achieved in the major recent randomized phase III trials. Considering these results, are we confident that in 2006 a nonanthracycline-containing chemotherapy regimen is still the best for our next patient with advanced gastric cancer who does not wish to participate in a clinical trial? Every meta-analysis, much like every clinical trial, may have weaknesses which we have discussed, but waiting for the perfect meta-analysis and the ideal trial is like waiting for Godot, and that would be depressing indeed.

View larger version (17K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Median survival times (months) achieved in recent phase III chemotherapy trials for advanced gastric cancer. ECF, epirubicin, cisplatin, and fluorouracil; FAMTX, fluorouracil (FU), doxorubicin, methotrexate; FUP, FU, cisplatin; ELF, etoposide, leucovorin, FU; MCF, mitomycin, cisplatin, FU; IF, irinotecan/FU; CF, cisplatin/FU; DCF, docetaxel, cisplatin, FU; EOF, epirubicin, cisplatin, FU; ECX, epirubicin, cisplatin, capecitabine; EOX, epirubicin, oxaliplatin, and capecitabine; XP, capecitabine/cisplatin; FP, FU/cisplatin.

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by the Coordinating Centre for Clinical Trials, Martin-Luther-University Halle-Wittenberg, Germany, (Ministry for Education and Research Grant No. BMBF/FKZ: 01GH 0105 KKS-Halle).

REFERENCES

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				A. D. Wagner, W. E. Fleig, and J. Haerting In Reply J. Clin. Oncol., February 20, 2007; 25(6): 730 - 730. [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wagner, A. D. Articles by Haerting, J. Search for Related Content PubMed Articles by Wagner, A. D. Articles by Haerting, J. Social Bookmarking                            What's this?