© The Author 2007. Published by Oxford University Press.
CORRESPONDENCE |
Response: Re: Survival With Aromatase Inhibitors and Inactivators Versus Standard Hormonal Therapy in Advanced Breast Cancer: Meta-analysis
Affiliations of authors: Department of Hygiene and Epidemiology (JPAI, NPP) and Department of Medical Oncology (DM, NP), University of Ioannina School of Medicine, Ioannina, Greece
Correspondence to: John P. A. Ioannidis, MD, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, University Campus, Ioannina 45110, Greece (e-mail: jioannid{at}cc.uoi.gr).
Bria et al. assert that phase II trials should not be included in analyses of survival simply because these trials do not have survival as the primary objective but only as a secondary objective. However, this point goes against the fundamental concept and practice that a meta-analysis should be systematically inclusive. An inclusive approach provides the best chance to explore diversity (i.e., heterogeneity) in the trial results (1).
We strongly believe that overall survival should be considered as a key endpoint, especially in meta-analysis of several clinical trials. Crossover is unavoidable: trials that deny patients other available treatments when they have had disease progression on the originally assigned treatment may be not only unrealistic but also occasionally unethical. In the intention-to-treat principle, survival is an outcome that makes most sense, and a meta-analysis of many trials is the best opportunity to assess this outcome. The notion that meta-analysis can only address the outcomes that were primary outcomes in the combined trials is a misunderstanding of the method.
We fully agree with Bria et al. that efficacy should be balanced against safety. We did make this point in our paper, and we have previously voiced serious concerns about the quality of harms data from clinical trials and about the need for its improvement (2). As for aromatase inhibitors, we were fortunate to have a previously published meta-analysis of toxicity outcomes, which we did cite (3).
The assertion that a single still-unpublished trial with preliminary results should have been included is debatable (4). Reports of trials that have not yet completed peer review may contain incorrect or incomplete data, and thus, incorporation of such reports could introduce biases into a meta-analysis. Nevertheless, results of the European Organization for Research and Treatment of Cancer trial, to which Bria et al. refer (5), were fully consistent with those of our meta-analysis; i.e., as first-line treatment, statistically significantly improved progression-free survival (primary outcome) was associated with exemestane treatment, compared with tamoxifen treatment, but inconclusive results were obtained for survival (secondary outcome). Inclusion of survival data from that trial in the meta-analysis would not have changed the results (summary relative hazard = 0.88, instead of 0.87, for the third-generation agents versus standard therapy).
The lack of a survival benefit with aromatase inhibitors obtained by the meta-analysis of Ferretti et al. (6) is easily explained: that meta-analysis considered only six of the 19 available trials because extremely strict inclusion criteria were used to dismiss most of the available data. That meta-analysis also merged data on second- and third-generation regimens. In our meta-analysis, these regimens were analyzed separately according to line of treatment, in contrast to what Bria et al. claimed, and we found that the survival benefit was limited to third-generation agents.
Finally, we do not understand how the inclusion of arms that use nonapproved drug dosages would interfere with the approval of a drug for use in standard practice because nonapproved dosages could vary from country to country and over time. Moreover, we were very careful to avoid making statements that one dose was better than another dose because the meta-analysis could not address this issue.
REFERENCES
(1) Lau J, Ioannidis JP, Schmid CH. Summing up evidence: one answer is not always enough. Lancet 1998;351:123–7.[CrossRef][Web of Science][Medline]
(2) Ioannidis JP, Evans SJ, Gotzsche PC, O'Neill RT, Altman DG, Schulz K, et al. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004;141:781–8.
(3) Carlini P, Bria E, Giannarelli D, Ferretti G, Felici A, Papaldo P, et al. New aromatase inhibitors as second-line endocrine therapy in postmenopausal patients with metastatic breast carcinoma: a pooled analysis of the randomized trials. Cancer 2005;104:1335–42.[CrossRef][Web of Science][Medline]
(4) Dundar Y, Dodd S, Dickson R, Walley T, Haycox A, Williamson PR. Comparison of conference abstracts and presentations with full-text articles in the health technology assessments of rapidly evolving technologies. Health Technol Assess 2006;10:iii–iv, ix–145.[Web of Science][Medline]
(5) Paridaens R, Therasse P, Dirix L, Beex L, Piccart M, Cameron D, et al. First line hormonal treatment (HT) for metastatic breast cancer (MBC) with exemestane (E) or tamoxifen (T) in postmenopausal patients (pts)—a randomized phase III trial of the EORTC Breast Group. 2004 ASCO Annual Meeting Proceedings (post-meeting edition). J Clin Oncol 2004;22(Suppl):515.
(6) Ferretti G, Bria E, Giannarelli D, Felici A, Papaldo P, Fabi A, et al. Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials. Br J Cancer 2006;94: 1789–96.[CrossRef][Web of Science][Medline]
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J Natl Cancer Inst 2007 99: 176.
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