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Journal of Clinical Oncology, Vol 22, No 4 (February 15), 2004: pp. 753-754 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.253
Trial of Antidepressants for Mildly Depressed Cancer Patients Should Have Been Reported in a Manner Allowing Independent Evaluation of Investigators' ClaimsUniversity of Pennsylvania School of Medicine, Philadelphia, PA To the Editor: Fisch and his colleagues [1] sought to evaluate the effectiveness of antidepressant treatment among a diverse sample of patients with advanced cancer and at least minimal depressive symptoms. Their provocative report comes in the context of only a few methodologically limited studies of the efficacy of antidepressants for cancer patients with major depressive disorder [2-4], of evidence of dramatic increases in the prescription of antidepressants by nonpsychiatric physicians, including oncologists [5], and of generally inadequate treatment of depression when it is managed exclusively by nonpsychiatric physicians [6]. Undoubtedly, oncologists and policy makers would be interested in empirical evidence demonstrating that quality of life among cancer patients with minimal levels of depressive symptoms can be improved simply by dispensing antidepressants in routine cancer care. Unfortunately, Fisch et al fail to report the methods and findings of their trial in a manner that allows for independent evaluation of the treatment sample, clinical management, and results. Overall, their report does not provide a ready basis for generalization, for guiding clinical practice, or for replication. Historical deficiencies and inaccuracies in the reporting of clinical trials have led to the development and refinement of standards to improve the adequacy (eg, Consolidated Standards of Reporting Trials [CONSORT]) [7] and accuracy [8] of reporting randomized controlled trials. The primary objectives of such standards are to guide investigators in designing trials, implementing protocols, and reporting findings from randomized controlled trials in ways that facilitate evaluation and replication of study findings; to communicate appropriate patient care; and to conform to a high standard of ethics expected by society [8]. Deficiencies in the report by Fisch et al highlight the need for trial investigators to implement uniform standards when reporting clinical trials. Who participated in the trial, and who was excluded either by design or by unspecified and uncontrolled factors? Patients enrolled onto the trial were required to have endorsed at least minimal severity of symptoms of depression on an unvalidated screening instrument (the Two-Question Screening Survey [TQSS]) and not to have been diagnosed recently with a current major depressive disorder. Such broad selection criteria are difficult to reconcile with the small number of patients (N = 163) recruited during more than 2 years from multiple sites encompassing a large geographical area. Left to speculation are unreported factors influencing selection that may account for such a small sample. Because the authors neglected to report the number or characteristics of patients who were assessed for eligibility but who either declined participation or were excluded, it is not possible to associate the sample of trial participants and the population of patients for which inferences are to be made, a goal that should guide the reporting of selection criteria in clinical trials [9]. Was adequate clinical management provided? The effectiveness of treatment with antidepressants is contingent on patient education, frequent monitoring, adjustments in dose, and changes in medication [10]. The clinical care reported by Fisch et al does not meet suggested guidelines [11], modeling poor patient care and giving the impression of inadequate study control. The authors reported that the study drug was mailed to patients to be self-administered and that the check on adherence consisted of an unspecified self-report assessment. Furthermore, clinical management appears to have been limited to asking patients the number of times they vomited in the previous week, on which basis the medication was either continued or discontinued, not adjusted. Did the patients receiving antidepressants differ at any point from those receiving placebo? The largest mean difference in depressive symptoms appears to have been at baseline, which is not controlled for in the analyses. Similarly, the authors did not provide a rationale for assessment of quality of life as the primary outcome and of depressive symptoms as the secondary outcome. Improvement in quality of life would be expected to be a secondary effect of antidepressants acting on depressive symptoms and provides a weaker assessment of any benefits of the antidepressants [12]. The authors apparently failed to control for baseline depression scores (ie, the nonstandard Brief Zung Self-Rating Depression Scale [BZSDS], used as an outcome measure) when using generalized estimating equations to evaluate group membership as a predictor of quality of life. Rather, the authors controlled for the TQSS, a questionable surrogate to the BZSDS. Standards for reporting clinical trails arguably have improved the quality of randomized controlled trials; failure of trial investigators to implement standards such as those represented in CONSORT likely is associated with exaggerated treatment effects and dissemination of inaccurate information to treatment providers and consumers [7]. Conforming one's clinical practice to the recommendations put forth by Fisch et al would raise yet another barrier to cancer patients receiving appropriate care and to treatment providers and consumers putting faith in the products of research. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Thomas R. Ten Have, Johnson & Johnson. Acted as a consultant within the last 2 years: Thomas R. Ten Have, GlaxoSmithKline. Received more than $2,000 per year from a company for either of the last 2 years: Thomas R. Ten Have, GlaxoSmithKline. REFERENCES
1. Fisch MJ, Loehrer PJ, Kristeller J, et al: Fluoxetine versus placebo in advanced cancer outpatients: A double-blinded trial of the Hoosier Oncology Group. J Clin Oncol 21:1937-1943, 2003 2. Holland JC, Romano SJ, Heiligenstein JH, et al: A controlled trial of fluoxetine and desipramine in depressed women with advanced cancer. PsychoOncology 7:291-300, 1998[CrossRef][Medline] 3. Pezzella G, Moslinger-Gehmayr R, Contu A: Treatment of depression in patients with breast cancer: A comparison between paroxetine and amitriptyline. Breast Cancer Res Treat 70:1-10, 2001[CrossRef][Medline] 4. Razavi D, Allilaire J-F, Smith M, et al: The effect of fluoxetine on anxiety and depression symptoms in cancer patients. Acta Psychiatr Scand 94:205-210, 1996[Medline] 5. Ashbury FD, Madlensky L, Raich P, et al: Antidepressant prescribing in community cancer care. Support Care Cancer 11:278-285, 2003[Medline]
6. Kessler RC, Berglund P, Demler O, et al: The epidemiology of major depressive disorder: Results from the National Comorbidity Survey Replication (NCS-R). JAMA 289:3095-3105, 2003
7. Altman DG, Schulz KF, Moher D, et al: The revised CONSORT statement for reporting randomized trials: Explanation and elaboration. Ann Intern Med 134:663-694, 2001 8. Shapiro SH, Weijer C, Freedman B: Reporting the study populations of clinical trials: Clear transmission or static on the line? J Clin Epidemiol 53:973-979, 2000[CrossRef][Medline] 9. Bailar JC, Mosteller F: Guidelines for statistical reporting in articles for medical journals. Ann Intern Med 108:266-273, 1988 10. Simon GE: Evidence review: Efficacy and effectiveness of antidepressant treatment in primary care. Gen Hosp Psychiatry 24:213-224, 2002[CrossRef][Medline] 11. Depression Guideline Panel: Depression in primary care, vol 1. Detection and diagnosis. Clinical Practice Guideline, no 5. Rockville, MD, U S Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research, 1993 12. Sturm R, Unutzer J, Katon W: Effectiveness research and implications for study design: Sample size and statistical power. Gen Hosp Psychiatry 21:274-283, 1999[CrossRef][Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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