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Originally published as JCO Early Release 10.1200/JCO.2009.22.5219 on July 13 2009 © 2009 American Society of Clinical Oncology.
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and DepressionMassachusetts General Hospital Cancer Center, Supportive Oncology Research Program; and Massachusetts General Hospital, Department of Psychiatry, Boston, MA
Massachusetts General Hospital Center, Center for Thoracic Oncology, Boston, MA
Massachusetts General Hospital, Department of Psychiatry; and Massachusetts General Hospital Center, Center for Thoracic Oncology, Boston, MA
Massachusetts General Hospital Center, Center for Thoracic Oncology, Boston, MA To the Editor: While we appreciate the observations by Quek et al,1 we are cautious about generalizing increased risk of depression and suicidal ideation to other small molecule tyrosine kinase inhibitors (TKIs). TKIs are a class of medications that differ in their specific molecular targets and mechanisms of action. Quek et al discussed imatinib and dastinib, active therapies against GI stromal tumors and chronic myelogenous leukemia through their inhibition of the BCR-ABL, c-kit, and SRC proteins. But other small-molecule TKIs inhibit a wide range of receptor tyrosine kinases involved in various cancer cell signaling, and hence may deliver a spectrum of potential adverse effects, including the hypothesized development of depression. The epidermal growth factor receptor (EGFR) TKIs, gefitinib and erlotinib, have been studied in advanced non–small-cell lung cancer (NSCLC) for nearly a decade. Unfortunately, there have been no clinical trials to date of these EGFR TKIs in advanced NSCLC that have included repeated, validated assessments of depression; however, gefitinib and erlotinib have clearly shown benefit on measures of quality of life in this population.2,3 Given that depression is associated with reports of lower quality of life in all domains in patients with thoracic cancers, these trials may provide some support that gefitinib and erlotinib may not be associated with a substantially increased risk of depression.4 In our own clinical experience, we have not observed an increase in depression in patients with advanced NSCLC attributable to gefitinib and erlotinib. In fact, we have had cases in which the initiation of gefitinib or erlotinib actually improved the mood of patients, most likely by reducing distressing physical symptoms of their cancer. To formally examine our experience with EGFR TKIs and risk of depression, we analyzed our prospective clinical database of patients with newly diagnosed thoracic cancers. This database includes baseline and repeated assessments of depressive symptoms approximately every 8 weeks with the Patient Health Questionnaire-9, a validated instrument derived from the Diagnostic and Statistical Manual of Mental Disorders-IV criteria.5,6 Since August 2007, over 400 consecutive patients presenting at their initial oncology consultation have been recruited to participate in this prospective, longitudinal assessment of physical and psychological symptoms, approved by our institutional review board. For the purposes of this analysis, we analyzed data from the 176 patients with advanced NSCLC (stage IIIb with effusion or stage IV) enrolled between August 15, 2007, and September 15, 2008. At some point during the study period, 29 patients (16.5%) were taking either gefitinib or erlotinib. To investigate a possible association between depressive symptoms and EGFR TKIs, a linear mixed effects model was used with the Patient Health Questionnaire-9 score as the dependent variable and EGFR TKI administration as a time varying covariate. There was not a statistically significant association between depressive symptoms and EGFR TKI treatment status. Although the power to detect an association may be limited by the modest number of participants in our analytic sample who were prescribed an EGFR TKI, the results resonate with our clinical experience and the quality-of-life data from randomized trials. Because depression and suicidal ideation can have serious consequences in individuals with cancer,7–9 a suggestion that TKI medications might increase the risk of these must be taken seriously. More research is needed to confirm the findings from the case series presented by Quek et al.1 In the meantime, medical oncologists must remember that small molecule TKIs encompass a wide range of compounds that can differ in many respects, and that not all agents may carry a possible increased risk of depression and suicidal ideation. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Thomas J. Lynch, Genentech (C), Roche (C), Boehringer-Ingelheim (C), OSI Pharmaceuticals (C), AstraZeneca (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Quek R, Morgan JA, George S, et al: Small-molecule tyrosine kinase inhibitor and depression. J Clin Oncol 27:312–313, 2009. 2. Bezjak A, Tu D, Seymour L, et al: Symptom improvement in lung cancer patients treated with erlotinib: Quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR.21. J Clin Oncol 24:3831–3837, 2006. 3. Cella D, Herbst RS, Lynch TJ, et al: Clinically meaningful improvement in symptoms and quality of life for aptients with non–small-cell lung cancer receiving gefitinib in a randomized controlled trial. J Clin Oncol 23:2946–2954, 2005. 4. Pirl WF, Temel J, Cashavelly C, et al: Coping with illness and depressive symptoms in thoracic oncology patients. Psychooncology 15:S78–S79, 2006 (suppl. 5. Fann JR, Berry DL, Wolpin S, et al: Depression screening using the Patient Health Questionnaire-9 administered on a touch screen computer. Psychooncology 18:14–22, 2009.[CrossRef][Medline] 6. Spitzer RL, Kroenke K, Williams JBW: Validation and utitlity of a self-report version of PRIME-MD: The PHQ primary care study—Primary care evaluation of mental disorders, Patient Health Questionnaire. JAMA 282:1737–1744, 1999. 7. Walker J, Waters RA, Murray G, et al: Better off dead: Suicidal thoughts in cancer patients. J Clin Oncol 26:4725–4730, 2008. 8. Misono S, Weiss NS, Fann JR, et al: Incidence of suicide in persons with cancer. J Clin Oncol 26:4731–4738, 2008. 9. Miller M, Mogun H, Azrael D, et al: Cancer and the risk of suicide in older Americans. J Clin Oncol 26:4720–4724, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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