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Journal of Clinical Oncology, Vol 25, No 35 (December 10), 2007: pp. 5546-5547 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.9444
Flash Points1 Indiana University School of Nursing, Indianapolis, IN
2 Indiana University School of Medicine, Indianapolis, IN For millions of breast cancer survivors, hot flashes are frequent, severe, and bothersome events that can interfere with daily life and can negatively influence mood, affect, and sleep. Unfortunately, the scientific basis for managing hot flashes is limited. The major conclusion from the 2005 National Institutes of Health State-of-the-Science Conference on Management of Menopause-Related Symptoms (Bethesda, MD) was that additional data are needed on the efficacy and appropriateness of nonhormonal hot flash treatments.1-7 In this issue of Journal of Clinical Oncology, Deng and colleagues8 report results of a randomized clinical trial comparing acupuncture with sham needle insertion for hot flashes in breast cancer survivors. The treatment condition involved true acupuncture needle insertion at 19 separate body points twice-weekly over 4 weeks. The placebo condition was delivered on the same schedule and involved a sham needle that appeared to (but did not actually) penetrate the skin. No significant changes were seen during treatment (1, 2, 3, 4 weeks) or after treatment (5 and 6 weeks or 3 and 6 months). Both true and sham acupuncture reduced subjective hot flash frequency by approximately one hot flash per day or 20% of baseline. This is far below the 50% reduction in hot flashes desired by women seeking treatment9or that seen with other nonhormonal alternatives, such as paced respiration.10,11 Deng and colleagues’ negative study results8 point to challenges in researching hot flash treatments. Perhaps the greatest challenge in researching hot flash treatments is the unclear or unknown etiology of hot flashes. Lack of etiologic understanding renders it difficult if not impossible to describe potential mechanisms of action for treatments, justify selection of one treatment over another, anticipate optimal intensity or duration of dosing and subsequent timing of outcome measures, or evaluate biomarkers of treatment effectiveness. Current etiologic understanding has primarily come from carefully controlled laboratory experiments12,13 or laboratory-based pharmaceutical studies14,15 rather than clinical trials of nonpharmaceutical alternatives. For example, previously published studies of acupuncture are equivocal about whether positive effects are due to changes in serum hormones16,17 or neuropeptides involved in inflammation or vasodilation.18 Etiologic understanding can be undermined when hot flashes are measured via self-report alone. Hot flashes are one of a few symptoms that can be measured objectively using technology that has been available for nearly 20 years.19,20 Although there has been debate as to whether the best measure of hot flashes is objective (physiologic)21 or subjective (self-reported),22 recent recommendations are to combine both.23,24 Objective sternal skin conductance monitoring is not biased by placebo effects, sleep-wake cycles, or reporting difficulties20,21,25,26 but captures hot flash frequency only.27 Subjective measures tend to under-estimate objective hot flash frequency26,28 and are prone to placebo effects25 but appear to be the only way to capture intensity (severity) and bother (distress).27 To date, published studies of acupuncture have included only subjective measures.7,8 Indeed, most treatment studies to date have included only subjective measures. Thus, when positive results are found, it remains unclear whether the mechanism of treatment action is via physiological pathways or subjective perception. Treatment studies have the ability to provide additional mechanistic insights by incorporating objective sternal skin conductance monitoring of hot flashes, genetic or pharmacogenetic approaches that allow for the identification of candidate genes that might provide mechanistic insights into the pathophysiology of hot flashes, and metabolomic or proteomic biomarkers of effect that will have value in the development of new treatments. The addition of objective monitoring can help validate which treatments might act via specific physiological pathways and thus, provide new directions for etiologic studies. Treatments that alter only subjective perception might be equally as beneficial for symptomatic women as those that alter physiological pathways; however, disentangling which treatments alter subjective perception alone would help narrow the focus of future etiologic investigations. The addition of genetic and pharmacogenetic approaches in treatment studies could provide new mechanistic insights through identification of predictive genes and simultaneously allow for evaluation of differential efficacy in specific subpopulations. Thus, we recommend quantifying efficacy on both objective (physiologic) and subjective (perceived) hot flashes, incorporating genetic and other biomarker approaches in trials of nonpharmacologic alternatives, and incorporating pharmacogenetic approaches in trials of pharmaceuticals. 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: Janet S. Carpenter, UFI (C), Eli Lilly and Company (C); David Flockhart, LabCore Scientific Advisory Board (C) Stock Ownership: None Honoraria: None Research Funding:David Flockhart, Pfizer, Novartis Expert Testimony: None Other Remuneration: None AUTHOR CONTRIBUTIONS Conception and design: Janet S. Carpenter Financial support: Janet S. Carpenter Administrative support: Janet S. Carpenter Manuscript writing: Janet S. Carpenter, David Flockhart Final approval of manuscript: Janet S. Carpenter, David Flockhart ACKNOWLEDGMENTS Supported in part by Department of Defense Breast Cancer Program (BC043199), the Indiana University General Clinical Research Center (NIH M01 RR00750), and the Consortium on Breast Cancer Pharmacogenetics (U01 GM061373). REFERENCES
1. Nedrow A, Miller J, Walker M, et al: Complementary and alternative therapies for the management of menopause-related symptoms: A systematic evidence review. Arch Intern Med 166:1453-1465, 2006 2. Nelson HD, Haney E, Humphrey L, et al: Management of menopause-related symptoms. Summary, evidence report/technology assessment No. 120, in 290-02-0024 OE-bPCucN (ed). Rockville, MD, Agency for Healthcare Research and Quality, 2005m pp 1-915 3. Nelson HD, Vesco KK, Haney E, et al: Nonhormonal therapies for menopausal hot flashes: Systematic review and meta-analysis. JAMA 295:2057-2071, 2006 4. Sherman S: Introduction. Am J Med 118:1S-2S, 2005[Medline] 5. Low Dog T: Menopause: A review of botanical dietary supplements. Am J Med 118:98S-108S, 2005[CrossRef] 6. Loprinzi CL, Stearns V, Barton D: Centrally active nonhormonal hot flash therapies. Am J Med 118:118S-123S, 2005[CrossRef] 7. Carpenter JS, Neal JG: Other complementary and alternative medicine modalities: Acupuncture, magnets, reflexology, and homeopathy. Am J Med 118:109S-117S, 2005 8. Deng G, Vickers A, Yeung S, et al: Acupuncture for the treatment of hot flashes in breast cancer patients: A randomized controlled trial. J Clin Oncol 25:5584-5590, 2007 9. Butt DA, Deng LYR, Lewis JE, et al: Minimal decrease in hot flashes desired by postmenopausal women in family practice. Menopause 14:203-207, 2007[CrossRef][Medline] 10. Freedman RR: Biochemical, metabolic, and vascular mechanisms in menopausal hot flashes. Fertil Steril 70:332-337, 1998[CrossRef][Medline] 11. Freedman RR, Woodward S: Behavioral treatment of menopausal hot flushes: Evaluation by ambulatory monitoring. Am J Obstet Gynecol 167:436-439, 1992[Medline] 12. Dormire SL, Reame NK: Menopausal hot flash frequency changes in response to experimental manipulation of blood glucose. Nurs Res 52:338-343, 2003[CrossRef][Medline] 13. Freedman RR: Physiology of hot flashes. Am J Hum Biol 13:453-464, 2001[CrossRef][Medline] 14. Freedman RR, Dinsay R: Clonidine raises the sweating threshold in symptomatic but not in asymptomatic postmenopausal women. Fertil Steril 74:20-23, 2000[CrossRef][Medline] 15. Freedman RR, Blacker CM: Estrogen raises the sweating threshold in postmenopausal women with hot flashes. Fertil Steril 77:487-490, 2002[CrossRef][Medline] 16. Dong H, Ludicke F, Comte I, et al: An exploratory pilot study of acupuncture on the quality of life and reproductive hormone secretion in menopausal women. J Altern Complement Med 7:651-658, 2001[CrossRef][Medline] 17. Ping J, Ren-hai M, Zhong-xiang W: Body acupuncture plus ear pressing in the treatment of menopausal syndrome. Int J Clin Acupunct 9:471-473, 1998 18. Wyon Y, Lindgren R, Lundeberg T, et al: Effects of acupuncture on climacteric vasomotor symptoms, quality of life, and urinary excretion of neuropeptides among postmenopausal women. Menopause 2:3-12, 1995 19. Freedman RR: Laboratory and ambulatory monitoring of menopausal hot flashes. Psychophysiology 26:573-579, 1989[Medline] 20. Carpenter JS, Andrykowski MA, Freedman RR, et al: Feasibility and psychometrics of an ambulatory hot flash monitoring device. Menopause 6:209-215, 1999[Medline] 21. Freedman RR: It's all in your head. Menopause 12:483, 2005[CrossRef][Medline] 22. Sloan JA, Loprinzi CL, Novotny PJ, et al: Methodologic lessons learned from hot flash studies. J Clin Oncol 19:4280-4290, 2001 23. Carpenter JS, Rand KL: Modeling the hot flash experience in breast cancer survivors. Menopause (in press) 24. Miller HG, Li RM: Measuring hot flashes: Summary of a National Institutes of Health workshop. Mayo Clin Proc 79:777-781, 2004[Medline] 25. Carpenter JS, Storniolo AM, Johns S, et al: Randomized, double-blind, placebo-controlled crossover trials of venlafaxine for hot flashes after breast cancer. Oncologist 12:124-135, 2007 26. Carpenter JS, Monahan PO, Azzouz F: Accuracy of subjective hot flush reports compared with continuous sternal skin conductance monitoring. Obstet Gynecol 104:1322-1326, 2004 27. Carpenter JS, Azzouz F, Monahan PO, et al: Is sternal skin conductance monitoring a valid measure of hot flash intensity or distress? Menopause 12:512-519, 2005[CrossRef][Medline] 28. Thurston RC, Blumenthal JA, Babyak MA, et al: Emotional antecedents of hot flashes during daily life. Psychosom Med 67:137-146, 2005 Related Article
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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