Breast Cancer Research and Treatment

, Volume 156, Issue 3, pp 415–426 | Cite as

Informing hot flash treatment decisions for breast cancer survivors: a systematic review of randomized trials comparing active interventions

  • Claire Johns
  • Susan M. Seav
  • Sally A. Dominick
  • Jessica R. Gorman
  • Hongying Li
  • Loki Natarajan
  • Jun James Mao
  • H. Irene SuEmail author


Patient-centered decision making about hot flash treatments often incorporates a balance of efficacy and side effects in addition to patient preference. This systematic review examines randomized controlled trials (RCTs) comparing at least two non-hormonal hot flash treatments in breast cancer survivors. In July 2015, PubMed, SCOPUS, CINAHL, Cochrane, and Web of Science databases were searched for RCTs comparing active, non-hormonal hot flash treatments in female breast cancer survivors. Thirteen trials were included after identifying 906 potential studies. Four trials were dose comparison studies of pharmacologic treatments citalopram, venlafaxine, gabapentin, and paroxetine. Hot flash reduction did not differ by tamoxifen or aromatase inhibitor use. Citalopram 10, 20, and 30 mg daily had comparable outcomes. Venlafaxine 75 mg daily improved hot flashes without additional side effects from higher dosing. Gabapentin 900 mg daily improved hot flashes more than 300 mg. Paroxetine 10 mg daily had fewer side effects than 20 mg. Among four trials comparing different pharmacologic treatments, venlafaxine alleviated hot flash symptoms faster than clonidine; participants preferred venlafaxine over gabapentin. Five trials compared pharmacologic to non-pharmacologic treatments. Acupuncture had similar efficacy to venlafaxine and gabapentin but may have longer durability after completing treatment and fewer side effects. We could not perform a pooled meta-analysis because outcomes were not reported in comparable formats. Clinical trial data on non-hormonal hot flash treatments provide comparisons of hot flash efficacy and other patient important outcomes to guide clinical management. Clinicians can use the information to help patients select hot flash interventions.


Breast cancer Hot flashes Vasomotor symptoms Treatment Non-hormonal Randomized controlled trials 



The authors wish to thank Jennifer Ehren, PhD, Diana T. Chingos, MS, MFA, and Michael Krychman, MD, MPH for their contributions to the study. This study was financially supported by the California Breast Cancer Research Program Translational Award 200B-0 144. The funding organization was not involved in the study design, data collection, data analyses, or writing of the manuscript for publication.

Compliance with ethical standards

Conflicts of interest

The study complies with the current laws of the United States. The authors declare no conflicts of interest.

Informed consent

This type of study is exempt from institutional review board review, and human consent is not required.

Supplementary material

10549_2016_3765_MOESM1_ESM.docx (13 kb)
Supplementary material 1 (DOCX 13 kb)
10549_2016_3765_MOESM2_ESM.png (134 kb)
Supplementary material 2 Risk of bias summaries for trials on A pharmacologic treatment dose comparisons, B two different pharmacological treatments, C pharmacological versus non-pharmacological treatments (PNG 134 kb)


  1. 1.
    Couzi RJ, Helzlsouer KJ, Fetting JH (1995) Prevalence of menopausal symptoms among women with a history of breast cancer and attitudes toward estrogen replacement therapy. J Clin Oncol 13(11):2737–2744PubMedGoogle Scholar
  2. 2.
    Bernhard J, Luo W, Ribi K, Colleoni M, Burstein HJ, Tondini C, Pinotti G, Spazzapan S, Ruhstaller T, Puglisi F, Pavesi L, Parmar V, Regan MM, Pagani O, Fleming GF, Francis PA, Price KN, Coates AS, Gelber RD, Goldhirsch A, Walley BA (2015) Patient-reported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): a combined analysis of two phase 3 randomised trials. Lancet Oncol 16(7):848–858. doi: 10.1016/s1470-2045(15)00049-2 CrossRefPubMedGoogle Scholar
  3. 3.
    Day R, Ganz PA, Costantino JP, Cronin WM, Wickerham DL, Fisher B (1999) Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Clin Oncol 17(9):2659–2669PubMedGoogle Scholar
  4. 4.
    Leining MG, Gelber S, Rosenberg R, Przypyszny M, Winer EP, Partridge AH (2006) Menopausal-type symptoms in young breast cancer survivors. Ann Oncol 17(12):1777–1782. doi: 10.1093/annonc/mdl299 CrossRefPubMedGoogle Scholar
  5. 5.
    Yoo C, Yun MR, Ahn JH, Jung KH, Kim HJ, Kim JE, Park JY, Park KO, Yoon DH, Kim SB (2013) Chemotherapy-induced amenorrhea, menopause-specific quality of life, and endocrine profiles in premenopausal women with breast cancer who received adjuvant anthracycline-based chemotherapy: a prospective cohort study. Cancer Chemother Pharmacol 72(3):565–575. doi: 10.1007/s00280-013-2227-5 CrossRefPubMedGoogle Scholar
  6. 6.
    Gupta P, Sturdee DW, Palin SL, Majumder K, Fear R, Marshall T, Paterson I (2006) Menopausal symptoms in women treated for breast cancer: the prevalence and severity of symptoms and their perceived effects on quality of life. Climacteric 9(1):49–58. doi: 10.1080/13697130500487224 CrossRefPubMedGoogle Scholar
  7. 7.
    Marino JL, Saunders CM, Emery LI, Green H, Doherty DA, Hickey M (2014) Nature and severity of menopausal symptoms and their impact on quality of life and sexual function in cancer survivors compared with women without a cancer history. Menopause 21(3):267–274. doi: 10.1097/GME.0b013e3182976f46 CrossRefPubMedGoogle Scholar
  8. 8.
    Stein KD, Jacobsen PB, Hann DM, Greenberg H, Lyman G (2000) Impact of hot flashes on quality of life among postmenopausal women being treated for breast cancer. J Pain Symptom Manage 19(6):436–445CrossRefPubMedGoogle Scholar
  9. 9.
    Barnabei VM, Cochrane BB, Aragaki AK, Nygaard I, Williams RS, McGovern PG, Young RL, Wells EC, O’Sullivan MJ, Chen B, Schenken R, Johnson SR (2005) Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol 105(5 Pt 1):1063–1073. doi: 10.1097/01.aog.0000158120.47542.18 CrossRefPubMedGoogle Scholar
  10. 10.
    Holmberg L, Iversen OE, Rudenstam CM, Hammar M, Kumpulainen E, Jaskiewicz J, Jassem J, Dobaczewska D, Fjosne HE, Peralta O, Arriagada R, Holmqvist M, Maenpaa J (2008) Increased risk of recurrence after hormone replacement therapy in breast cancer survivors. J Natl Cancer Inst 100(7):475–482. doi: 10.1093/jnci/djn058 CrossRefPubMedGoogle Scholar
  11. 11.
    von Schoultz E, Rutqvist LE (2005) Menopausal hormone therapy after breast cancer: the Stockholm randomized trial. J Natl Cancer Inst 97(7):533–535. doi: 10.1093/jnci/dji071 CrossRefGoogle Scholar
  12. 12.
    Barton DL, LaVasseur BI, Sloan JA, Stawis AN, Flynn KA, Dyar M, Johnson DB, Atherton PJ, Diekmann B, Loprinzi CL (2010) Phase III, placebo-controlled trial of three doses of citalopram for the treatment of hot flashes: nCCTG trial N05C9. J Clin Oncol 28(20):3278–3283. doi: 10.1200/jco.2009.26.6379 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Goldberg RM, Loprinzi CL, O’Fallon JR, Veeder MH, Miser AW, Mailliard JA, Michalak JC, Dose AM, Rowland KM, Burnham NL (1994) Transdermal clonidine for ameliorating tamoxifen-induced hot flashes. J Clin Oncol 12(1):155–158PubMedGoogle Scholar
  14. 14.
    Loprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, Novotny PJ, Dakhil SR, Rodger K, Rummans TA, Christensen BJ (2000) Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 356(9247):2059–2063. doi: 10.1016/s0140-6736(00)03403-6 CrossRefPubMedGoogle Scholar
  15. 15.
    Loprinzi CL, Qin R, Balcueva EP, Baclueva EP, Flynn KA, Rowland KM, Graham DL, Erwin NK, Dakhil SR, Jurgens DJ, Burger KN (2010) Phase III, randomized, double-blind, placebo-controlled evaluation of pregabalin for alleviating hot flashes, N07C1. J Clin Oncol 28(4):641–647. doi: 10.1200/jco.2009.24.5647 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pandya KJ, Morrow GR, Roscoe JA, Zhao H, Hickok JT, Pajon E, Sweeney TJ, Banerjee TK, Flynn PJ (2005) Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial. Lancet 366(9488):818–824. doi: 10.1016/s0140-6736(05)67215-7 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Stearns V, Slack R, Greep N, Henry-Tilman R, Osborne M, Bunnell C, Ullmer L, Gallagher A, Cullen J, Gehan E, Hayes DF, Isaacs C (2005) Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial. J Clin Oncol 23(28):6919–6930. doi: 10.1200/jco.2005.10.081 CrossRefPubMedGoogle Scholar
  18. 18.
    Bao T, Cai L, Snyder C, Betts K, Tarpinian K, Gould J, Jeter S, Medeiros M, Chumsri S, Bardia A, Tan M, Singh H, Tkaczuk KH, Stearns V (2014) Patient-reported outcomes in women with breast cancer enrolled in a dual-center, double-blind, randomized controlled trial assessing the effect of acupuncture in reducing aromatase inhibitor-induced musculoskeletal symptoms. Cancer 120(3):381–389. doi: 10.1002/cncr.28352 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Bokmand S, Flyger H (2013) Acupuncture relieves menopausal discomfort in breast cancer patients: a prospective, double blinded, randomized study. Breast 22(3):320–323. doi: 10.1016/j.breast.2012.07.015 CrossRefPubMedGoogle Scholar
  20. 20.
    Carson JW, Carson KM, Porter LS, Keefe FJ, Seewaldt VL (2009) Yoga of awareness program for menopausal symptoms in breast cancer survivors: results from a randomized trial. Support Care Cancer 17(10):1301–1309. doi: 10.1007/s00520-009-0587-5 CrossRefPubMedGoogle Scholar
  21. 21.
    Deng G, Vickers A, Yeung S, D’Andrea GM, Xiao H, Heerdt AS, Sugarman S, Troso-Sandoval T, Seidman AD, Hudis CA, Cassileth B (2007) Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients. J Clin Oncol 25(35):5584–5590. doi: 10.1200/jco.2007.12.0774 CrossRefPubMedGoogle Scholar
  22. 22.
    Elkins G, Marcus J, Stearns V, Perfect M, Rajab MH, Ruud C, Palamara L, Keith T (2008) Randomized trial of a hypnosis intervention for treatment of hot flashes among breast cancer survivors. J Clin Oncol 26(31):5022–5026. doi: 10.1200/jco.2008.16.6389 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Hervik JB, Mjaland O (2011) Acupuncture for the treatment of hot flashes in breast cancer patients, a randomized, controlled trial. Support Care Cancer 19(2 suppl. 1):S102. doi: 10.1007/s00520-011-1184-y Google Scholar
  24. 24.
    Liljegren A, Gunnarsson P, Landgren BM, Robéus N, Johansson H, Rotstein S (2012) Reducing vasomotor symptoms with acupuncture in breast cancer patients treated with adjuvant tamoxifen: a randomized controlled trial. Breast Cancer Res Treat 135(3):791–798. doi: 10.1007/s10549-010-1283-3 CrossRefPubMedGoogle Scholar
  25. 25.
    Mao JJ, Bowman MA, Xie SX, Bruner D, DeMichele A, Farrar JT (2015) Electroacupuncture versus gabapentin for hot flashes among breast cancer survivors: a randomized placebo-controlled trial. J Clin Oncol 33(31):3615–3620. doi: 10.1200/jco.2015.60.9412 CrossRefPubMedGoogle Scholar
  26. 26.
    Dodin S, Blanchet C, Marc I, Ernst E, Wu T, Vaillancourt C, Paquette J, Maunsell E (2013) Acupuncture for menopausal hot flushes. Cochrane Database Syst Rev 7:Cd007410. doi: 10.1002/14651858.CD007410.pub2 PubMedGoogle Scholar
  27. 27.
    L’Esperance S, Frenette S, Dionne A, Dionne JY (2013) Pharmacological and non-hormonal treatment of hot flashes in breast cancer survivors: CEPO review and recommendations. Support Care Cancer 21(5):1461–1474. doi: 10.1007/s00520-013-1732-8 CrossRefPubMedGoogle Scholar
  28. 28.
    Loprinzi CL, Sloan J, Stearns V, Slack R, Iyengar M, Diekmann B, Kimmick G, Lovato J, Gordon P, Pandya K, Guttuso T Jr, Barton D, Novotny P (2009) Newer antidepressants and gabapentin for hot flashes: an individual patient pooled analysis. J Clin Oncol 27(17):2831–2837. doi: 10.1200/jco.2008.19.6253 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Rada G, Capurro D, Pantoja T, Corbalan J, Moreno G, Letelier LM, Vera C (2010) Non-hormonal interventions for hot flushes in women with a history of breast cancer. Cochrane Database Syst Rev. doi: 10.1002/14651858.CD004923.pub2 PubMedGoogle Scholar
  30. 30.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097. doi: 10.1371/journal.pmed.1000097 CrossRefGoogle Scholar
  31. 31.
    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods Group, Cochrane Statistical Methods Group (2011) The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343:d5928. doi: 10.1136/bmj.d5928 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Atkins D, Best D, Briss PA, Eccles M, Falck-Ytter Y, Flottorp S, Guyatt GH, Harbour RT, Haugh MC, Henry D, Hill S, Jaeschke R, Leng G, Liberati A, Magrini N, Mason J, Middleton P, Mrukowicz J, O’Connell D, Oxman AD, Phillips B, Schünemann HJ, Edejer T, Varonen H, Vist GE, Williams JW, Zaza S, Group GW (2004) Grading quality of evidence and strength of recommendations. BMJ 328(7454):1490. doi: 10.1136/bmj.328.7454.1490 CrossRefPubMedGoogle Scholar
  33. 33.
    Boekhout AH, Vincent AD, Dalesio OB, Bosch J, Foekema-Töns JH, Adriaansz S, Sprangers S, Nuijen B, Beijnen JH, Schellens JH (2011) Management of hot flashes in patients who have breast cancer with venlafaxine and clonidine: a randomized, double-blind, placebo-controlled trial. J Clin Oncol 29(29):3862–3868. doi: 10.1200/jco.2010.33.1298 CrossRefPubMedGoogle Scholar
  34. 34.
    Bordeleau L, Pritchard KI, Loprinzi CL, Ennis M, Jugovic O, Warr D, Haq R, Goodwin PJ (2010) Multicenter, randomized, cross-over clinical trial of venlafaxine versus gabapentin for the management of hot flashes in breast cancer survivors. J Clin Oncol 28(35):5147–5152. doi: 10.1200/jco.2010.29.9230 CrossRefPubMedGoogle Scholar
  35. 35.
    Buijs C, Mom CH, Willemse PH, Marike Boezen H, Maurer JM, Wymenga AN, Jong RS, Nieboer P, Vries EG, Mourits MJ (2009) Venlafaxine versus clonidine for the treatment of hot flashes in breast cancer patients: a double-blind, randomized cross-over study. Breast Cancer Res Treat 115(3):573–580. doi: 10.1007/s10549-008-0138-7 CrossRefPubMedGoogle Scholar
  36. 36.
    Loibl S, Schwedler K, von Minckwitz G, Strohmeier R, Mehta KM, Kaufmann M (2007) Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients–a double-blind, randomized study. Ann Oncol 18(4):689–693. doi: 10.1093/annonc/mdl478 CrossRefPubMedGoogle Scholar
  37. 37.
    Biglia N, Sgandurra P, Peano E, Marenco D, Moggio G, Bounous V, Tomasi Cont N, Ponzone R, Sismondi P (2009) Non-hormonal treatment of hot flushes in breast cancer survivors: gabapentin vs. vitamin E. Climacteric 12(4):310–318. doi: 10.1080/13697130902736921 CrossRefPubMedGoogle Scholar
  38. 38.
    Maclaughlan David S, Salzillo S, Bowe P, Scuncio S, Malit B, Raker C, Gass JS, Granai CO, Dizon DS (2013) Randomised controlled trial comparing hypnotherapy versus gabapentin for the treatment of hot flashes in breast cancer survivors: a pilot study. BMJ Open 3(9):e003138. doi: 10.1136/bmjopen-2013-003138 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Othman AH, Zaky AH (2014) Management of hot flushes in breast cancer survivors: comparison between stellate ganglion block and pregabalin. Pain Med 15(3):410–417. doi: 10.1111/pme.12331 CrossRefPubMedGoogle Scholar
  40. 40.
    Walker EM, Rodriguez AI, Kohn B, Ball RM, Pegg J, Pocock JR, Nunez R, Peterson E, Jakary S, Levine RA (2010) Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: a randomized controlled trial. J Clin Oncol 28(4):634–640. doi: 10.1200/jco.2009.23.5150 CrossRefPubMedGoogle Scholar
  41. 41.
    American Congress of Obstetrics and Gynecology (2012) ACOG practice bulletin no. 126: management of gynecologic issues in women with breast cancer. Obstet Gynecol 119(3):666–682. doi: 10.1097/AOG.0b013e31824e12ce CrossRefGoogle Scholar
  42. 42.
    Desmarais JE, Looper KJ (2009) Interactions between tamoxifen and antidepressants via cytochrome P450 2D6. J Clin Psychiatry 70(12):1688–1697. doi: 10.4088/JCP.08r04856blu CrossRefPubMedGoogle Scholar
  43. 43.
    Bardia A, Novotny P, Sloan J, Barton D, Loprinzi C (2009) Efficacy of nonestrogenic hot flash therapies among women stratified by breast cancer history and tamoxifen use: a pooled analysis. Menopause 16(3):477–483. doi: 10.1097/gme.0b013e31818c91ca CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl H (2001) Methodologic lessons learned from hot flash studies. J Clin Oncol 19(23):4280–4290PubMedGoogle Scholar
  45. 45.
    Curran S, Andrykowski M, Stadts J (1995) Short form of the profile of mood states (POMS-SF): Psychometric information. Psychol Assess 7(1):80–83CrossRefGoogle Scholar
  46. 46.
    National Cancer Institute (2016) Protocol Development: Common Terminology Criteria for Adverse Events (CTCAE). Accessed Feb 12 2016
  47. 47.
    Beck AT, Steer RA, Garbin MG (1988) Psychometric properties of the Beck Depression Inventory: 25 years of evaluation. Clin Psychol Rev 8(1):77–100CrossRefGoogle Scholar
  48. 48.
    Cleeland CS, Mendoza TR, Wang XS, Chou C, Harle MT, Morrissey M, Engstrom MC (2000) Assessing symptom distress in cancer patients: the M.D. Anderson Symptom Inventory. Cancer 89(7):1634–1646CrossRefPubMedGoogle Scholar
  49. 49.
    Radloff LS (1977) The CES-D Scale: a self-report depression scale for research in the general population. Appl Psychol Measurement 1:385–401CrossRefGoogle Scholar
  50. 50.
    Zigmond AS, Snaith RP (1983) The Hospital Anxiety and Depression scale. Acta Psychiatr Scand 67(6):361–370CrossRefPubMedGoogle Scholar
  51. 51.
    Stewart AL, Ware JE (1992) Measuring Function and Well Being: The Medical Outcomes Study Approach. Duke University Press, DurhamGoogle Scholar
  52. 52.
    Brooks R (2013) The EuroQOL Group after 25 Years. Springer, NetherlandsCrossRefGoogle Scholar
  53. 53.
    Meijman TF, de Vries-Griever AH, de Vries G (1988) The evaluation of the Groningen sleep quality scale. Heymans Bulletin (HB 88-13-EX), GroningenGoogle Scholar
  54. 54.
    Thirlaway K, Fallowfield L, Cuzick J (1996) The sexual activity questionnaire: a measure of women’s sexual functioning. Qual Life Res 5(1):81–90CrossRefPubMedGoogle Scholar
  55. 55.
    Ware JE, Snow KK, Konsinski M, Gandek B (1993) SF-36 health survey: manual and interpretation guide. The Health Institute, BostonGoogle Scholar
  56. 56.
    Zung WW (1965) A self-rating depression scale. Arch Gen Psychiatry 12:63–70CrossRefPubMedGoogle Scholar
  57. 57.
    Buysse DJ, Reynolds CF 3rd, Monk TH, Berman SR, Kupfer DJ (1989) The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 28(2):193–213CrossRefPubMedGoogle Scholar
  58. 58.
    Heinemann K, Ruebig A, Potthoff P, Schneider HP, Strelow F, Heinemann LA, Do MT (2004) The Menopause Rating Scale (MRS) scale: a methodological review. Health Qual Life Outcomes 2:45. doi: 10.1186/1477-7525-2-45 CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Hilditch JR, Lewis J, Peter A, van Maris B, Ross A, Franssen E, Guyatt GH, Norton PG, Dunn E (1996) A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas 24(3):161–175CrossRefPubMedGoogle Scholar
  60. 60.
    Ware JE, Kosinski M, Keller SD (1996) A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 34(3):220–233CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.School of MedicineUniversity of California, San FranciscoSan FranciscoUSA
  2. 2.School of MedicineUniversity of California, San DiegoLa JollaUSA
  3. 3.Department of Reproductive Medicine, Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA
  4. 4.College of Public Health and Human SciencesOregon State UniversityCorvallisUSA
  5. 5.Department of Biostatistics, Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA
  6. 6.Department of Family Medicine & Public Health, Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA
  7. 7.The Bendheim Center for Integrative MedicineMemorial Sloan-Kettering Cancer CenterNew York CityUSA

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