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The effect of melatonin on sleep and quality of life in patients with advanced breast cancer

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Abstract

Background

Fatigue and sleep problems are prevalent in cancer patients and can be associated with disruption of circadian rhythmicity. In this prospective phase II trial, we sought to assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in breast cancer patients.

Methods

Thirty-two patients with metastatic breast cancer, receiving hormonal or trastuzumab therapy, took 5 mg of melatonin at bedtime for 2 months. Before starting and after 2 months on melatonin therapy, sleep and circadian rhythmicity were assessed by actigraphy, diurnal patterns of serum cortisol, and the expression of the core clock genes PER2 and BMAL1 in peripheral blood mononuclear cells. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was completed for subjective parameters.

Results

Bedtime melatonin was associated with a significant improvement in a marker of objective sleep quality, sleep fragmentation and quantity, subjective sleep, fatigue severity, global quality of life, and social and cognitive functioning scales. Morning clock gene expression was increased following bedtime melatonin intake. Melatonin did not affect actigraphy measure of circadian rhythmicity, or the diurnal cortisol pattern.

Conclusion

These results invite further investigation of melatonin as a potentially useful therapeutic agent for improving sleep and quality of life in cancer patients.

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References

  1. Palesh OG, Roscoe JA, Mustian KM, Roth T, Savard J, Ancoli-Israel S, Heckler C, Purnell JQ, Janelsins MC, Morrow GR (2010) Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. J Clin Oncol 28(2):292–298

    Article  PubMed Central  PubMed  Google Scholar 

  2. Innominato PF, Mormont MC, Rich TA, Waterhouse J, Levi FA, Bjarnason GA (2009) Circadian disruption, fatigue, and anorexia clustering in advanced cancer patients: implications for innovative therapeutic approaches. Integr Cancer Ther 8(4):361–370

    Article  PubMed  Google Scholar 

  3. Minton O, Richardson A, Sharpe M, Hotopf M, Stone P (2008) A systematic review and meta-analysis of the pharmacological treatment of cancer-related fatigue. J Natl Cancer Inst 100(16):1155–1166

    Article  CAS  PubMed  Google Scholar 

  4. Mohawk JA, Green CB, Takahashi JS (2012) Central and peripheral circadian clocks in mammals. Annu Rev Neurosci 35:445–462

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Bass J (2012) Circadian topology of metabolism. Nature 491(7424):348–356

    Article  CAS  PubMed  Google Scholar 

  6. Scheer FA, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 106(11):4453–4458

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Innominato PF, Levi FA, Bjarnason GA (2010) Chronotherapy and the molecular clock: clinical implications in oncology. Adv Drug Deliv Rev 62(9–10):979–1001

    Article  CAS  PubMed  Google Scholar 

  8. Megdal SP, Kroenke CH, Laden F, Pukkala E, Schernhammer ES (2005) Night work and breast cancer risk: a systematic review and meta-analysis. Eur J Cancer 41(13):2023–2032

    Article  PubMed  Google Scholar 

  9. Bonde JP, Hansen J, Kolstad HA, Mikkelsen S, Olsen JH, Blask DE, Harma M, Kjuus H, de Koning HJ, Olsen J, Moller M, Schernhammer ES, Stevens RG, Akerstedt T (2012) Work at night and breast cancer—report on evidence-based options for preventive actions. Scand J Work Environ Health 38(4):380–390

    Article  PubMed  Google Scholar 

  10. Filipski E, King VM, Li X, Granda TG, Mormont MC, Liu X, Claustrat B, Hastings MH, Levi F (2002) Host circadian clock as a control point in tumor progression. J Natl Cancer Inst 94(9):690–697

    Article  PubMed  Google Scholar 

  11. Fu L, Pelicano H, Liu J, Huang P, Lee C (2002) The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 111(1):41–50

    Article  CAS  PubMed  Google Scholar 

  12. Li JC, Xu F (1997) Influences of light–dark shifting on the immune system, tumor growth and life span of rats, mice and fruit flies as well as on the counteraction of melatonin. Biol Signals 6(2):77–89

    Article  PubMed  Google Scholar 

  13. Ancoli-Israel S, Liu L, Marler MR, Parker BA, Jones V, Sadler GR, Dimsdale J, Cohen-Zion M, Fiorentino L (2006) Fatigue, sleep, and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer 14(3):201–209

    Article  PubMed Central  PubMed  Google Scholar 

  14. Sephton S, Spiegel D (2003) Circadian disruption in cancer: a neuroendocrine-immune pathway from stress to disease? Brain Behav Immun 17(5):321–328

    Article  CAS  PubMed  Google Scholar 

  15. Innominato PF, Giacchetti S, Bjarnason GA, Focan C, Garufi C, Coudert B, Iacobelli S, Tampellini M, Durando X, Mormont MC, Waterhouse J, Levi FA (2012) Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer. Int J Cancer 131(11):2684–2692

    Article  CAS  PubMed  Google Scholar 

  16. Innominato PF, Focan C, Gorlia T, Moreau T, Garufi C, Waterhouse J, Giacchetti S, Coudert B, Iacobelli S, Genet D, Tampellini M, Chollet P, Lentz MA, Mormont MC, Levi F, Bjarnason GA (2009) Circadian rhythm in rest and activity: a biological correlate of quality of life and a predictor of survival in patients with metastatic colorectal cancer. Cancer Res 69(11):4700–4707

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D (2000) Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst 92(12):994–1000

    Article  CAS  PubMed  Google Scholar 

  18. Cohen L, Cole SW, Sood AK, Prinsloo S, Kirschbaum C, Arevalo JM, Jennings NB, Scott S, Vence L, Wei Q, Kentor D, Radvanyi L, Tannir N, Jonasch E, Tamboli P, Pisters L (2012) Depressive symptoms and cortisol rhythmicity predict survival in patients with renal cell carcinoma: role of inflammatory signaling. PLoS One 7(8), e42324

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Sephton SE, Lush E, Dedert EA, Floyd AR, Rebholz WN, Dhabhar FS, Spiegel D, Salmon P (2013) Diurnal cortisol rhythm as a predictor of lung cancer survival. Brain Behav Immun 30:S163–170

    Article  CAS  PubMed  Google Scholar 

  20. Schrepf A, Thaker PH, Goodheart MJ, Bender D, Slavich GM, Dahmoush L, Penedo F, DeGeest K, Mendez L, Lubaroff DM, Cole SW, Sood AK, Lutgendorf SK (2015) Diurnal cortisol and survival in epithelial ovarian cancer. Psychoneuroendocrinology 53:256–267

    Article  CAS  PubMed  Google Scholar 

  21. Innominato PF, Roche VP, Palesh OG, Ulusakarya A, Spiegel D, Levi FA (2014) The circadian timing system in clinical oncology. Ann Med 46(4):191–207

    Article  CAS  PubMed  Google Scholar 

  22. Waterhouse J, Reilly T, Atkinson G, Edwards B (2007) Jet lag: trends and coping strategies. Lancet 369(9567):1117–1129

    Article  PubMed  Google Scholar 

  23. Mazzoccoli G, Carughi S, De Cata A, La Viola M, Vendemiale G (2005) Melatonin and cortisol serum levels in lung cancer patients at different stages of disease. Med Sci Monit 11(6):CR284–288

    CAS  PubMed  Google Scholar 

  24. Parker KP, Bliwise DL, Ribeiro M, Jain SR, Vena CI, Kohles-Baker MK, Rogatko A, Xu Z, Harris WB (2008) Sleep/Wake patterns of individuals with advanced cancer measured by ambulatory polysomnography. J Clin Oncol 26(15):2464–2472

    Article  PubMed  Google Scholar 

  25. Lissoni P, Barni S, Mandala M, Ardizzoia A, Paolorossi F, Vaghi M, Longarini R, Malugani F, Tancini G (1999) Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status. Eur J Cancer 35(12):1688–1692

    Article  CAS  PubMed  Google Scholar 

  26. Ancoli-Israel S, Cole R, Alessi C, Chambers M, Moorcroft W, Pollak CP (2003) The role of actigraphy in the study of sleep and circadian rhythms. Sleep 26(3):342–392

    PubMed  Google Scholar 

  27. Lim AS, Yu L, Costa MD, Buchman AS, Bennett DA, Leurgans SE, Saper CB (2011) Quantification of the fragmentation of rest-activity patterns in elderly individuals using a state transition analysis. Sleep 34(11):1569–1581

    PubMed Central  PubMed  Google Scholar 

  28. Roscoe JA, Morrow GR, Hickok JT, Bushunow P, Matteson S, Rakita D, Andrews PL (2002) Temporal interrelationships among fatigue, circadian rhythm and depression in breast cancer patients undergoing chemotherapy treatment. Support Care Cancer 10(4):329–336

    Article  PubMed  Google Scholar 

  29. Mormont MC, Waterhouse J, Bleuzen P, Giacchetti S, Jami A, Bogdan A, Lellouch J, Misset JL, Touitou Y, Levi F (2000) Marked 24-h rest/activity rhythms are associated with better quality of life, better response, and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 6(8):3038–3045

    CAS  PubMed  Google Scholar 

  30. Witting W, Kwa IH, Eikelenboom P, Mirmiran M, Swaab DF (1990) Alterations in the circadian rest-activity rhythm in aging and Alzheimer’s disease. Biol Psychiatry 27(6):563–572

    Article  CAS  PubMed  Google Scholar 

  31. Pati AK, Parganiha A, Kar A, Soni R, Roy S, Choudhary V (2007) Alterations of the characteristics of the circadian rest-activity rhythm of cancer in-patients. Chronobiol Int 24(6):1179–1197

    Article  PubMed  Google Scholar 

  32. Lim AS, Chang AM, Shulman JM, Raj T, Chibnik LB, Cain SW, Rothamel K, Benoist C, Myers AJ, Czeisler CA, Buchman AS, Bennett DA, Duffy JF, Saper CB, De Jager PL (2012) A common polymorphism near PER1 and the timing of human behavioral rhythms. Ann Neurol 72(3):324–334.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Mormont MC, Hecquet B, Bogdan A, Benavides M, Touitou Y, Levi F (1998) Non-invasive estimation of the circadian rhythm in serum cortisol in patients with ovarian or colorectal cancer. Int J Cancer 78(4):421–424

    Article  CAS  PubMed  Google Scholar 

  34. James FO, Boivin DB, Charbonneau S, Belanger V, Cermakian N (2007) Expression of clock genes in human peripheral blood mononuclear cells throughout the sleep/wake and circadian cycles. Chronobiol Int 24(6):1009–1034

    Article  CAS  PubMed  Google Scholar 

  35. Osoba D, Rodrigues G, Myles J, Zee B, Pater J (1998) Interpreting the significance of changes in health-related quality-of-life scores. J Clin Oncol 16(1):139–144

    CAS  PubMed  Google Scholar 

  36. Dai H, Zhang L, Cao M, Song F, Zheng H, Zhu X, Wei Q, Zhang W, Chen K (2011) The role of polymorphisms in circadian pathway genes in breast tumorigenesis. Breast Cancer Res Treat 127(2):531–540

    Article  CAS  PubMed  Google Scholar 

  37. Yang X, Wood PA, Oh EY, Du-Quiton J, Ansell CM, Hrushesky WJ (2009) Down regulation of circadian clock gene Period 2 accelerates breast cancer growth by altering its daily growth rhythm. Breast Cancer Res Treat 117(2):423–431

    Article  PubMed  Google Scholar 

  38. Climent J, Perez-Losada J, Quigley DA, Kim IJ, Delrosario R, Jen KY, Bosch A, Lluch A, Mao JH, Balmain A (2010) Deletion of the PER3 gene on chromosome 1p36 in recurrent ER-positive breast cancer. J Clin Oncol 28(23):3770–3778

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Del Fabbro E, Dev R, Hui D, Palmer L, Bruera E (2013) Effects of melatonin on appetite and other symptoms in patients with advanced cancer and cachexia: a double-blind placebo-controlled trial. J Clin Oncol 31(10):1271–1276

    Article  PubMed Central  PubMed  Google Scholar 

  40. Fayers PM (2001) Interpreting quality of life data: population-based reference data for the EORTC QLQ-C30. Eur J Cancer 37(11):1331–1334

    Article  CAS  PubMed  Google Scholar 

  41. Ligibel JA (2011) Role of adjuvant and posttreatment exercise programs in breast health. J Natl Compr Canc Netw 9(2):251–256

    PubMed  Google Scholar 

  42. Van Reeth O, Sturis J, Byrne MM, Blackman JD, L’Hermite-Baleriaux M, Leproult R, Oliner C, Refetoff S, Turek FW, Van Cauter E (1994) Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men. Am J Physiol 266(6 Pt 1):E964–974

    PubMed  Google Scholar 

  43. Buxton OM, Frank SA, L’Hermite-Baleriaux M, Leproult R, Turek FW, Van Cauter E (1997) Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms. Am J Physiol 273(3 Pt 1):E536–542

    CAS  PubMed  Google Scholar 

  44. Liu L, Rissling M, Natarajan L, Fiorentino L, Mills PJ, Dimsdale JE, Sadler GR, Parker BA, Ancoli-Israel S (2012) The longitudinal relationship between fatigue and sleep in breast cancer patients undergoing chemotherapy. Sleep 35(2):237–245

    PubMed Central  PubMed  Google Scholar 

  45. Savard J, Liu L, Natarajan L, Rissling MB, Neikrug AB, He F, Dimsdale JE, Mills PJ, Parker BA, Sadler GR, Ancoli-Israel S (2009) Breast cancer patients have progressively impaired sleep-wake activity rhythms during chemotherapy. Sleep 32(9):1155–1160.

    PubMed Central  PubMed  Google Scholar 

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Acknowledgments

Supported by a grant from the Ontario Cancer Research Network 03-APR-0316OCRN to Dr. Bjarnason, the National Cancer Institute K07CA132916 to Dr. Palesh, and the Canadian Institutes of Health Research OOG MOP125934 to Dr. Lim.

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The authors have no conflict of interest to declare.

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Correspondence to Georg A. Bjarnason.

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Innominato, P.F., Lim, A.S., Palesh, O. et al. The effect of melatonin on sleep and quality of life in patients with advanced breast cancer. Support Care Cancer 24, 1097–1105 (2016). https://doi.org/10.1007/s00520-015-2883-6

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  • DOI: https://doi.org/10.1007/s00520-015-2883-6

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