Preventing adverse events of chemotherapy by educating patients about the nocebo effect (RENNO study) - study protocol of a randomized controlled trial with gastrointestinal cancer patients

Julia Quidde, Yiqi Pan, Melanie Salm, Armin Hendi, Sven Nilsson, Karin Oechsle, Alexander Stein, Yvonne Nestoriuc, Julia Quidde, Yiqi Pan, Melanie Salm, Armin Hendi, Sven Nilsson, Karin Oechsle, Alexander Stein, Yvonne Nestoriuc

Abstract

Background: Patients undergoing chemotherapy are highly burdened by side effects. These may be caused by the pharmacodynamics of the drug or be driven by psychological factors such as negative expectations or pre-conditioning, which reflect nocebo effects. As such, negative pre-treatment expectations or prior experiences might exacerbate the burden of chemotherapy side effects. Educating patients about this nocebo effect has been put forward as a potential strategy to optimize patients' pre-treatment expectations. In this study, we evaluate whether a briefing about the nocebo effect is efficacious in reducing side effects.

Methods: In this exploratory study, a total number of n = 100 outpatients with newly diagnosed gastrointestinal cancers are randomized 1:1 to an information session about the nocebo effect (nocebo-education) or an attention control group (ACG) with matching interaction time. Assessments take place before the intervention (T1 pre), post-intervention (T1 post), and 10 days (T2) and 12 weeks (T3) after the initial chemotherapy. The primary outcomes are the patient-rated number and intensity of side effects at 10-days and at 12-weeks follow-up. Secondary outcomes include coping with side effects, tendency to misattribute symptoms, compliance intention, attitude towards the chemotherapy, co-medication to treat side effects and the clinician-rated severity of toxicity. Further analyses are conducted to investigate whether a potential beneficial effect is mediated by a change of expectations before and after the intervention.

Discussion: Informing patients about the nocebo effect might be an innovative and feasible intervention to reduce the burden of side effects and strengthen patients' perceived control over adverse symptoms.

Trial registration: The trial is registered at the German Clinical Trials Register (ID: DRKS00009501 ; retrospectively registered on March 27, 2018). The first patient was enrolled on September 29, 2015.

Keywords: Chemotherapy; Gastrointestinal cancer; Informed consent; Nocebo effect; Side effects; Treatment expectations.

Conflict of interest statement

Ethics approval and consent to participate

Ethics approval to the trial protocol version 1.0 (Hamburg, June 16, 2015) has been given by the local ethics committee of the University of Hamburg (Reference number: 2015_03). Any amendments to the protocol will be communicated and re-approved by the ethics committee. All participants will be informed about the study in verbal and written form before the consent procedure. Informed consent is obtained from all participants prior enrolment.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

    1. Robert Koch-Institute: Krebs in Deutschland für 2013/2014. Edited by Zentrum für Krebsregisterdaten und der Gesellschaft der epidemiologischen Krebsregister in Deutschland e.V.; 2017.
    1. DeSantis CE, Lin CC, Mariotto AB, Siegel RL, Stein KD, Kramer JL, Alteri R, Robbins AS, Jemal A. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014;64(4):252–271. doi: 10.3322/caac.21235.
    1. Wagland R, Richardson A, Ewings S, Armes J, Lennan E, Hankins M, Griffiths P. Prevalence of cancer chemotherapy-related problems, their relation to health-related quality of life and associated supportive care: a cross-sectional survey. Support Care Cancer. 2016;24(12):4901–4911. doi: 10.1007/s00520-016-3346-4.
    1. Cohen L, de Moor CA, Eisenberg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting-incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15(5):497–503. doi: 10.1007/s00520-006-0173-z.
    1. Clarke G, Johnston S, Corrie P, Kuhn I, Barclay S. Withdrawal of anticancer therapy in advanced disease: a systematic literature review. BMC Cancer. 2015;15:892. doi: 10.1186/s12885-015-1862-0.
    1. Kuchuk I, Bouganim N, Beusterien K, Grinspan J, Vandermeer L, Gertler S, Dent SF, Song X, Segal R, Mazzarello S, et al. Preference weights for chemotherapy side effects from the perspective of women with breast cancer. Breast Cancer Res Treat. 2013;142(1):101–107. doi: 10.1007/s10549-013-2727-3.
    1. Kennedy WP. The nocebo reaction. Med World. 1961;95:203–205.
    1. Di Blasi Z, Harkness E, Ernst E, Georgiou A, Kleijnen J. Influence of context effects on health outcomes: a systematic review. Lancet. 2001;357(9258):757–762. doi: 10.1016/S0140-6736(00)04169-6.
    1. Colloca L, Finniss D. Nocebo effects, patient-clinician communication, and therapeutic outcomes. JAMA. 2012;307(6):567–568. doi: 10.1001/jama.2012.115.
    1. de la Cruz M, Hui D, Parsons HA, Bruera E. Placebo and nocebo effects in randomized double-blind clinical trials of agents for the therapy for fatigue in patients with advanced cancer. Cancer. 2010;116(3):766–774. doi: 10.1002/cncr.24751.
    1. Petersen GL, Finnerup NB, Colloca L, Amanzio M, Price DD, Jensen TS, Vase L. The magnitude of nocebo effects in pain: a meta-analysis. Pain. 2014;155(8):1426–1434. doi: 10.1016/j.pain.2014.04.016.
    1. Mondaini N, Gontero P, Giubilei G, Lombardi G, Cai T, Gavazzi A, Bartoletti R. Finasteride 5 mg and sexual side effects: how many of these are related to a nocebo phenomenon? J Sex Med. 2007;4(6):1708–1712. doi: 10.1111/j.1743-6109.2007.00563.x.
    1. Varelmann D, Pancaro C, Cappiello EC, Camann WR. Nocebo-induced hyperalgesia during local anesthetic injection. Anesth Analg. 2010;110(3):868–870. doi: 10.1213/ANE.0b013e3181cc5727.
    1. Bingel U, Wanigasekera V, Wiech K, Ni Mhuircheartaigh R, Lee MC, Ploner M, Tracey I. The effect of treatment expectation on drug efficacy: imaging the analgesic benefit of the opioid remifentanil. Sci Transl Med. 2011;3(70):70ra14. doi: 10.1126/scitranslmed.3001244.
    1. Colloca L, Petrovic P, Wager TD, Ingvar M, Benedetti F. How the number of learning trials affects placebo and nocebo responses. Pain. 2010;151(2):430–439. doi: 10.1016/j.pain.2010.08.007.
    1. Benedetti F, Durando J, Vighetti S. Nocebo and placebo modulation of hypobaric hypoxia headache involves the cyclooxygenase-prostaglandins pathway. Pain. 2014;155(5):921–928. doi: 10.1016/j.pain.2014.01.016.
    1. Benedetti F, Lanotte M, Lopiano L, Colloca L. When words are painful: unraveling the mechanisms of the nocebo effect. Neuroscience. 2007;147(2):260–271. doi: 10.1016/j.neuroscience.2007.02.020.
    1. Bingel U, Placebo Competence T. Avoiding nocebo effects to optimize treatment outcome. JAMA. 2014;312(7):693–694. doi: 10.1001/jama.2014.8342.
    1. Sohl SJ, Schnur JB, Montgomery GH. A meta-analysis of the relationship between response expectancies and cancer treatment-related side effects. J Pain Symptom Manag. 2009;38(5):775–784. doi: 10.1016/j.jpainsymman.2009.01.008.
    1. Hofman M, Morrow GR, Roscoe JA, Hickok JT, Mustian KM, Moore DF, Wade JL, Fitch TR. Cancer patients' expectations of experiencing treatment-related side effects: a University of Rochester Cancer Center--Community Clinical Oncology Program study of 938 patients from community practices. Cancer. 2004;101(4):851–857. doi: 10.1002/cncr.20423.
    1. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo phenomenon. JAMA. 2002;287(5):622–627. doi: 10.1001/jama.287.5.622.
    1. Geers AL, Helfer SG, Weiland PE, Kosbab K. Expectations and placebo response: a laboratory investigation into the role of somatic focus. J Behav Med. 2006;29(2):171–178. doi: 10.1007/s10865-005-9040-5.
    1. Crichton F, Petrie KJ. Health complaints and wind turbines: the efficacy of explaining the nocebo response to reduce symptom reporting. Environ Res. 2015;140:449–455. doi: 10.1016/j.envres.2015.04.016.
    1. Howick Jeremy, Moscrop Andrew, Mebius Alexander, Fanshawe Thomas R, Lewith George, Bishop Felicity L, Mistiaen Patriek, Roberts Nia W, Dieninytė Eglė, Hu Xiao-Yang, Aveyard Paul, Onakpoya Igho J. Effects of empathic and positive communication in healthcare consultations: a systematic review and meta-analysis. Journal of the Royal Society of Medicine. 2018;111(7):240–252. doi: 10.1177/0141076818769477.
    1. Miller SM. Monitoring versus blunting styles of coping with Cancer influence the information patients want and need about their disease - implications for Cancer screening and management. Cancer. 1995;76(2):167–177. doi: 10.1002/1097-0142(19950715)76:2<167::AID-CNCR2820760203>;2-K.
    1. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5(6):649–655. doi: 10.1097/00000421-198212000-00014.
    1. Mehnert A, Müller D, Lehmann C, Koch U. Die deutsche Version des NCCN Distress-Thermometers: Empirische Prüfung eines Screening-Instruments zur Erfassung psychosozialer Belastung bei Krebspatienten. Z Psychiatr Psychol Psychother. 2006;54(3):213–223.
    1. Abramson JH. WINPEPI (PEPI-for-windows): computer programs for epidemiologists. Epidemiol Perspect Innov. 2004;1(1):6. doi: 10.1186/1742-5573-1-6.
    1. Zimmermann T, Heinrichs N. Seite an Seite - eine Krebserkrankung in der Partnerschaft gemeinsam bewältigen. Ein Ratgeber für Paare. Göttingen: Hogrefe; 2008.
    1. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, Silberman M, Yellen SB, Winicour P, Brannon J, et al. The functional assessment of Cancer therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11(3):570–579. doi: 10.1200/JCO.1993.11.3.570.
    1. Rief W, Barsky AJ, Glombiewski JA, Nestoriuc Y, Glaesmer H, Braehler E. Assessing general side effects in clinical trials: reference data from the general population. Pharmacoepidemiol Drug Saf. 2011;20(4):405–415. doi: 10.1002/pds.2067.
    1. Chen AB, Cronin A, Weeks JC, Chrischilles EA, Malin J, Hayman JA, Schrag D. Expectations about the effectiveness of radiation therapy among patients with incurable lung cancer. J Clin Oncol. 2013;31(21):2730–2735. doi: 10.1200/JCO.2012.48.5748.
    1. Hochster HS, Hart LL, Ramanathan RK, Childs BH, Hainsworth JD, Cohn AL, Wong L, Fehrenbacher L, Abubakr Y, Saif MW, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE study. J Clin Oncol. 2008;26(21):3523–3529. doi: 10.1200/JCO.2007.15.4138.
    1. von Blanckenburg P, Schuricht F, Albert US, Rief W, Nestoriuc Y. Optimizing expectations to prevent side effects and enhance quality of life in breast cancer patients undergoing endocrine therapy: study protocol of a randomized controlled trial. BMC Cancer. 2013;13:426. doi: 10.1186/1471-2407-13-426.
    1. National Institutes of Health, National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE). Version 4.03. In.; 2010.
    1. Goldstein D, Bennett B, Friedlander M, Davenport T, Hickie I, Lloyd A. Fatigue states after cancer treatment occur both in association with, and independent of, mood disorder: a longitudinal study. BMC Cancer. 2006;6:240. doi: 10.1186/1471-2407-6-240.
    1. Bower JE, Ganz PA, Desmond KA, Bernaards C, Rowland JH, Meyerowitz BE, Belin TR. Fatigue in long-term breast carcinoma survivors: a longitudinal investigation. Cancer. 2006;106(4):751–758. doi: 10.1002/cncr.21671.
    1. Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, Johnson DH, Miaskowski C, Scherr SL, Portenoy RK, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the fatigue coalition. Oncologist. 2000;5(5):353–360. doi: 10.1634/theoncologist.5-5-353.
    1. Pedersen B, Koktved DP, Nielsen LL. Living with side effects from cancer treatment--a challenge to target information. Scand J Caring Sci. 2013;27(3):715–723. doi: 10.1111/j.1471-6712.2012.01085.x.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться