A phase 2 randomized trial to evaluate the impact of a supervised exercise program on cardiotoxicity at 3 months in patients with HER2 overexpressing breast cancer undergoing adjuvant treatment by trastuzumab: design of the CARDAPAC study

Quentin Jacquinot, Nathalie Meneveau, Marion Chatot, Franck Bonnetain, Bruno Degano, Malika Bouhaddi, Gilles Dumoulin, Dewi Vernerey, Xavier Pivot, Fabienne Mougin, Quentin Jacquinot, Nathalie Meneveau, Marion Chatot, Franck Bonnetain, Bruno Degano, Malika Bouhaddi, Gilles Dumoulin, Dewi Vernerey, Xavier Pivot, Fabienne Mougin

Abstract

Background: The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer is a poor prognosis. Trastuzumab improves overall survival but is associated with cardiotoxicity, especially a decline in left ventricular ejection fraction (LVEF). In addition, chemotherapy and radiotherapy increase fatigue and pain, decrease physical capacity and health-related quality of life. To date, no study has evaluated the benefits of physical activity on the side effects of treatment in patients with HER2 positive breast cancer. The aim of this study is to evaluate the impact of 3 months' exercise intervention on myocardial function and in particular on the rate of cardiotoxicity.

Methods: This multicenter, randomized clinical trial will include 112 patients treated by adjuvant trastuzumab for HER2 positive breast cancer to investigate the effects of a 3 months' supervised exercise program (intermittent exercise, combining moderate and high intensities; 55 minutes duration, 3 times per week), on the rate of cardiotoxicity [defined by either a decrease of the LVEF under 50% or an absolute drop of LVEF of 10%] between baseline and at 3 months and on strength, aerobic capacity, metabolic, inflammatory and hormonal parameters. Health-related quality of life, fatigue, pain and level of physical activity will also be assessed. Participants are randomly allocated to one of the two groups ("training group" vs "standard oncological care"). Performance-based and self-reported outcomes are assessed at baseline, at the end of supervised exercise program and at six months follow-up.

Discussion: Although physical exercise is recommended to reduce the side effects of adjuvant treatments in breast cancer patients, no randomized study has been conducted to assess the benefits of a physical training program in patients with HER2 overexpressing breast cancer. Cardiac toxicity of trastuzumab may be minimized with an exercise program combining high and moderate intensities. This type of program may be safe, feasible and effective but also increase cardiorespiratory fitness and improve health-related quality of life. If these benefits are confirmed, this exercise intervention could be systematically proposed to patients during the course of treatment by trastuzumab in addition to standard oncological care.

Trial registration: National Clinical Trials Number ( NCT02433067 ); Registration 28 april 2015.

Keywords: Breast cancer; Cardiotoxicity; Exercise; HER2 overexpression; Study protocol; Supportive care.

Figures

Fig. 1
Fig. 1
Flowchart of the study design
Fig. 2
Fig. 2
Representation of treatment schedule and study inclusion for patients with HER2 positive breast cancer
Fig. 3
Fig. 3
Supervised exercise program

References

    1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. doi: 10.3322/caac.20107.
    1. INCa. Les données - Institut National Du cancer. 2012. . Accessed 9 Mar 2016.
    1. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177–182. doi: 10.1126/science.3798106.
    1. Bilous M, Ades C, Armes J, Bishop J, Brown R, Cooke B, et al. Predicting the HER2 status of breast cancer from basic histopathology data: an analysis of 1500 breast cancers as part of the HER2000 international study. Breast Edinb Scotl. 2003;12:92–98. doi: 10.1016/S0960-9776(02)00273-4.
    1. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing Metastatic breast cancer that has progressed after chemotherapy for Metastatic disease. J Clin Oncol 1999;17:2639–2639.
    1. Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet Lond Engl. 2007;369:29–36. doi: 10.1016/S0140-6736(07)60028-2.
    1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CEJ, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–1684. doi: 10.1056/NEJMoa052122.
    1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for Metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101.
    1. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncologia. 2002;20:1215–1221.
    1. Procter M, Suter TM, de Azambuja E, Dafni U, van Dooren V, Muehlbauer S, et al. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin adjuvant (HERA) trial. J Clin Oncol Off J Am Soc Clin Oncol. 2010;28:3422–3428. doi: 10.1200/JCO.2009.26.0463.
    1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–1672. doi: 10.1056/NEJMoa052306.
    1. Suter TM, Procter M, Veldhuisen DJ van, Muscholl M, Bergh J, Carlomagno C, et al. Trastuzumab-associated cardiac adverse effects in the Herceptin adjuvant trial. J Clin Oncol 2007;25:3859–3865.
    1. Goodwin PJ, Ennis M, Pritchard KI, McCready D, Koo J, Sidlofsky S, et al. Adjuvant treatment and onset of menopause predict weight gain after breast cancer diagnosis. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncologia. 1999;17:120–129.
    1. Curt GA, Breitbart W, Cella D, Groopman JE, Horning SJ, Itri LM, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the fatigue coalition. Oncologist. 2000;5:353–360. doi: 10.1634/theoncologist.5-5-353.
    1. Courneya KS. Exercise in cancer survivors: an overview of research. Med Sci Sports Exerc. 2003;35:1846–1852. doi: 10.1249/01.MSS.0000093622.41587.B6.
    1. Peel JB, Sui X, Adams SA, Hébert JR, Hardin JW, Blair SN. A prospective study of cardiorespiratory fitness and breast cancer mortality. Med Sci Sports Exerc. 2009;41:742–748. doi: 10.1249/MSS.0b013e31818edac7.
    1. Kayl AE, Meyers CA. Side-effects of chemotherapy and quality of life in ovarian and breast cancer patients. Curr Opin Obstet Gynecol. 2006;18:24–28. doi: 10.1097/01.gco.0000192996.20040.24.
    1. Courneya KS, Segal RJ, Mackey JR, Gelmon K, Reid RD, Friedenreich CM, et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J Clin Oncol. 2007;25:4396–4404. doi: 10.1200/JCO.2006.08.2024.
    1. Cheema B, Gaul CA, Lane K, Fiatarone Singh MA. Progressive resistance training in breast cancer: a systematic review of clinical trials. Breast Cancer Res Treat. 2008;109:9–26. doi: 10.1007/s10549-007-9638-0.
    1. Galvão DA, Newton RU. Review of exercise intervention studies in cancer patients. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncologia. 2005;23:899–909.
    1. Mutrie N, Campbell AM, Whyte F, McConnachie A, Emslie C, Lee L, et al. Benefits of supervised group exercise programme for women being treated for early stage breast cancer: pragmatic randomised controlled trial. BMJ. 2007;334:517. doi: 10.1136/.
    1. van Waart H, Stuiver MM, van Harten WH, Geleijn E, Kieffer JM, Buffart LM, et al. Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial. J. Clin. Oncol. 2015;JCO.2014.59.1081.
    1. Haykowsky MJ, Mackey JR, Thompson RB, Jones LW, Paterson DI. Adjuvant trastuzumab induces ventricular remodeling despite aerobic exercise training. Clin. Cancer res. Off. J. Am. Assoc. Cancer Res. 2009;15:4963–4967.
    1. Wisløff U, Støylen A, Loennechen JP, Bruvold M, Rognmo Ø, Haram PM, et al. Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients. Circulation. 2007;115:3086–3094. doi: 10.1161/CIRCULATIONAHA.106.675041.
    1. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s guidelines and standards committee and the chamber quantification writing group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr Off Publ Am Soc Echocardiogr. 2005;18:1440–1463. doi: 10.1016/j.echo.2005.10.005.
    1. Gottdiener JS, Bednarz J, Devereux R, Gardin J, Klein A, Manning WJ, et al. American Society of Echocardiography recommendations for use of echocardiography in clinical trials. J Am Soc Echocardiogr. 2004;17:1086–1119.
    1. Jones EC, Devereux RB, Roman MJ, Liu JE, Fishman D, Lee ET, et al. Prevalence and correlates of mitral regurgitation in a population-based sample (the strong heart study) Am J Cardiol. 2001;87:298–304. doi: 10.1016/S0002-9149(00)01362-X.
    1. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and doppler echocardiography. J Am Soc Echocardiogr. 2003;16:777–802. doi: 10.1016/S0894-7317(03)00335-3.
    1. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011;107:1375–1380. doi: 10.1016/j.amjcard.2011.01.006.
    1. Anavekar NS, Gerson D, Skali H, Kwong RY, Kent Yucel E, Solomon SD. Two-dimensional assessment of right ventricular function: an echocardiographic–MRI correlative study. Echocardiography. 2007;24:452–456. doi: 10.1111/j.1540-8175.2007.00424.x.
    1. Standardization of spirometry--1987 update. Statement of the American Thoracic Society. Am. Rev. Respir. Dis. 1987;136:1285–98.
    1. Wasserman K. The anaerobic threshold: definition, physiological significance and identification. Adv Cardiol. 1986;35:1–23. doi: 10.1159/000413434.
    1. Godfrey S, Wozniak ER, Courtenay Evans RJ, Samuels CS. Ear lobe blood samples for blood gas analysis at rest and during exercise. Br J Dis Chest. 1971;65:58–64. doi: 10.1016/0007-0971(71)90006-4.
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883.
    1. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–376. doi: 10.1093/jnci/85.5.365.
    1. Gentile S, Delarozière JC, Favre F, Sambuc R, San Marco JL. Validation of the French “multidimensional fatigue inventory” (MFI 20) Eur J Cancer Care (Engl) 2003;12:58–64. doi: 10.1046/j.1365-2354.2003.00295.x.
    1. Larue F, Colleau SM, Brasseur L, Cleeland CS. Multicentre study of cancer pain and its treatment in France. BMJ. 1995;310:1034–1037. doi: 10.1136/bmj.310.6986.1034.
    1. Gauthier AP, Lariviere M, Young N. Psychometric properties of the IPAQ: a validation study in a sample of northern Franco-Ontarians. J. Phys. Act. Health. 2009;6 Suppl 1:S54–60.
    1. Craig CL, Marshall AL, Sjöström M, Bauman AE, Booth ML, Ainsworth BE, et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc. 2003;35:1381–1395. doi: 10.1249/01.MSS.0000078924.61453.FB.
    1. Bassett DR, Ainsworth BE, Swartz AM, Strath SJ, O’Brien WL, King GA. Validity of four motion sensors in measuring moderate intensity physical activity. Med Sci Sports Exerc. 2000;32:S471–S480. doi: 10.1097/00005768-200009001-00006.
    1. Hamidou Z, Dabakuyo TS, Mercier M, Fraisse J, Causeret S, Tixier H, et al. Time to deterioration in quality of life score as a modality of longitudinal analysis in patients with breast cancer. Oncologist. 2011;16:1458–1468. doi: 10.1634/theoncologist.2011-0085.
    1. Mock V, Burke MB, Sheehan P, Creaton EM, Winningham ML, McKenney-Tedder S, et al. A nursing rehabilitation program for women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum. 1994;21:899–907.
    1. Segal R, Evans W, Johnson D, Smith J, Colletta S, Gayton J, et al. Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 2001;19:657–665. doi: 10.1200/JCO.2001.19.3.657.
    1. Freedman RJ, Aziz N, Albanes D, Hartman T, Danforth D, Hill S, et al. Weight and body composition changes during and after adjuvant chemotherapy in women with breast cancer. J Clin Endocrinol Metab. 2004;89:2248–2253. doi: 10.1210/jc.2003-031874.
    1. Schwartz AL, Winters-Stone K, Gallucci B. Exercise effects on bone mineral density in women with breast cancer receiving adjuvant chemotherapy. Oncol Nurs Forum. 2007;34:627–633. doi: 10.1188/07.ONF.627-633.
    1. Velthuis MJ, Agasi-Idenburg SC, Aufdemkampe G, Wittink HM. The effect of physical exercise on cancer-related fatigue during cancer treatment: a meta-analysis of randomised controlled trials. Clin Oncol R Coll Radiol G B. 2010;22:208–221. doi: 10.1016/j.clon.2009.12.005.
    1. Kuchinski A-M, Reading M, Lash AA. Treatment-related fatigue and exercise in patients with cancer: a systematic review. Medsurg Nurs. Off J Acad Med-Surg Nurses. 2009;18:174–180.
    1. Knols R, Aaronson NK, Uebelhart D, Fransen J, Aufdemkampe G. Physical exercise in cancer patients during and after medical treatment: a systematic review of randomized and controlled clinical trials. J Clin Oncol Off J Am Soc Clin Oncol. 2005;23:3830–3842. doi: 10.1200/JCO.2005.02.148.
    1. Peel AB, Thomas SM, Dittus K, Jones LW, Lakoski SG. Cardiorespiratory fitness in breast cancer patients: a call for normative values. J Am Heart Assoc. 2014;3 doi: 10.1161/JAHA.113.000432.
    1. Gimenez M, Servera E, Saunier C, Lacoste J. Square-Wave endurance exercise test (SWEET) for training and assessment in trained and untrained subjects. Eur J Appl Physiol. 1982;49:369–377. doi: 10.1007/BF00441298.
    1. Geny B, Saini J, Mettauer B, Lampert E, Piquard F, Follenius M, et al. Effect of short-term endurance training on exercise capacity, haemodynamics and atrial natriuretic peptide secretion in heart transplant recipients. Eur J Appl Physiol. 1996;73:259–266. doi: 10.1007/BF02425485.
    1. Lampert E, Mettauer B, Hoppeler H, Charloux A, Charpentier A, Lonsdorfer J. Skeletal muscle response to short endurance training in heart transplant recipients. J Am Coll Cardiol. 1998;32:420–426. doi: 10.1016/S0735-1097(98)00227-7.
    1. Tordi N, Dugue B, Klupzinski D, Rasseneur L, Rouillon JD, Lonsdorfer J. Interval training program on a wheelchair ergometer for paraplegic subjects. Spinal Cord. 2001;39:532–537. doi: 10.1038/sj.sc.3101206.
    1. Gimenez M, Predine E, Marchand M, Servera E, Ponz JL, Polu JM. Implications of lower- and upper-limb training procedures in patients with chronic airway obstruction. Chest. 1992;101:279S–288S. doi: 10.1378/chest.101.5_Supplement.279S.

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