Multicomponent Prehabilitation and Outcomes in Elderly Patients With Frailty

Effect of Multicomponent Prehabilitation on Early and Long-term Outcomes in Elderly Patients With Frailty After Digestive Surgery for Cancer: A Randomized-controlled Study

The study is designed to investigate the effect of a multicomponent prehabilitation pathway on early and long-term outcomes in elderly patients with frailty recovering from surgery for digestive cancer.

Frailty is an age-related syndrome characterized with diminished physiological reserve that results in decreased homeostatic capacity and increased vulnerability to any stress from minor to major. Approximately 10% to 20% of adults aged 65 years and older present with frailty, and the incidence doubles among those of 85 years and older. Among elderly cancer patients especially those with digestive cancer, the prevalence of frailty and pre-frailty can be as high as 50%. Malnutrition often coexists with frailty, and indeed contribute to the development of frailty. As a matter of fact, the proportion of malnutrition also increases with age even in high-income countries. Frailty is strongly associated with worsening outcomes in surgical patients, including higher delirium, high non-delirium complications, high perioperative mortality, as well as decreased activity of daily life, cognitive dysfunction and work disability in long-term survivors. Furthermore, malnutrition as a prominent factor in the development of frailty also has adverse impacts on the duration of hospitalization, complications, and survival after surgery. Therefore, it is urgently needed to understand how to enhance the recovery of these patients following surgery. Exercises and rehabilitation, in combination with nutritional supplement, may reverse or mitigate frailty, promote postoperative recovery, and improve clinical outcomes. However, the reported effectiveness varies with interventions and are not sufficiently robust to guide good clinical practice. The purpose of this study is to investigate the effect of multimodal prehabilitation on early and long-term outcomes in elderly patients with frailty.

Old Age; Debility, Digestive Cancer, Surgery, Preoperative Rehabilitation, Nutrition Therapy, Outcomes

Patients in the intervention group will receive nutritional optimization and exercise training before the surgery, exercise training after the surgery, and home-based rehabilitation after discharge.

Patients in the control group will maintain normal diet and normal activity before surgery, normal activity after surgery, and normal activity after discharge.

Indication for oral nutritional supplementation: Patients at risk of malnutrition (MNA-SF 8-11) or with malnutrition (MNA-SF 0-7). Protocol of nutritional optimization: Enteral nutritional powder (Ensure for patients without diabetes and Glucerna for patients with diabetes) twice a day. The target protein intake is 1.5-1.8 g/kg/d. Patients with iron deficient anemia (hemoglobin <130 g/L for men and <120 g/L for women) will be given oral iron therapy. The duration of nutritional optimization: The day admitted to the hospital to the surgery to one day prior to the surgery.

The respiratory training will be performed for at least 2-3 times per day. Respiratory training include thoracic breathing exercise and cough training. Aerobic exercise will be performed for at least 1-2 times per day. Aerobic exercise includes jogging, walking or climbing stairs. Exercise intensity will be based on patients' tolerance. The goal of the training is to complete the training plan as far as possible. Every training should be last for 45 minutes to 1 hour. If the patient can not tolerate, the training time should be reduce to 30 minutes. The duration of exercise training: The day admitted to the hospital to the surgery to one day prior to the surgery.

Muscle strength training in the bedside and walking in the ward. Aerobic exercise includes jogging, walking or climbing stairs. Exercise intensity will be based on patients' tolerance. The goal of the training is to complete the training plan as far as possible. Exercise training is performed under the supervision of physiotherpists durign hospital stay, and is reminded by regular telephone calls and phone messages after hospital discharge.

Delirium will be assessed with the 3-Dimensional Confusion Assessment Method. Non-delirium complications are defined as new onset medical events other than delirium that are harmful to patients' recovery and required therapeutic intervention, i.e., grade II or higher on Clavien-Dindo classification.

Non-delirium complications are defined as new onset medical events other than delirium that are harmful to patients' recovery and required therapeutic intervention, i.e., grade II or higher on Clavien-Dindo classification.

Quality of life will be assessed with the World Health Organization Quality of Life brief version (WHOQOL-BREF) which is a 24-item questionnaire that assesses the quality of life in physical, psychological, and social relationship, and environmental domains. The score ranges from 0 to 100 for each domain, with higher score indicating better function.

Cognitive function will be assessed with the Modified Telephone Interview for Cognitive Status (TICS-m) which is a 12-item questionnaire that verbally assesses global cognitive function via telephone. The score ranges from 0 to 50, with higher score indicating better function.

Sleep quality will be assessed with the Pittsburgh sleep quality index which is a 9-item questionnaire that assess subjective quality of sleep during the past 1 month. The score ranges from 0 to 21, with higher score indicating poor sleep quality.

Events are cancer-specific death which is defined as death fully attributable to the cancer for which the index surgery is performed and usually involving cancer recurrence and/or metastasis after exclusion of other causes such as stroke and myocardial infarction. Deaths from other causes are censored at the time of death.

Events include recurrence/metastasis, new-onset diseases, new-onset tumors, or all-cause mortality, whichever come first.

Intensity of pain will be assessed twice daily with the numeric rating scale which is a 11-point scale where 0=no pain and 10=the worst pain.

Subjective sleep quality will be assessed daily with the numeric rating scale which is a 11-point scale where 0=the best sleep and 10=the worst sleep.

Quality of life will be assessed with the World Health Organization Quality of Life brief version (WHOQOL-BREF) which is a 24-item questionnaire that assesses the quality of life in physical, psychological, and social relationship, and environmental domains. The score ranges from 0 to 100 for each domain, with higher score indicating better function.

Cognitive function will be assessed with the Modified Telephone Interview for Cognitive Status (TICS-m) which is a 12-item questionnaire that verbally assesses global cognitive function via telephone. The score ranges from 0 to 50, with higher score indicating better function.

Blood samples will be collected before anesthesia. Serum will be separated and immediately frozen at -80 °C. Irisin concentration will be measured using a commercial ELISA kit, according to the manufacturer's instructions.

Blood samples will be collected before anesthesia. Serum will be separated and immediately frozen at -80 °C. Irisin concentration will be measured using a commercial ELISA kit, according to the manufacturer's instructions.

Inclusion criteria: Age ≥65 years but <90 years; Scheduled to undergo major surgery for digestive cancer with an expected duration of 2 hours and longer, including cancers of esophagus, stomach, small intestine, colon, rectum, pancreas, liver, and biliary tract; Clinical Frailty Scale ≥5; Provide written informed consent. Exclusion Criteria: Preoperative history of schizophrenia, epilepsy, Parkinsonism, or myasthenia gravis; Inability to communicate due to coma, profound dementia, or language barrier; Inability to participate in preoperative rehabilitation due to paralysis, fracture or other movement disorder; Inability to take oral diet due to preoperative gastrointestinal disease or other disease; Severe heart dysfunction (left ventricular ejection fraction <30% or New York Heart Association classification IV), severe hepatic dysfunction (Child-Pugh class C), severe renal dysfunction (undergoing dialysis before surgery), or American Society of Anesthesiologists classification of grade 4 or higher; Other reasons that are considered unsuitable for study participation.

Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.

Collard RM, Boter H, Schoevers RA, Oude Voshaar RC. Prevalence of frailty in community-dwelling older persons: a systematic review. J Am Geriatr Soc. 2012 Aug;60(8):1487-92. doi: 10.1111/j.1532-5415.2012.04054.x. Epub 2012 Aug 6.

Song X, Mitnitski A, Rockwood K. Prevalence and 10-year outcomes of frailty in older adults in relation to deficit accumulation. J Am Geriatr Soc. 2010 Apr;58(4):681-7. doi: 10.1111/j.1532-5415.2010.02764.x. Epub 2010 Mar 22.

Mohile SG, Xian Y, Dale W, Fisher SG, Rodin M, Morrow GR, Neugut A, Hall W. Association of a cancer diagnosis with vulnerability and frailty in older Medicare beneficiaries. J Natl Cancer Inst. 2009 Sep 2;101(17):1206-15. doi: 10.1093/jnci/djp239. Epub 2009 Jul 28.

Verlaan S, Ligthart-Melis GC, Wijers SLJ, Cederholm T, Maier AB, de van der Schueren MAE. High Prevalence of Physical Frailty Among Community-Dwelling Malnourished Older Adults-A Systematic Review and Meta-Analysis. J Am Med Dir Assoc. 2017 May 1;18(5):374-382. doi: 10.1016/j.jamda.2016.12.074. Epub 2017 Feb 24.

Guyonnet S, Rolland Y. Screening for Malnutrition in Older People. Clin Geriatr Med. 2015 Aug;31(3):429-37. doi: 10.1016/j.cger.2015.04.009. Epub 2015 May 13.

Zhang DF, Su X, Meng ZT, Cui F, Li HL, Wang DX, Li XY. Preoperative severe hypoalbuminemia is associated with an increased risk of postoperative delirium in elderly patients: Results of a secondary analysis. J Crit Care. 2018 Apr;44:45-50. doi: 10.1016/j.jcrc.2017.09.182. Epub 2017 Sep 29.

Zhang Y, Shan GJ, Zhang YX, Cao SJ, Zhu SN, Li HJ, Ma D, Wang DX; First Study of Perioperative Organ Protection (SPOP1) Investigators. Preoperative vitamin D deficiency increases the risk of postoperative cognitive dysfunction: a predefined exploratory sub-analysis. Acta Anaesthesiol Scand. 2018 Aug;62(7):924-935. doi: 10.1111/aas.13116. Epub 2018 Mar 26.

Cruz-Jentoft AJ, Kiesswetter E, Drey M, Sieber CC. Nutrition, frailty, and sarcopenia. Aging Clin Exp Res. 2017 Feb;29(1):43-48. doi: 10.1007/s40520-016-0709-0. Epub 2017 Feb 2.

Wei K, Nyunt MSZ, Gao Q, Wee SL, Ng TP. Frailty and Malnutrition: Related and Distinct Syndrome Prevalence and Association among Community-Dwelling Older Adults: Singapore Longitudinal Ageing Studies. J Am Med Dir Assoc. 2017 Dec 1;18(12):1019-1028. doi: 10.1016/j.jamda.2017.06.017. Epub 2017 Aug 10.

Laur CV, McNicholl T, Valaitis R, Keller HH. Malnutrition or frailty? Overlap and evidence gaps in the diagnosis and treatment of frailty and malnutrition. Appl Physiol Nutr Metab. 2017 May;42(5):449-458. doi: 10.1139/apnm-2016-0652. Epub 2017 Mar 21.

Ethun CG, Bilen MA, Jani AB, Maithel SK, Ogan K, Master VA. Frailty and cancer: Implications for oncology surgery, medical oncology, and radiation oncology. CA Cancer J Clin. 2017 Sep;67(5):362-377. doi: 10.3322/caac.21406. Epub 2017 Jul 21.

Lin HS, Watts JN, Peel NM, Hubbard RE. Frailty and post-operative outcomes in older surgical patients: a systematic review. BMC Geriatr. 2016 Aug 31;16(1):157. doi: 10.1186/s12877-016-0329-8.

Fagard K, Leonard S, Deschodt M, Devriendt E, Wolthuis A, Prenen H, Flamaing J, Milisen K, Wildiers H, Kenis C. The impact of frailty on postoperative outcomes in individuals aged 65 and over undergoing elective surgery for colorectal cancer: A systematic review. J Geriatr Oncol. 2016 Nov;7(6):479-491. doi: 10.1016/j.jgo.2016.06.001. Epub 2016 Jun 21.

Richards SJG, Frizelle FA, Geddes JA, Eglinton TW, Hampton MB. Frailty in surgical patients. Int J Colorectal Dis. 2018 Dec;33(12):1657-1666. doi: 10.1007/s00384-018-3163-y. Epub 2018 Sep 14.

Inouye SK, Westendorp RG, Saczynski JS, Kimchi EY, Cleinman AA. Delirium in elderly people--authors'reply. Lancet. 2014 Jun 14;383(9934):2045. doi: 10.1016/S0140-6736(14)60994-6. No abstract available.

Witlox J, Eurelings LS, de Jonghe JF, Kalisvaart KJ, Eikelenboom P, van Gool WA. Delirium in elderly patients and the risk of postdischarge mortality, institutionalization, and dementia: a meta-analysis. JAMA. 2010 Jul 28;304(4):443-51. doi: 10.1001/jama.2010.1013.

Persico I, Cesari M, Morandi A, Haas J, Mazzola P, Zambon A, Annoni G, Bellelli G. Frailty and Delirium in Older Adults: A Systematic Review and Meta-Analysis of the Literature. J Am Geriatr Soc. 2018 Oct;66(10):2022-2030. doi: 10.1111/jgs.15503. Epub 2018 Sep 21.

Bellelli G, Moresco R, Panina-Bordignon P, Arosio B, Gelfi C, Morandi A, Cesari M. Is Delirium the Cognitive Harbinger of Frailty in Older Adults? A Review about the Existing Evidence. Front Med (Lausanne). 2017 Nov 8;4:188. doi: 10.3389/fmed.2017.00188. eCollection 2017.

Nomura Y, Nakano M, Bush B, Tian J, Yamaguchi A, Walston J, Hasan R, Zehr K, Mandal K, LaFlam A, Neufeld KJ, Kamath V, Hogue CW, Brown CH 4th. Observational Study Examining the Association of Baseline Frailty and Postcardiac Surgery Delirium and Cognitive Change. Anesth Analg. 2019 Aug;129(2):507-514. doi: 10.1213/ANE.0000000000003967.

Brown CH 4th, Max L, LaFlam A, Kirk L, Gross A, Arora R, Neufeld K, Hogue CW, Walston J, Pustavoitau A. The Association Between Preoperative Frailty and Postoperative Delirium After Cardiac Surgery. Anesth Analg. 2016 Aug;123(2):430-5. doi: 10.1213/ANE.0000000000001271.

Mazzola P, Ward L, Zazzetta S, Broggini V, Anzuini A, Valcarcel B, Brathwaite JS, Pasinetti GM, Bellelli G, Annoni G. Association Between Preoperative Malnutrition and Postoperative Delirium After Hip Fracture Surgery in Older Adults. J Am Geriatr Soc. 2017 Jun;65(6):1222-1228. doi: 10.1111/jgs.14764. Epub 2017 Mar 6.

Ringaitiene D, Gineityte D, Vicka V, Zvirblis T, Sipylaite J, Irnius A, Ivaskevicius J, Kacergius T. Impact of malnutrition on postoperative delirium development after on pump coronary artery bypass grafting. J Cardiothorac Surg. 2015 May 20;10:74. doi: 10.1186/s13019-015-0278-x.

Liu X, Wu X, Zhou C, Hu T, Ke J, Chen Y, He X, Zheng X, He X, Hu J, Zhi M, Gao X, Hu P, Wu X, Lan P. Preoperative hypoalbuminemia is associated with an increased risk for intra-abdominal septic complications after primary anastomosis for Crohn's disease. Gastroenterol Rep (Oxf). 2017 Nov;5(4):298-304. doi: 10.1093/gastro/gox002. Epub 2017 Feb 20.

Ensrud KE, Blackwell TL, Ancoli-Israel S, Redline S, Cawthon PM, Paudel ML, Dam TT, Stone KL. Sleep disturbances and risk of frailty and mortality in older men. Sleep Med. 2012 Dec;13(10):1217-25. doi: 10.1016/j.sleep.2012.04.010. Epub 2012 Jun 15.

Su X, Wang DX. Improve postoperative sleep: what can we do? Curr Opin Anaesthesiol. 2018 Feb;31(1):83-88. doi: 10.1097/ACO.0000000000000538.

Fernandes NM, Nield LE, Popel N, Cantor WJ, Plante S, Goldman L, Prabhakar M, Manlhiot C, McCrindle BW, Miner SE. Symptoms of disturbed sleep predict major adverse cardiac events after percutaneous coronary intervention. Can J Cardiol. 2014 Jan;30(1):118-24. doi: 10.1016/j.cjca.2013.07.009. Epub 2013 Oct 16.

Armstrong KW, Bravo-Iniguez CE, Jacobson FL, Jaklitsch MT. Recent trends in surgical research of cancer treatment in the elderly, with a primary focus on lung cancer: Presentation at the 2015 annual meeting of SIOG. J Geriatr Oncol. 2016 Sep;7(5):368-74. doi: 10.1016/j.jgo.2016.07.004. Epub 2016 Jul 25.

Bolshinsky V, Li MH, Ismail H, Burbury K, Riedel B, Heriot A. Multimodal Prehabilitation Programs as a Bundle of Care in Gastrointestinal Cancer Surgery: A Systematic Review. Dis Colon Rectum. 2018 Jan;61(1):124-138. doi: 10.1097/DCR.0000000000000987.

Minnella EM, Awasthi R, Loiselle SE, Agnihotram RV, Ferri LE, Carli F. Effect of Exercise and Nutrition Prehabilitation on Functional Capacity in Esophagogastric Cancer Surgery: A Randomized Clinical Trial. JAMA Surg. 2018 Dec 1;153(12):1081-1089. doi: 10.1001/jamasurg.2018.1645.

Cho H, Yoshikawa T, Oba MS, Hirabayashi N, Shirai J, Aoyama T, Hayashi T, Yamada T, Oba K, Morita S, Sakamoto J, Tsuburaya A. Matched pair analysis to examine the effects of a planned preoperative exercise program in early gastric cancer patients with metabolic syndrome to reduce operative risk: the Adjuvant Exercise for General Elective Surgery (AEGES) study group. Ann Surg Oncol. 2014 Jun;21(6):2044-50. doi: 10.1245/s10434-013-3394-7. Epub 2014 Mar 27.

Soares SM, Nucci LB, da Silva MM, Campacci TC. Pulmonary function and physical performance outcomes with preoperative physical therapy in upper abdominal surgery: a randomized controlled trial. Clin Rehabil. 2013 Jul;27(7):616-27. doi: 10.1177/0269215512471063. Epub 2013 Feb 12.

Barakat HM, Shahin Y, Khan JA, McCollum PT, Chetter IC. Preoperative Supervised Exercise Improves Outcomes After Elective Abdominal Aortic Aneurysm Repair: A Randomized Controlled Trial. Ann Surg. 2016 Jul;264(1):47-53. doi: 10.1097/SLA.0000000000001609.

Barberan-Garcia A, Ubre M, Roca J, Lacy AM, Burgos F, Risco R, Momblan D, Balust J, Blanco I, Martinez-Palli G. Personalised Prehabilitation in High-risk Patients Undergoing Elective Major Abdominal Surgery: A Randomized Blinded Controlled Trial. Ann Surg. 2018 Jan;267(1):50-56. doi: 10.1097/SLA.0000000000002293.

Luther A, Gabriel J, Watson RP, Francis NK. The Impact of Total Body Prehabilitation on Post-Operative Outcomes After Major Abdominal Surgery: A Systematic Review. World J Surg. 2018 Sep;42(9):2781-2791. doi: 10.1007/s00268-018-4569-y.

Thomas G, Tahir MR, Bongers BC, Kallen VL, Slooter GD, van Meeteren NL. Prehabilitation before major intra-abdominal cancer surgery: A systematic review of randomised controlled trials. Eur J Anaesthesiol. 2019 Dec;36(12):933-945. doi: 10.1097/EJA.0000000000001030.

Kristjansson SR, Nesbakken A, Jordhoy MS, Skovlund E, Audisio RA, Johannessen HO, Bakka A, Wyller TB. Comprehensive geriatric assessment can predict complications in elderly patients after elective surgery for colorectal cancer: a prospective observational cohort study. Crit Rev Oncol Hematol. 2010 Dec;76(3):208-17. doi: 10.1016/j.critrevonc.2009.11.002. Epub 2009 Dec 14.

Tan KY, Kawamura YJ, Tokomitsu A, Tang T. Assessment for frailty is useful for predicting morbidity in elderly patients undergoing colorectal cancer resection whose comorbidities are already optimized. Am J Surg. 2012 Aug;204(2):139-43. doi: 10.1016/j.amjsurg.2011.08.012. Epub 2011 Dec 16.

Lu J, Cao LL, Zheng CH, Li P, Xie JW, Wang JB, Lin JX, Chen QY, Lin M, Tu RH, Huang CM. The Preoperative Frailty Versus Inflammation-Based Prognostic Score: Which is Better as an Objective Predictor for Gastric Cancer Patients 80 Years and Older? Ann Surg Oncol. 2017 Mar;24(3):754-762. doi: 10.1245/s10434-016-5656-7. Epub 2016 Nov 2.

Clavien PA, Barkun J, de Oliveira ML, Vauthey JN, Dindo D, Schulick RD, de Santibanes E, Pekolj J, Slankamenac K, Bassi C, Graf R, Vonlanthen R, Padbury R, Cameron JL, Makuuchi M. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg. 2009 Aug;250(2):187-96. doi: 10.1097/SLA.0b013e3181b13ca2.