The good, the bad, and the frail – the role of prehabilitation in frail patients undergoing cancer surgery

According to international guidelines and the current body of evidence,1-5 surgery with or without chemo-radiotherapy, is the primary curative approach for selected patients with cancer, providing significant long-term survival benefit. While surgery is a common approach and widely used treatment modality for cancer, it must be carefully weighed against the considerable risks of experiencing adverse events, including haemorrhage, wound infection, anastomotic leakage, pulmonary embolism, and other complications, contributing to delayed recovery.6 Postoperative complications are very common following cancer surgery (ranging from 20% to 80%), especially in cases of lung cancer,7 gastric cancer,8 oesophageal cancer,9 and colorectal cancer,10 significantly impacting hospital length of stay, quality of life, treatment costs and overall survival.11, 12 Therefore, reducing the incidence of postoperative complications in cancer patients has the potential to improve recovery time and quality of life outcomes, and also ensure improved return to intended adjuvant oncologic therapy (RIOT). Frailty is a multi-domain clinical syndrome characterized by a decline in homeostatic mechanisms resulting in increased vulnerability to adverse health outcomes from stressors.13, 14 Based on a systematic review aimed to establish the prevalence and outcomes of frailty and pre-frailty in older cancer patients, more than half of older cancer patients suffer from pre-frailty or frailty, and these patients are at increased risk of chemotherapy intolerance, postoperative complications, and mortality.15 Additionally, it was demonstrated that frailty independently predicts postoperative complications, delirium, reduced quality of life, longer length of hospital stay, mortality, and morbidity,16-19 as well as serving as an independent factor for not achieving RIOT.20 Studies reported that frailty is strongly associated with poor prognosis in patients with colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma undergoing surgery.21-23 Therefore, frail cancer patients are most susceptible to worse surgical outcomes. Traditionally, rehabilitation has been the cornerstone of patient recovery, with a primary focus on post-surgical care. However, as medical technology has advanced, physicians have recognized the need to optimize patients' health before surgery. A poor pre-surgical health status can prolong recovery, and significantly increase the risk of postoperative complications and mortality.24, 25 The evidence suggests that preoperative interventions, including medical, exercise, psychological, and nutritional support, may enhance the physical fitness of those with poor health, likely contributing to better postoperative outcomes.24 Rehabilitation aims to return patients to their preoperative baseline however frailty can impact how patients respond to rehabilitation. Compared to their fit counterparts, frail patients suffer a greater deterioration in function from similar stressors and may not return to baseline homeostasis.26 Consequently, their recovery process requires a greater investment of effort, time, and resources. Specifically, identifying preoperative modifiable risk factors that can be addressed through prehabilitation shows great promise in enhancing patient outcomes following cancer surgery.27 At an individual level, the Clinical Frailty Scale is the recommended frailty measure both nationally and internationally due to its feasibility of use and accuracy in predicting perioperative mortality and failure to discharge home.28, 29 However, validation of an electronic frailty index will enable wider preoperative cohort screening and intervention.30 Comprehensive geriatric assessment is an effective frailty intervention in older surgical patients and failure to address medical optimization may have contributed to lack of benefit in previous prehabilitation interventions.31, 32 Prehabilitation refers to a multidisciplinary intervention aimed at improving patients' preoperative physical, psychological, and/or nutritional statuses, to enhance their preoperative functional reserves.33 Evidence suggests that prehabilitation can improve the physical condition, including exercise capacity, of patients during the perioperative period,34, 35 and positively impact postoperative complications and functional recovery among frail older patients.36 Berkel et al.37 conducted a community-based randomized clinical trial to compare exercise prehabilitation with usual care in frail colorectal cancer patients, indicated that exercise prehabilitation has a significant effect in reducing postoperative complications in frail colorectal patients, and suggested that prehabilitation should be considered as usual care in frail cancer patients. Carli et al.38 investigated the impact of a prehabilitation program, in frail individuals undergoing colorectal cancer resection, in comparison to postoperative rehabilitation, but no significant difference was reported in 30-day overall and severe complications, as well as primary and total length of hospital stay. This could be explained by the benefit that preoperative and postoperative interventions have on frail patients, or the difference in the frequency and intensity of treatment between the two studies may contribute to the inconsistency in the results. Additionally, a systemic review published in 2023 investigated the effects of prehabilitation on frail patients undergoing colorectal cancer resection. Prehabilitation was effective in reducing severe (Clavien-Dindo Grade ≥ 3) postoperative complications (Odds ratio = 0.51; 95% CI = 0.34 to 0.78) and length of stay (Standardized mean difference = −0.34; 95% CI = −0.46 to −0.23).39 However, as this review included non-randomized studies (e.g., retrospective cohorts), caution should be taken when interpreting these results. Although evidence37, 38 is exploring the impact of prehabilitation and rehabilitation on postoperative outcomes in frail patients undergoing cancer surgery, the results are mixed. Moreover, there is only one clinical trials40 conducted in Australia, where factors such as geographical, social, and educational disparities may require a different approach to the delivery of preoperative and postoperative interventions. Frailty presents a significant and challenging burden to cancer patients, markedly slowing their postoperative recovery. Traditional postoperative rehabilitation offers limited benefits in addressing preoperative risk factors, including frailty. Given frailty is a dynamic, multidimensional risk state, there is growing evidence for potential risk modification or prevention with multicomponent interventions.41 Conducting preoperative frailty assessments and employing a multidisciplinary approach seems beneficial to frail patients undergoing cancer surgery. Multimodal preoperative interventions for frail patients could substantially reduce the incidence of postoperative complications and mortality rates. However, larger powered trials are needed to determine the definitive role of prehabilitation in patients undergoing cancer surgery. Identifying the optimal frailty screening tool (with appropriate sensitivity, specificity, and predictivity), prehabilitation intervention (including type, mode of delivery, and duration), and what patients would benefit from prehabilitation would support the current evidence and provide the best possible outcomes to patients undergoing cancer surgery. Zirong Bai: Conceptualization; methodology; project administration; writing – original draft; writing – review and editing. Michael Solomon: Conceptualization; methodology; supervision; writing – review and editing. Rihan Shahab: Conceptualization; supervision; writing – review and editing. Cherry Koh: Conceptualization; supervision; writing – review and editing. Daniel Steffens: Conceptualization; supervision; writing – review and editing. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians.