Given the high prevalence of CRC worldwide, and the high relevance of cardiometabolic health on the risk of recurrence and mortality in CRC survivors, prehabilitation strategies are sought and proposed throughout the scientific literature. Exercise-based prehabilitation interventions have proven to induce significant gains in functional capacity which are related with cardiometabolic health and associated with a low risk of adverse events and post-surgery morbidity 39. Therefore, this study aimed to compare the efficacy of concurrent exercise (i.e., aerobic and strength exercise) during prehabilitation on functional capacity assessed through the 6MWT in comparison with standard cancer care strategies in CRC patients scheduled for surgery. Thus, this is the first systematic review that analyzes the effect of concurrent exercise prehabilitation intervention on functional capacity in CRC patients prior to surgery. In addition, the statistical approach employed, allows comparing the efficacy of concurrent exercise eliciting adaptations in the 6MWT and to establish some meta-regression models among age, body mass index, baseline walking ability and program duration. The search performed yielded 6 studies that met the inclusion criteria 26,27,29–31,45. Although from studies with some concern or high risk of bias, meta-analysis results revealed significant small effects (SCMD = 0.28 [0.03 to 0.54]) towards higher improvements after concurrent exercise interventions in comparison with traditional/standard cancer care strategies, such as ERAS. In addition, subgroup analysis and meta-regression models showed that age, and likely age-related variables, seems to be a key factor in prehabilitation effectiveness on functional capacity, since younger (i.e., < 70 years) CRC patients showed larger effects compared to their older counterparts (SCMD 0.48 [0.00 to 0.98] vs. 0.10 [0.08 to 0.11]).
Surgical complications, which are linked to increased hospital mortality and higher likelihood of remaining hospitalized 4 are associated with preoperative physical status 6,7. Therefore, strategies such as prehabilitation are implemented in order to improve physical capacity, since physical activity level before or after cancer diagnosis has been associated with lower risk of cancer-specific and all-cause mortality 11. Thus, prehabilitation programs usually include an exercise component 27–29,31,45,47,48. Particularly in CCR patients this is especially important, since surgical stress induces an increase in metabolic demand throughout the perioperative period, which is clinically manifested with a marked increase in oxygen consumption and cardiac output aimed at maintaining the systemic delivery of nutrients and oxygen-rich blood and mobilization of energy reserves to maintain energy processes, repair tissues and synthesize proteins involved in the immune response 49. Thus, an adequate preoperative physiological reserve is necessary to cope with surgically-induced detrimental responses, especially to manage the increase in oxygen consumption during the operation 49. Those patients with a low preoperative cardiorespiratory status are not able to perform and adequated management of metabolic demands enhancements generated by surgery, which in turn makes them more susceptible to perioperative complications. However, it is well-known that regular exercise improves the cardiometabolic status. Consequently, it is necessary to implement functional capacity assessments in order to analyze the effectiveness of prehabilitation interventions and to predict surgical outcomes. All studies included in this systematic review and meta-analysis used the 6MWT to assess functional capacity, since it has been found to be a valid test to measure physical capacity in cancer patients 24, and it is well-correlated with VO2peak. So, the larger walking distance covered by patients waiting for surgery the better postoperative recovery and the lower morbidity rate 21.
Regarding the results of this systematic review and meta-analysis, significant improvements after exercise-based prehabilitation program on functional capacity were observed in those studies including CRC patients younger than 70 years compared to CRC patients older than 70 years (Fig. 2, < 70 years: SCMD 0.48 [0.00 to 0.98]; >70 years: SCMD 0.10 [0.08 to 0.11]).). Interestingly, although significant differences were found in CRC patients older than 70 years, SCMD revealed a trivial effect on this variable. To our knowledge, no study has previously analyzed the association between age and training-induced effects after exercise-based prehabilitation in CRC patients. However, the tendency showed towards greater improvements in younger patients (i.e., < 70 years) compared to the older ones (Fig. 3). This finding might be explained due to the association between age and age-related comorbidities that may limit older patients to exercise either by walking, pedaling or strengthening, as well as frailty and sarcopenia. Indeed, it is widely known that frailty is prevalent in about 45% of over 65-years cancer patients. Moreover, frailty is also associated with sarcopenia and perceived fatigue 50, which is prevalent in CRC patients having elective surgery and is a predictive factor for mortality 51. Thus, older patients at higher risk of frailty and sarcopenia, may be also the ones at higher risk of postoperative complications since trivial effects have been shown after exercise-based prehabilitation and they are also the ones with the lower functional capacity. However, a worse baseline physical status has not been associated with higher improvements on functional capacity after prehabilitation. Although previous studies had found greater benefits in CRC patients with lower baseline functional capacity (i.e., less total distance covered in the pre-test), those studies were performed with patients younger than 70 years 25,29. Therefore, baseline physical status might be a predictive factor for improvements in 6MWT in younger patients but not in patients older than 70 years. In addition, the detrimental effect of aging on body composition could also explain the observed relationship between exercise-induced effects and age. Despite the fact that a previous review reported that exercise post-diagnosis in CRC survivors had the strongest association with a mortality index reduction in those patients with BMI < 25 11, our results showed no significant association between BMI and walking ability improvements, although a slight tendency toward greater adaptations was observed in those with higher BMI. This might be explained because cancer patients with a higher BMI generally have a greater amount of muscle mass, and thereafter, the best prognosis 52. However, these results should be considered with caution, since the vast majority of included studies did not report data regarding lean tissue mass, fat mass percentage or fat mass distribution 53. Hence, further research is needed to implement not only effective interventions (e.g., exercise mode and intensity, longer intervention duration, higher frequency) for older CCR patients (i.e., > 70 years) but also more precise measurements.
Our analysis did not find a significant association between prehabilitation program duration and gains achieved. However, this might be due to the short and similar length of time between interventions (2–4 weeks). A previous meta-analysis about exercise interventions in CRC patients found no significant effects on cardiovascular fitness after interventions lasting < 12 weeks, but it did on those lasting 12 weeks or longer, which leads to think that the longer prehabilitation interventions the greater changes 39. However, prehabilitation duration is usually determined by time until surgery, limiting prehabilitation to a very short time frame, but sufficient to improve preoperative walking capacity 36. Nonetheless, it has been reported that prolonged treatment delay does not lead to lower overall or cancer-free survival in patients with primary CRC who underwent curative surgical treatment, which in turn supports the idea of adapting waiting times to implement effective preoperative programs 54. However, the lack of a positive correlation between a longer prehabilitation program and greater effects on functional capacity found in this study implies the need to modify other variables of the exercise program, such as intensity, selection of exercises or weekly training frequency. Regarding exercise selection, it has been proven that resistance training is the unique training mode that has the ability to improve not only functional capacity but also muscle mass and fat percentage and fat distribution in cancer patients undergoing neoadjuvant and adjuvant therapy 55. Hence, and given the fact that concurrent training is recommended during cancer care 35, its inclusion, in combination with aerobic exercise, seems to be essential in prehabilitation programs of CCR patients 26,28,29,31,56–61.
Consequently, the most important variable to manipulate during exercise prescription in cancer patients is intensity. Due to the lack of information regarding exercise intensity in the included studies, it has not been possible to establish a comparison between changes achieved in the 6MWT after exercise-based prehabilitation intervention and exercise intensity. However, previous research has established that moderate-to-vigorous intensity exercise interventions resulted in fitness level improvements in: VO2peak 62, muscle strength and endurance 62, functional capacity (including 6MWT) 63, as well as measures of immune and cognitive function, depression and anxiety. Although more research is needed, especially regarding resistance training, to determine the percentage of 1-RM or movement velocity (i.e., specific intensity), number of repetitions, total number of exercises or the optimal weekly training volume for a precise exercise prescription program both in prehabilitation and co-adjuvant treatment of cancer patients. However, increasing exercise intensity requires supervision by qualified health care providers. In fact, supervised exercise yielded superior benefits compared to unsupervised programs, and implies a significant decrease in adverse events prevalence.
The findings of this systematic review and meta-analysis need to be considered with some limitations. One of the main limitations is the small number of studies (k = 6) that met the eligibility criteria, and thereafter, that could be included in the meta-regression models (being an inferior number than that recommended by the Cochrane guidelines 42 to perform meta-regression models). In addition, there were few studies throughout scientific literature analyzing the effects of concurrent training during prehabilitation in CRC patients. Furthermore, interventions were heterogeneous, since some were described as multimodal prehabilitation while others only involved an exercise component. Despite all included studies in this review prescribed aerobic and resistance training, adherence and compliance or standard care practices varied between studies. Moreover, the exercise intervention was not reported in detail in all of them. Which in turn supposes that results may have been altered by many other factors, such as exercise intensity or load management strategies. Future research should further investigate the effects of different exercise intensities during prehabilitation in CRC patients. In addition, since age, BMI or baseline walking capacity might influence exercise adaptations, it is warren to analyze the relationship between patient biometric and clinical characteristics and performance achieved during prehabilitation, in order to fully understand the effects of concurrent exercise during the preoperative period and to deliver effective and individualized interventions.
In conclusion, although moderate intensity aerobic activities are the most popular mode of exercise during prehabilitation in cancer patients, the results of this systematic review and meta-analysis indicate that its combination with resistance exercise (i.e., concurrent exercise) is associated with greater improvements in functional capacity, assessed through the 6MWT, in CRC patients. Therefore, implementing concurrent exercise 3–4 times a week for 2–4 weeks before surgery is recommended to increase walking capacity in CRC patients, which is positively correlated with the cardiometabolic status and with a lower risk of post-operative complications. In addition, subgroup analysis has demonstrated that younger patients (i.e., < 70 years) showed greater changes in walking ability compared to their older counterparts. Meta-regression models showed that training-induced effects are no dependent on baseline 6MWT distance covered, duration of intervention or BMI. Thus, to fully understand the effects of concurrent exercise during the preoperative period, future research should involve individualized programs based on patients biometric and clinical characteristics.