Abstract
Purpose of Review
This review summarizes the effects of prehabilitative exercise interventions on the physical, psychosocial, and biological outcomes among patients with cancer. Current gaps and future directions in prehabilitative exercise research will be addressed.
Recent Findings
Prehabilitative exercise mitigates the detrimental impact of cancer surgery on physical fitness, noted by increases in maximal oxygen consumption and 6-min walk distance. Beneficial effects on psychosocial and biological outcomes remain inconclusive. Aerobic exercise interventions were often prescribed and included low-, moderate-, or high-intensity exercise. Resistance exercise interventions were often performed in conjunction with aerobic exercise.
Summary
Prehabilitative exercise elicits robust improvements in physical fitness; however, effect on psychosocial and biological outcomes remains inconclusive. Exercise prescription parameters varied greatly by frequency, intensity, time, and type across multiple cancer diagnoses. Future investigations are needed to systematically dose exercise for a wider variety of outcome measures, with an overall goal to set forth pre-operative exercise guidelines.
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Introduction
Exercise oncology research has expanded in recent years to include prehabilitative exercise focusing largely on improving physical fitness prior to surgery in patients with cancer [1,2,3, 4•]. Prehabilitative exercise historically has been employed in the orthopedic patient population to improve or maintain muscular strength, endurance, and range of motion prior to surgery [5]. More recently, prehabilitative exercise research for patients with cancer has utilized physical, nutritional, and psychological interventions [6•] or varying combinations of the three [7], in order to address physical function and quality of life declines often associated with cancer treatment.
Decreased physical function as a result from major surgery can vary in severity dependent upon the success of surgery, associated complications, or length of hospital stay [8]. Patients experience larger decreases in physical functioning if surgical complications arise or length of hospital stay increases [9]. Declines often include decreased VO2peak [10], lean body mass, muscle strength [11], and ability to perform activities of daily living [12]. Prehabilitative exercise-induced increases in aerobic capacity or muscular endurance and strength before surgery can result in a shorter hospital stay or fewer postoperative complications among patients with cancer [6•, 13]. For example, the rate of pneumonia, thromboembolism, and urinary tract infections are all reduced by improving mobility in the acute period following surgery [14]. Since physical measures such as baseline fitness level, body mass index, lean body mass, and body fat percentage are negatively affected throughout the course of cancer treatment and influence postoperative outcomes [15], prehabilitative exercise is a non-pharmacologic strategy that may positively impact postoperative outcomes through modulation of these physical measures.
With cancer treatment that includes but is not limited to chemotherapy, radiotherapy, hormone therapy, and tumor removal surgery, patients often report lower quality of life due to decreased independence, anxiety, fatigue, or other specific impairments [16]. Side effects of chemotherapy, preoperative stress, and the burden of a cancer diagnosis can profoundly affect psychological well-being [16, 17], and exercise interventions concurrent with cancer treatment or prior to surgery may potentially offset associated weakness, fatigue, and malaise [18]. In addition to physical and psychosocial benefits, prehabilitative exercise may also affect biological outcomes related to tumor biology, modulating biomarkers associated with tumor growth, immune function, or inflammation based on pre-clinical models [19]. Therefore, the purpose of this review is to summarize the effects of prehabilitative exercise interventions on the physical, psychosocial, and biological outcomes among patients with cancer (Fig. 1). The review will discuss current gaps in the prehabilitative exercise literature and future directions for relevant studies in patients diagnosed with cancer.
Prehabilitative exercise can potentially improve physical outcomes, psychosocial outcomes, and cancer-related biomarkers, creating a better foundation for success and recovery after surgery. *Effects of prehabilitative exercise alone or in combination with rehabilitation exercise on improvements in post-surgical outcomes or long-term survivorship remain inconclusive
Physical Outcomes (Table 1)
Declines in physical function observed in patients with cancer result in profound increases in mortality rates [44, 45•]. While physical outcomes include a variety of measures such as muscular strength, flexibility, and body composition, cardiorespiratory fitness is the most widely studied measure to predict mortality in cancer patients [46]. Cardiorespiratory fitness, often assessed by maximal oxygen update (VO2peak) or 6-min walk test (6MWT) distance, is an important element to measure during cancer survivorship because reduced VO2peak or 6MWT distance strongly predicts an increase in cancer mortality [47, 48]. In fact, for each 1 metabolic equivalent (MET) increase in VO2peak, there is a 5% reduction in risk for cancer mortality (p = 0.01) as observed in a cohort of 447 men with all cancer types [49]. VO2peak is 17% lower prior to adjuvant therapy and 25% lower after adjuvant therapy in patients with cancer than age-matched individuals without a cancer history [50]. Therefore, patients with cancer may be able to exploit the prehabilitative period with exercise to improve cardiorespiratory fitness as there is a waiting period of approximately 7 to 52 days (median 21 days) from time of diagnosis until date of surgery [51, 52].
Lung Cancer
Surgical resection is the most effective curative option in the treatment of lung cancer; however, patients with lung cancer often experience reduced cardiorespiratory fitness before lung resection, which is detrimental to overall survival rate [44]. The importance of cardiorespiratory fitness in this patient population is notable given that patients with lung cancer with high cardiorespiratory fitness levels (> 10 MET) at the time of diagnosis exhibit a longer survival time compared with those with low cardiorespiratory fitness (< 5 MET; 11.5 years vs 4.6 years, respectively) [44]. Table 2 lists examples of exercises by intensity or metabolic equivalent (MET) level.
It is evident that prehabilitative exercise incorporating aerobic training of moderate or high intensity improves cardiorespiratory fitness in lung cancer patients. Jones et al. (2007) reported that a preoperative exercise intervention on a cycle ergometer improved postoperative VO2peak (+16%) and 6MWT distance (+15%) in 25 patients with lung cancer [20•, 43]. This finding is further supported by a recent study conducted by Gravier et al. (2019) in patients with lung cancer (n = 50) awaiting resection surgery, showing that VO2peak significantly increased (+12%) in patients who performed aerobic + resistance training and inspiratory muscle training [35]. The authors found that patients who performed 15 sessions or greater of prehabilitative exercise had improved VO2peak compared with those who completed less than 15 sessions [35]. Lastly, Stefanelli et al. (2013) found a 19% increase in VO2peak using aerobic exercise in patients with lung cancer (n = 40). Duration of each session incorporated by Stefanelli et al. (2013) was 150 min longer than those executed by Jones et al. (2007) and Gravier et al. (2019); thus, this prescription may have resulted in greater improvements in VO2peak out of the three studies [10]. High-intensity aerobic exercise utilized by Jones et al. (2007) and Stefanelli et al. (2013) resulted in greater improvements in VO2peak than the moderate-intensity aerobic exercise used by Gravier et al. (2019). Therefore, duration and intensity of each training session may affect the amount of improvement seen in patients with lung cancer.
High-intensity interval training has recently gained notable attention in prehabilitative oncology care. In addition to the two aforementioned studies utilizing high-intensity training, Karenovics et al. (2017) reported a significant increase in VO2peak (+18%), among patients with lung cancer (n = 164) awaiting surgery who participated in an intervention comprised of sprint intervals on a cycle ergometer. VO2peak significantly declined (− 6%) in the usual care group during the preoperative waiting period [53•]. At the 1-year follow-up, however, both groups experienced similar reductions in VO2peak (−12%) compared with the preoperative VO2peak [23], which indicates that the benefits of the exercise intervention may not persist long-term. In summary, studies to date have demonstrated the efficacy of exercise interventions to improve VO2peak prior to surgery for lung cancer, ranging from an increase in VO2peak of 12–19% in the exercise group and a decrease of 6–12% in the usual care group [10, 20•, 53•]. Cancer survivors experienced similar improvements in VO2peak (+ 13%) following a 3-month period of aerobic exercise; however, the rehabilitation period for cancer survivors offers more freedom for longer interventions (from months to years) than prehabilitative interventions, which are often only for a few weeks [54].
In relation to physical function, other measures studied include shuttle walk test [21], pulmonary function [10, 20•], and postoperative outcomes [21], but no significant differences were found. Barassi et al. (2018) was the only study to date to report a change in pulmonary function among patients with lung cancer (n = 32); however, this was in the absence of exercise. The authors compared yoga-style breathing and deep breathing in the lung cancer population and found significant improvement in FVC (12%), FEV1 (18%), peak expiratory flow (14%), and peak inspiratory flow (10%) in the yoga breathing group [27]. Overall, prehabilitative exercise appears to mitigate the detrimental impact of surgery, particularly noted by an increase in cardiorespiratory fitness in patients with lung cancer. Both high- and moderate-intensity aerobic exercise improve cardiorespiratory fitness for this cancer type.
Colorectal Cancer
Although colorectal cancer is commonly treated by surgical removal of the tumor, patients who undergo surgery often present with low VO2peak (range, 16.7–18.6 mL/kg/min), and patients with higher VO2peak experience a lower risk [odd ratio 0.76 (0.67–0.85); P 0.0001] of postsurgical complications [55]. Recent clinical trials among patients with colorectal cancer have demonstrated the benefits of prehabilitative exercise on cardiorespiratory fitness outcomes such as VO2peak and 6MWT distance, often as a multi-modal prehabilitation program [3, 4•]. West et al. (2014) implemented a supervised aerobic interval training program in patients with rectal cancer (n = 39) and reported a significant improvement in VO2peak and lactate threshold (p < 0.001) [56]. This study was supported by Li et al. (2013) which utilized an exercise intervention comprising of aerobic exercise and resistance band exercises combined with whey protein supplementation and an anxiety reduction program among patients with colorectal cancer (n = 87) [3]. Following the intervention, 6MWT distance significantly increased (+ 10%) in the exercise group [3]. Importantly, 81% (34 out of 42) of the prehabilitated patients returned to their baseline 6MWT distance 8 weeks post-surgery after an immediate post-surgical decline, compared with 40% (18 of 45) from the control group (p = 0.01).
Gillis et al. (2014) directly compared differences in 6MWT distance between patients in a prehabilitative setting or rehabilitative setting, participating in a home-based aerobic and resistance exercise program combined with whey protein supplementation and an anxiety reduction program among patients with colorectal cancer (n = 77). The prehabilitative group received the intervention for 4 weeks prior to surgery, and both groups received the intervention for 8 weeks following surgery. The 6MWT distance was significantly higher in the prehabilitation group (+ 6%) before surgery as well as 8 weeks after surgery (+ 5%) when compared with baseline levels, whereas the rehabilitation group deteriorated 3% before surgery and 5% 8 weeks after surgery [4•]. This finding was supported by a supervised multi-modal intervention (exercise, nutrition, and anxiety coping) study conducted by Minnella et al. (2017) which implemented a combined moderate-intensity aerobic and resistance training program defined by the Borg scale in patients with colorectal cancer (n = 185). The prehabilitative group participated in a 4-week intervention prior to surgery and continued the intervention for 8 weeks following surgery, while the rehabilitative group only received the intervention for 8 weeks post-surgery. The 6MWT distance was higher in the prehabilitative group immediately before surgery (+ 7% vs − 1%), and at 4 weeks (− 3% vs − 17%), and 8 weeks following surgery (+ 4% vs − 2%) compared with baseline and the rehabilitation group [24•]. Chen et al. (2016) also reported a beneficial effect on the 6MWT distance with a combined aerobic and resistance training in patients with colorectal cancer (n = 116) [57]. In contrast, five studies reported no change in the 6MWT [2, 28] distance or VO2peak [26, 32, 33] with a combined aerobic and resistive training program. Within these studies that found no change, one included a high-intensity interval training intervention with an intensity of 100–120% maximum cardiopulmonary exercise test (CPET) wattage that found no significant changes in VO2peak [33]. Lastly, aerobic exercise and body weight exercise sessions found a trend towards improved VO2peak despite a low frequency and study duration, yet this was not significant [32].
Regarding lesser studied outcome measures, Dronkers et al. (2010) was the only study assessing changes in physical function measured by timed up and go in older (> 60 years old) patients (n = 42) undergoing elective abdominal oncological surgery. The timed up and go test is designed to assess mobility of a participant by measuring total time (seconds) taken from standing up from the chair, walk 3 m forward, walk back to the chair, and sit down. The intervention was comprised of aerobic exercise and resistance exercise; however, no significant change was reported [1].
Only one study thus far has examined changes in body composition in this patient population. Gillis et al. (2019) with the same intervention and design as we previously described by Gillis et al. (2014) reported a significant increase in lean body mass (p < 0.001) and a decrease in fat mass (p < 0.001) at 4- and 8-week post-surgery in an intervention utilizing both prehabilitative and continued rehabilitative exercise among 139 patients after surgery [34]. In summary, exercise interventions effectively improve VO2peak and 6MWT distance among patients with colorectal cancer; however, the impact on functional measures and body composition is lacking conclusive evidence.
Esophageal and Gastric Cancer
Among patients diagnosed with esophageal and gastric cancers, declines in cardiorespiratory fitness may translate to poorer survival [8]. VO2peak < 13.9 ml/kg/min is associated with reduced 1 year survival in the upper gastrointestinal cancer, and furthermore, VO2peak < 12 ml/kg/min is associated with increased postoperative complications in lower gastrointestinal cancer compared with those with a VO2peak > 12 ml/kg/min [58]. Thus, improving cardiorespiratory fitness is a critical outcome in these patients in the preoperative phase. Currently, three randomized controlled trials have utilized prehabilitative exercise in patients with esophageal and gastric cancer, but all three utilized different methodology to assess cardiorespiratory fitness [18, 29, 31]. Minnella et al. (2018) implemented a home-based aerobic exercise intervention and resistance training in patients with esophagogastric cancer (n = 68). The intervention was complimented with daily whey protein supplementation. Following the intervention, 6MWT distance was greater in the prehabilitative group (+ 10%) before surgery compared with the control group (+2%) [59]. Notably, the positive effect of prehabilitative exercise on the 6MWT distance was maintained immediately after surgery in the prehabilitative group, while the control group experienced further deterioration in the 6MWT distance (− 23%). While these changes in physical function are robust, the authors did not note any changes in rate of complications, length of hospital stay, emergency department visits, or readmission rates. Christensen et al. (2018) reported the effect of a high-intensity aerobic exercise program in patients with gastro-esophageal junction cancer (n = 62), though they did not specify the exact numerical intensity. The intervention found improvements in peak power and VO2peak (+ 8% and + 6%, respectively) [18]. Valkenet et al. (2018) in patients with esophageal cancer (n = 270) utilized an inspiratory muscle training intervention and found significant improvements in inspiratory muscle strength (+ 17%) [31]. These results are promising, as all studies in patients with this cancer type demonstrated improvements in these outcome measures utilizing either a multimodal program, high-intensity aerobic training, or breathing training.
Prostate Cancer
Decreases in cardiorespiratory fitness and lean body mass are associated with androgen deprivation therapy use and longer hospital stays following prostatectomy, and exercise can improve these physical outcomes [60]. Currently, two studies have been conducted in patients with prostate cancer, examining walking ability and body composition. Santa Mina et al. (2018) reported an improvement in the 6MWT distance (p = 0.006) and decreased body fat percentage (p = 0.001) at 4 weeks postoperatively among patients with prostate cancer (n = 86); this difference was only significant for decreased body fat percentage preoperatively. The authors utilized an aerobic and resistive exercise program combined with pelvic floor exercises [30]. Singh et al. (2016) also used a combined aerobic and resistive exercise program among patients with prostate cancer (n = 16) and found significant improvements in multiple physical tests, including the 6-m fast walk (− 7%), 400-m walk test (− 5%), the repeated chair rise test (− 7%), and 1 repetition maximum muscle strength (+ 8% seated row; + 24% leg press) [11]. However, Singh et al. (2016) found no differences in any body composition measure throughout the intervention. Overall, among patients with prostate cancer, combined aerobic and resistance exercise improves 6MWT distance, muscle strength, and a variety of physical function tests, yet the effects on body composition remain inconclusive.
Bladder Cancer
Patients undergoing radial cystectomy for bladder cancer often experience debilitating side effects, functional decline, longer hospital stays, and increased complication rates from surgery at a higher rate than patients undergoing surgeries for other cancers [61]; thus, interventions to preserve physical function during cancer treatment are critical. Two studies have examined prehabilitative exercise and physical function changes prior to radical cystectomy [13, 22, 26]. Jensen et al. (2016) used a home-based aerobic step-trainer program with six strength and endurance exercises among 107 patients, and found a significant improvement in leg extensor power (+ 18%) assessed by leg extensor power rig at the time of surgery compared to baseline [22]. This was supported by Banerjee et al. (2018) which reported an increase in power output (+ 13%) from the CPET along with improvements in ventilatory efficiency (+12%) and O2 pulse (+12%) after aerobic interval training among 60 patients [26]. This was consistent with the findings from studies of other cancer types in that changes in VO2peak may take a longer adaptation period of 6 weeks or greater [32, 33, 62].
Minnella et al. (2019) found improvements in the 6MWT distance after a multimodal aerobic exercise, nutrition, and anxiety reduction program among 70 patients. However, the authors also included surgical outcomes as secondary measures and found no change in postoperative complications, readmission rates, length of hospital stay, or emergency department visits after discharge in either group. Overall, for patients undergoing radical cystectomy, muscle-specific outcomes, CPET values, and cardiorespiratory fitness measures all showed improvement following these exercise programs; however, potential improvements of exercise on surgical outcomes have yet to be supported.
Pancreatic Cancer
Patients with pancreatic cancer demonstrate impaired cardiorespiratory fitness and maximal isometric muscle contraction following resection compared with the matched healthy population [63]. Interestingly, one previous study demonstrated that patients who engaged in regular exercise a year before diagnosis experienced significantly increased VO2peak and maximum isometric contraction of the knee extensors 12 weeks after surgery [63]. Thus, it is plausible that exercise in the preoperative period may be an efficient strategy to improve physical fitness. Currently, one study examined prehabilitative exercise in patients with resectable pancreatic cancer [25], and one study examined patients with hepato-pancreato-biliary cancer [37]. Ngo-Huang et al. (2017) utilized a combined aerobic and resistance exercise intervention in patients with pancreatic cancer (n = 20). The authors found a significant (p = 0.01) increase in patient reported MET-min/week from pre-treatment to preoperative visit. However, no significant changes were found in physical function outcome measures within or between groups. Nakajima et al. (2019) studied patients with hepato-pancreato-biliary cancer (n = 76), of which 72% had biliary tract cancer and 20% had pancreatic cancer, and utilized an aerobic exercise intervention combined with resistance exercises. The authors found improvements in 6MWT distance (5%), absolute fat mass (− 5%), and muscle/fat ratio (5%), but did not see improvements in lean mass preoperatively. In summary, a combined aerobic and resistance exercise program may improve physical fitness and body composition.
Overall, prehabilitative exercise can effectively improve physical function among patients diagnosed with lung [10, 20•, 35], colorectal [2, 4•, 34], esophagogastric [18, 29, 31], prostate [11, 30], bladder [13, 22, 26], and pancreatic [25, 37] cancers. However, optimal exercise prescription including frequency, intensity, time, and type as well as type of intervention setting (i.e., home-based or clinic-based) have not been established. Current evidence commonly targets VO2peak and 6MWT distance as physical fitness outcomes, while other measures such as frailty or gait speed should be assessed given their association with cancer morbidity [64, 65]. Future studies are warranted to identify the optimal prehabilitative exercise prescriptions to improve comprehensive physical function outcomes and to assess the short- and long-term benefits of the interventions on surgical outcomes and survival in patients including and beyond the aforementioned diagnoses.
Psychosocial Health Outcomes (Table 1)
Each cancer type presents unique symptoms that can have distinct effects on psychosocial health. Cancer diagnosis, treatment, and associated surgeries can also have a profound negative impact on a patient’s quality of life (QOL). For example, patients with prostate and bladder cancer often experience urinary incontinence or changes in the urinary stream following their surgical treatment [39]. Patients with colorectal and esophageal cancer experience declines in physical function with additional gastrointestinal symptoms, resulting in psychosocial burden throughout the course of treatment [66, 67]. Increased psychosocial burden can also arise in circumstances surrounding anticipation and results of surgery, imaging, or treatment outcomes [16]. Both aerobic and resistance exercise have been linked to the promotion of positive mood, increased sense of physical well-being, improved self-esteem, mood states, and QOL [68], and have been demonstrated to improve anxiety and depression among patients with cancer in rehabilitative settings [69]. However, the current literature demonstrates conflicting results on the effect of prehabilitative exercise on anxiety, depression, and QOL.
Lung Cancer
Patients with lung cancer may experience fatigue, dyspnea, and coughing, affecting their ability to perform daily activities resulting in decreased independence and decreased ability to perform societal roles, thereby negatively impacting psychosocial health [70]. Sebio Garcia et al. (2017) assessed QOL, before and following an exercise intervention among 40 patients, using the Short Form Health Survey (SF-36), which captures role limitations, vitality, emotional well-being, and social functioning. The intervention included an aerobic and resistance exercise program using interval aerobic training on a cycle ergometer, followed by resistance band exercises among 40 patients with lung cancer. Post-intervention, improvements (45%) in the physical summary component of the SF-36 were observed [43]. However, Peddle et al. (2009) used aerobic exercise on a cycle ergometer prior to surgery which resulted in no change in QOL or fatigue from baseline to pre-surgery using the Trial Outcome Index (TOI) and the Lung Cancer Subscale (LCS) from the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire among nine patients with lung cancer [40]. Peddle et al. (2009) noted a significant decline in QOL and fatigue from the pre-surgery to post-surgery time points in both prehabilitative and control groups (− 5% change overall in the FACT-L), supporting the detrimental effect of lung resection surgery on psychosocial health. Overall, it is difficult to draw any specific conclusions as to the impact of prehabilitative exercise on psychosocial health among patients with lung cancer in part due to the small sample sizes, paucity of studies in this area, primary focus on QOL, and varied exercise prescription parameters.
Colorectal Cancer
Poor emotional health is common in patients with colorectal cancer, with the incidence of depression up to 57% and anxiety up to 47% [71]. Therefore, targeted interventions that improve psychosocial health are vital to consider during the prehabilitative period, yet few studies to date have addressed this focus area. Carli et al. (2010) compared an unsupervised, home-based cycling program and body weight training intervention to a self-paced walking plus breathing intervention among patients with colorectal cancer (n = 133). Both groups exhibited improvements in depression scores on the Hospital Anxiety and Depression Scale (HADS; 6% cycling/weight training group; 7% walking/breathing group). No change in anxiety in either group was noted [2]. Alejo et al. (2019) prescribed educational sessions of aerobic and resistance exercises among patients with colorectal cancer (n = 12) and found reduced scores for depression on the HADS (−19%) and the QOL domain “emotional function” (10%) on the Health Related Quality of Life (HRQoL) questionnaire [32]. Interestingly, the intervention by Carli et al. (2010) was performed daily for 52 days with a compliance rate of 16%, and the intervention by Alejo et al. (2019) was performed once a week for 6 weeks with a compliance rate of 100%, yet both studies found improvements in depression scores [2, 32]. In opposition, Li et al. (2013) conducted a multimodal aerobic and resistance exercise program previously described in a sample of 87 patients with colorectal cancer and did not find a significant change on the HRQoL as a secondary outcome measure [3]. Null findings were also the case in other studies on prehabilitative exercise in patients with colorectal cancer that implemented either a walking program [36] or a combined aerobic and resistance program [1, 4•]. In sum, the inconclusive findings and limited number of studies in this population can only provide modest evidence that prehabilitative exercise improves psychosocial health among patients with colorectal cancer.
Esophageal and Gastric Cancer
Patients diagnosed with esophageal or gastric cancer may experience a multitude of symptoms including difficulty swallowing, coughing or hoarseness, vomiting, and indigestion, which can lead to pain, fatigue, weight loss, and difficulty with socializing over meals [72], ultimately resulting in compromised psychosocial health [73]. Christensen et al. (2018) studied the effect of an aerobic and resistance exercise program, which included supervised exercise on a cycle ergometer followed by eight resistance exercises in patients with gastro-esophageal junction adenocarcinoma (n = 62). The exercise group experienced significantly greater improvements (12.6-point mean increase; baseline values were not reported) in the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) as a secondary outcome measure at the time of surgery [18]. Valkenet et al. (2018) employed an unsupervised inspiratory muscle training intervention using a tapered flow resistive inspiratory loading device in patients with esophageal cancer (n = 270). No change in fatigue (using the Multidimensional Fatigue Inventory [MFI-20]) or QOL (using the EuroQol-5D [EQ-5D] and Short Form 12 [SF-12]) was observed as secondary outcome measures [31]. The intervention by Christensen et al. (2018) lasted up to 7–17 weeks longer, and also included aerobic and resistance exercise when compared with the inspiratory muscle training intervention by Valkenet et al. (2018), suggesting that type and duration of intervention impact exercise-induced benefits on psychosocial health. Ultimately, the impact of prehabilitative exercise on psychosocial health in patients with esophageal or gastric cancer is inconclusive, with only heterogenous studies to compare, and varied exercise prescription.
Prostate Cancer
Patients with prostate cancer often experience decreased QOL due to changes in urination or sexual function commonly associated with treatment [74]. Therefore, prehabilitative exercise studies have focused their interventions specifically on targeting symptomatic outcomes such as integration of pelvic floor exercises. Pelvic floor exercises with and without biofeedback produced mixed results on improvements in psychosocial health. Centemero et al. (2010) utilized a pelvic floor exercise intervention prior to surgery in patients with prostate cancer (n = 118). Post-intervention, significant improvements in the International Continence Society (ICS) Male Short Form, a QOL assessment more commonly used for benign prostate hyperplasia, was observed at 1 month (20% improvement over the control group) and 3 months (34% improvement over the control group) after surgery; baseline values were not reported [41•]. Sueppel et al. (2001) prescribed pelvic floor exercise combined with biofeedback prior to surgery among 16 patients and found an improvement in QOL (39%), using the American Urological Association Symptom Index for benign prostate hyperplasia, at 6 weeks postoperatively [38]. However, Sueppel et al. did not report if this improvement was statistically significant. Additional pelvic floor prehabilitation and prostate cancer studies did not find a significant change in QOL [39, 75]; this includes one study with a smaller sample size of 16 patients [75] and another study that employed an intervention lasting only 1 week [39].
Santa Mina et al. (2018) integrated a combined approach of both aerobic exercise and daily pelvic floor exercises and studied changes in anxiety and depression as secondary outcome measures in 86 patients. The authors found a significant reduction in anxiety as measured by the HADS in patients with prostate cancer immediately before surgery; HADS score was also significantly improved in the exercise group (1.59-point improvement compared with the control group) at 26 weeks following surgery [30].
On average, pelvic floor exercise programs were performed one to three times per day for one to 7 weeks prior to surgery; however, the studies that significantly improved psychosocial health included exercise performed for a longer duration (greater than 1 month) [30, 38, 41•] than studies with an intervention period less than 1 month [39]. Among this population, pelvic floor prehabilitative exercise interventions show promise in improving psychosocial health outcomes such as anxiety, depression, and QOL.
Bladder Cancer
Patients undergoing open, laparoscopic, or robotic-assisted radical cystectomy for bladder cancer experience complication rates as high as 59% with infection, cardiac, wound, or gastrointestinal complications appearing most commonly [61, 76], with notable side effects including changes in urinary or erectile function [61] that may impact psychosocial health. Despite this, investigations on the impact of prehabilitative exercise on psychosocial health among patients with bladder cancer are lacking. However, it is worth mentioning a study by Jensen et al. (2014) which examined the effect of prehabilitative exercise on disease-specific symptoms [42•] such as abdominal pain, flatulence, and constipation among 107 patients. Jensen et al. (2014) examined the effects of a home-based aerobic and resistance exercise intervention, which involved a step trainer and six strength and endurance exercises on QOL, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Core QOL questionnaire (QLQ-C30) [42•]. The intervention group experienced a significant decrease in single-item scales of abdominal flatulence and constipation (12% improvement), and a 10% improvement in dyspnea from baseline to 4 months post-surgery [42•]. The control group experienced a significant yet unexpected improvement in insomnia (14%) on the EORTC QLQ-C30 during the study period [42•]. This single study on prehabilitative exercise in patients with bladder cancer found changes in single-item scales on the EORTC QLQ-C30, but currently no other studies have addressed this cancer type and conclusions cannot be drawn.
In summary, the results of the aforementioned studies examining psychosocial outcomes were mixed, whereby some interventions improved psychosocial health [30, 32, 38, 41•, 42•, 43, 77] and others did not [1, 4•, 31, 36, 39]. This indicates the need for more comparative studies addressing the different types and volumes of exercise and perhaps the selection of qualitative measures used in these studies. Interventions ranged from 1 to 19 weeks and varied greatly by frequency, intensity, time, and type of exercise (Table 1). Controlled differences in duration, type, or intensity of interventions have not yet been explored in a single study. Though some qualitative measures used by aforementioned studies have been validated in their respective cancers (i.e., FACT-E, FACT-BL, and LCS), others are more related to general medicine and health (i.e., SF-36, HRQoL, HADS) and may not capture the nuances of psychosocial health specific to patients with cancer. When interpreting these data, it is important to consider baseline psychosocial health, as patients diagnosed with certain cancers may have a relatively high self-reported baseline compared with the general population (i.e., colorectal cancer), and therefore these patients may not see or experience significant change due to a ceiling effect [67]. Additional factors to consider are the individual patient’s physical limitations, mental outlook, motivation, and exercise preference during the course of the disease and treatment, which may affect how their psychosocial characteristics change with a prehabilitative intervention and subsequent follow-up assessments. Lastly, differing levels of motivation and human connection may contribute to changes in psychosocial health, especially when considering supervised vs. unsupervised exercise interventions. Overall, the benefit of prehabilitative exercise on psychosocial health immediately before surgery and in the months following surgery is inconclusive; however, no studies noted a decline in QOL in the intervention groups compared with the control groups.
Biological Outcomes (Table 3)
To date, few published studies have examined the effect of prehabilitative exercise on cancer-related biomarkers among patients with cancer, as work in this area remains bolstered by preclinical models. Cancer-related biomarkers such as the forkhead box P3 (FOXP3) gene [86], insulin receptor expression [87], interleukin-6, and tumor necrosis factor [88] have been linked to cancer pathogenesis via metabolic, inflammatory, and immune changes or dysregulations [89]. These biomarkers are often used to justify certain exercise interventions in humans [80•] as exercise has been shown to modulate systemic inflammation, upregulate immune pathways, or affect PI3K and other metabolic pathways in previous animal models [81,82,83]. Exercise initiated prior to cancer surgery may influence these biomarkers and subsequent tumor volumes [19], cellular proliferation [81, 83], systemic inflammation [19], and outcomes related to prognosis, survival, and mortality.
Clinical Trials
Presently, prehabilitative exercise studies among patients with cancer examined changes in Ki67 expression (breast cancer only) [80•], pro-inflammatory and immunological markers [78], tumor tissue and volume changes [56], and tumor gene expression [80•]. Ligibel et al. (2019) tested an aerobic and resistance training intervention consisting of supervised aerobic exercise, followed by strength training, on women diagnosed with breast cancer (n = 49). Additional exercise prescription consisted of home-based aerobic exercise to achieve a total of 220 min of exercise per week in a mean of 29.3 days prior to breast surgery. The primary outcome measure was Ki-67, while secondary outcome measures included metabolic, immune, and inflammatory biomarkers, tumor apoptosis, expression of insulin receptors, and tumor gene expression. The study demonstrated that the intervention, which increased exercise of the patients by 200 min per week from baseline, did not change Ki67 expression but significantly reduced leptin (− 12%) and upregulated cytokine–cytokine receptor interactions, NF-kB and chemokine signaling, and natural killer cell-mediated cell cytotoxicity [80•]. West et al. (2019) prescribed an aerobic interval training program on a cycle ergometer, administered to patients with rectal cancer (n = 35). The intervention led to significant increases in histological tumor regression postoperatively according to grade on magnetic resonance imaging (ymrTRG) compared with controls (p = 0.02) [56]. Lastly, Jones et al. (2009) reported a significant reduction in intracellular adhesion molecule (ICAM-1, 9.6% reduction) following aerobic exercise on a cycle ergometer in 20 patients with lung cancer (n = 20) [78].
Energetics may also play a role in tumor markers and pathogenesis, which was explored further by Demark-Wahnefried et al. (2017) in patients with prostate cancer (n = 40). The authors combined aerobic exercise with a nutritional intervention of 1250 kcal deficit per day and a target weight loss of 1 kg per week. Post-intervention, improvements were observed in testosterone (+15%), sex hormone-binding globulin (+25%), leptin (− 15%), Ki67 expression (+ 2.75%), upregulation in Cathepsin L (CTSL), glycogen synthase kinase 3 beta (GSK3B), mediator complex subunit 12 (MED12), and laminin subunit gamma 2 (LAMC2) genes in the prehabilitation group [79].
In summary, the limited number of studies that examined biological outcomes in patients with cancer provides promising insight regarding the benefits of exercise on cancer-related biomarkers, as well as a targeted energetics approach with exercise and caloric deficit. Additional studies are needed to examine the effect of specific exercise prescriptions on novel biomarkers that are specific to certain cancer types, and the subsequent impact on prognosis and recurrence.
Future Directions (Table 4)
Prehabilitative exercise recommendations for patients with cancer continue to evolve as new studies and trials explore novel outcomes or exercise interventions. Targeted or comparative exercise prescriptions, new or understudied outcome measures of interest, and challenges to prehabilitative exercise should be explored in this population to optimize participation and surgical outcomes. Prehabilitative exercise research is also scarce for other common cancers such as kidney, liver, lymph, blood, skin, head and neck, thyroid, leukemia, and lymphoma.
Studies thus far have prescribed prehabilitative exercise in the form of aerobic training [36], resistance training [4•], inspiratory muscle training [31], and/or pelvic floor exercise [39]. For aerobic exercise, high-intensity interval training [18], moderate-intensity steady-state training [42•], and low-intensity steady-state training [36] have been implemented in community and laboratory settings or in the form of home-based programs. All studies have either focused on one prehabilitative intervention in a single-group design [11, 20•] or a two-group design with a control group [10, 53•] or rehabilitation group [4•]. Direct comparisons of one type of intervention to another would be important to explore with the goal of determining the ideal prehabilitative exercise prescription in the cancer populations (i.e., comparing high-intensity training versus low-intensity training or aerobic exercises versus resistance exercise). Modifying and comparing the frequency, intensity, time, or type of intervention would offer greater insight in optimal exercise prescription in terms of total load or duration. For example, an intervention that incorporates 300 exercise min per week may be more efficacious than one that incorporates 150 exercise min per week; however, no studies have yet addressed this directly.
A wide range of physical outcome measures have been studied thus far in prehabilitative exercise studies in patients with cancer. VO2peak and 6MWT distance are the two most common outcomes for physical function [2, 3, 4•, 10, 20•, 23, 24•, 32, 33, 57, 90], but some studies have examined muscle strength [11], timed up and go [1], chair rise time [1, 11], and lung function [26, 27]. Muscular strength and body composition are hugely important given the treatment-related complications associated with sarcopenia, including increased incidence of chemotherapy-induced toxicity and poor survival [91]. Other clinically relevant physical function outcome measures such as short physical performance battery and gait speed are understudied, yet they are highly predictive of complications and morbidity in cancer patients [45•, 92].
Only three studies in the present review have studied the effect of prehabilitative exercise on surgical outcomes including length of hospital stay, complications, and readmission rates with no significant findings [13, 21, 29]. Due to large patient and hospital burden, surgical outcomes, length of stay, and complication rates require further study to determine optimal prehabilitative exercise guidelines. Prehabilitative exercise may favorably affect each of these variables and therefore implementation of individualized prescriptive exercise is a vital component of future investigations.
Studies measuring changes in psychosocial health following a prehabilitative exercise intervention largely utilize general questionnaires such as the HADS [2, 4•, 30] and the HRQoL questionnaire [32], but specific cancer side effects should also be addressed in order to quantify change with the patient’s entire presentation in mind. QOL studies of prostate and bladder cancer often employ questions related to incontinence, urgency, or pain during urination [41•], though studies of men with prostate cancer may also elect to use measures of QOL surrounding sexual function such as the EPIC-26 [93]. However, studies in this review only used outcome measures focused on urinary symptoms for prostate and bladder cancer [38, 41•], which may not capture the full scope of side effects in these cancer types. Psychosocial measures used in lung cancer focused on patient-reported physical function and fatigue [40, 43], but none examined dyspnea, wheezing, or coughing, all which are common symptoms in lung cancer patients and are directly tied in to patient well-being [70]. Finally, in regard to esophagogastric or colorectal cancer patients, an area for future studies to consider is bowel function and abdominal discomfort, which can change either positively or negatively with mobilization and exercise. Overall, examining cancer-specific psychosocial outcomes can help identify specific exercise prescriptions that will maximize benefits for patients and their most common and relevant side effects.
Lastly, given the paucity of research in prehabilitative exercise and cancer-related biomarkers, much remains to be explored in that realm. Not only do we require more research in the previously mentioned metabolic, inflammatory, immunologic, and tumor biomarkers, since they all play a critical role in cell proliferation and cancer pathogenesis, but we also require study into novel biomarkers such as microRNAs [94], cell-free DNA, circulating tumor DNA, and circulating tumor cells given these markers can characterize prognosis of both primary and metastatic cancers [95, 96]. These biomarkers are potentially useful targets for prehabilitative exercise in all cancer types.
The prehabilitative phase is a particularly complicated intervention period due to the timing in relation to when a patient is informed of a diagnosis and preparing for treatment strategies. Therefore, considerations to address compliance are necessary for future investigations. Patients may be more compliant with supervised programs compared with unsupervised programs, or in cases, with integrated social support [97]; however, no study has directly looked at factors affecting compliance to prehabilitative exercise programs. Distress from the diagnosis, fatigue from chemotherapy or radiation therapy, pre-surgical anxiety, socioeconomic status, prior activity level, or difficulty in navigating and interacting with the healthcare system, may contribute [98]. However, at this moment, no study to date has examined compliance to prehabilitation interventions in groups with different levels of social support. If a particular intervention has been shown to be particularly effective, the next step is modifying unique barriers to participation for improved outcomes.
Importantly, most studies in this review did not follow patients beyond 8 weeks post-surgery; therefore, sustained improvements induced by exercise are largely unknown. Sustained improvements are particularly important to study given that improved cardiorespiratory function is linked to decreases in all-cause mortality as seen in cancer survivors [99,100,101], though it is unclear if any patients sustained their exercise habits or functional gains in the months or years following these interventions. Overall, the future of research in prehabilitative exercise has considerable potential to expand to a wider range of cancer types, exercise interventions, outcome measures, and follow-up durations.
Ongoing Exercise Trials
A number of ongoing clinical trials show promise in expanding the literature in prehabilitative exercise and biological outcomes among patients with cancer. The exercise-induced changes in colorectal cancer tissues (EDICT) trial [102] seeks to examine the effect of a 2-week aerobic interval training intervention on insulin receptor signaling, DNA fragmentation, and insulin receptor gene expression in patients with colorectal cancer [102]. Among older adult patients with hematologic malignancies, an ongoing trial is examining the effects of a 4-month pre-transplant walking program performed 30 min two times per week combined with strengthening/balance retraining exercises for 30 min performed three times per week on cyclin-dependent kinase inhibitor 2A (p16) [103], which is essential for regulation of the cell cycle [104]. Lastly, an intervention is underway which is studying the effects of yoga practice three times per week for 6 weeks on pro-inflammatory biomarkers and natural killer cell and regulatory T cell levels among patients with prostate cancer prior to undergoing radical prostatectomy [105]. Based on the limited number of previous and ongoing trials in this area, there is immense opportunity and need to explore a variety of biomarkers and the different prehabilitative exercises that influence them among a broad spectrum of cancer types.
Preclinical Studies
Several preclinical studies have examined the effect of exercise on markers of tumor proliferation among rodents. However, only a few studies have involved pre-established tumors [83, 84], and no study to date included a surgical procedure to address the tumor(s). Gueritat et al. (2014) studied rats with pre-established prostate tumors who underwent treadmill running (22–25 m/min) for 40–60 min 5 days per week for 5 weeks. Post-exercise, Ki67 staining decreased in prostate tumor tissues (~ 75%) and increased enzymatic antioxidant defenses in the soleus muscle (approximately 20%) [83]. Similarly, Isanejad et al. (2016) examined rats with pre-established breast tumors performing treadmill running at 16–18 m/min for 10–14 min, 5 days per week for 5 weeks and found a decrease in tumor volume (~ 65%), tumor vascular endothelial growth factor level (~40%), and Ki67/CD31 protein expression (~ 50%) [84].
Studies by Jiang et al. (2009), Zhu et al. (2012), and Figueira et al. (2018) investigated healthy rats following injection of a carcinogen to examine the effects of physical activity on tumor growth [81, 82, 85]. Jiang et al. (2009) used a wheel running program with a pellet dispenser to enforce daily running for 40 days, combined with restricted feeding to restrict body weight gain, and found a significant reduction in cell proliferation associated proteins, though exact data was not reported [81]. Zhu et al. (2012) used a similar wheel running program to that of Jiang et al. for 40 days at high (3500 m per day) or low (1750 m per day) work load combined with restricted feeding and found reduced bioavailable insulin-like growth factor-1 (high 27%; low 25%), insulin (high 40%; low 24%), tumor necrosis factor (high 15%; low 14%), and leptin (high 48%; low 48%) in both groups of exercise rats following the intervention with no significant changes between groups [82]. Lastly, Figueira and colleagues (2018) implemented a supervised treadmill running program for 60 min per day, 5 days per week at 20 m per minute of running speed (approximately 70% of VO2max) for 35 weeks. Post-exercise, there was a decrease in immunopositive cells per μm2 of Ki67 (39% difference between exercised and control rats) and increased cell death per μm2 in established infiltrative lesions (50% difference between exercised and control rats) [85]. Of note, Zhu et al. (2012) and Jiang et al. (2009) incorporated intervention groups with a restricted feeding regime in combination with exercise [81, 82], and this nutritional component may account for a portion of the significant findings from these studies, especially in reduced cell proliferation and insulin-like growth factor-1 (IGF-1). Results from these preclinical studies are promising and highlight the work necessary to determine effects of aerobic or resistance exercise on pre-established tumors, with or without a restricted nutritional component.
Conclusions
A growing body of evidence has emerged in recent years highlighting the benefits of prehabilitative exercise for a multitude of cancer types. Cardiorespiratory fitness measures, in particular, show a robust and positive response to prehabilitative exercise with outcomes measured including VO2peak and 6MWT distance, with no reports of detrimental effects of prehabilitative exercise among patients diagnosed with lung, colorectal, or esophagogastric cancer when compared with control groups [3, 4•, 10, 11, 18, 20•, 23, 24•, 29, 30, 34, 37, 42•, 57, 90]. The preoperative waiting period, which in most cases is anywhere from 2 to 6 weeks, can therefore provide a window of opportunity for patients to improve cardiorespiratory fitness measures that often show a significant decline following cancer surgery [13, 34]. This decline from baseline in terms of cardiorespiratory fitness and body composition could be lessened with prehabilitative exercise and would be more effective in preventing overall decline than rehabilitation alone [34].
The effect of prehabilitative exercise on psychosocial health measures is inconclusive. Few studies reported a decrease in anxiety and depression [2, 32] and an improvement in symptoms specific to prostate cancer [38, 41•] and bladder cancer [42•] following the prehabilitative intervention, while other studies reported no significant change in QOL, anxiety, or depression [1, 36]. Different factors may account for this inconsistency such as varying baseline psychosocial health status, disease course, symptoms, treatment, individual coping strategies, resilience, amount of social support, and exercise prescription variations. Of importance, exercise did not decrease psychosocial health in any intervention groups studied (lung, prostate, colorectal, bladder, esophageal, or gastric cancers).
Lastly, prehabilitative exercise and cancer-related biomarkers are an up-and-coming area of research, with some preliminary knowledge emerging in patients with breast [80•], lung [78], prostate [79], and colorectal cancer [56]. Studies on animal models of breast and prostate cancer have explored exercise interventions after an injection of carcinogen, but most of the studies began the exercise intervention immediately, rather than after confirmed tumor establishment [81, 82, 85]. In these animal studies, the “prehabilitation window” is unclear given that no treatment or surgery was performed after the interventions. Nonetheless, this area presents an opportunity for further exploration given the potential impact exercise has on cancer recurrence [106•].
Regarding exercise prescription, most of the exercise interventions in the aforementioned studies were comprised of sessions of 30–60 min, 2–5 sessions per week, and incorporated both aerobic and resistance exercise [1, 3, 4•, 10, 11, 13, 18, 24•, 25, 28, 29, 32, 34, 35, 37, 42•, 57]. A multi-modal approach was occasionally used, as exercise prescriptions were supplemented by nutritional guidance and anxiety reduction techniques [3, 4•, 24•]. Compliance ranged from 16 to 100% but the vast majority reported rates > 70%, even for unsupervised home programs (Tables 2 and 3) [2, 3, 4•, 13, 24•, 28, 30, 34]. Supervised programs had a compliance range of 68.7 [18] to 100% [90], and unsupervised programs had a compliance range of 16 [2] to 98% [28].
Based on the current evidence, prehabilitative exercise can improve VO2peak and 6MWT distance; however, exercise has an inconclusive effect on other physical function measures, psychosocial health, and cancer-related biomarkers due to small sample size, few studies, and examination of only a handful of cancer types. Aerobic exercise prescription was most common in all cancer types, usually in conjunction with resistance exercise or a multi-modal program. Aerobic exercise programs were performed 15–30 min per session, with high-intensity interval interventions performed 3–4 days per week, and lower-intensity programs performed 3–7 days per week. Resistance training interventions utilizing weight machines or resistance bands were all performed in conjunction with aerobic exercise and similarly lasted 15–30 min for 2–3 days per week. Prehabilitative exercise has the potential to become a widely accessible intervention for cancer patients. In doing so, patients can be provided with exercise intervention before, during, and after cancer treatment to maximize individual wellness and projected outcomes.
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Lee, K., Zhou, J., Norris, M.K. et al. Prehabilitative Exercise for the Enhancement of Physical, Psychosocial, and Biological Outcomes Among Patients Diagnosed with Cancer. Curr Oncol Rep 22, 71 (2020). https://doi.org/10.1007/s11912-020-00932-9
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DOI: https://doi.org/10.1007/s11912-020-00932-9