The effects of resistance exercise on body composition and physical function in prostate cancer patients undergoing androgen deprivation therapy: an update systematic review and meta-analysis

Abstract Objective The aim of the meta-analysis was to explore effects of resistance exercise (RE) on body composition and physical function in patients with prostate cancer (PCa). Data sources We searched the electronic databases of Pubmed, Embase, Cochrane, and web of science. Published studies have been collected from these databases. Search terms include resistance training, strength training, RE, androgen suppression therapy, androgen deprivation therapy and PCa, with a deadline of 31 March 2022. Main results These studies showed significant improvements of body composition(Lean body mass MD: 1.12 95% CI [0.48, 1.76], p < 0.01; Body fat rate MD: –1.12 95% CI [–1.99,–0.24], p < 0.05; Appendicular skeletal mass MD: 0.74 95% CI [0.45, 1.03], p < 0.01) and physical function (leg press MD: 77.95 95% CI [38.90, 117.00], p < 0.01; stair climb MD:–0.30 95% CI [–0.49, –0.12], p < 0.01). In addition, the improvement of Body fat mass (MD: –0.21 95% CI [–0.79, 0.37], p > 0.05), 400 m walk (MD: –21.74 95% CI [–45.53, 2.05], p > 0.05) and times up and go (MD: –0.50 95% CI [–1.03, 0.03], p > 0.05) were not obvious. Subgroup analyses showed that RE for ≥ 6 months (compared with RE intervention for < 6 months) and starting exercise immediately after androgen deprivation therapy (ADT) (compared with delayed exercise after ADT) resulted in more significant improvements in body composition. Furthermore, the results showed that the exercise intensity of 8–12 RM significantly improved body composition. Conclusions RE seems to be a promising approach in order to improve body composition and physical function in PCa patients to offset their treatment-related side effects. RE should be used as a means of rehabilitation and care for PCa. Starting exercise immediately after ADT and extending exercise time while choosing the right intensity can better improve the patients’ body composition and function. Registration number INPLASY202280019


Introduction
Prostate cancer (PCa) is the second most common malignancy in males after lung cancer, accounting for 21% of new cancer cases in the world [1].The GLOBOCAN estimated that there will be almost 1.3 million new cases of PCa and 359,000 associated deaths worldwide in 2018 [2], which are higher than the estimates for 2012 (1.1 million new cases and 307,500 deaths) [3] and for 2008 (899,000 new cases and 258,000 deaths) [4]. Thus, PCa has become a hazard to the health of the elderly, as well as affecting the elderly life expectancy of an important factor.
ADT is widely used in the treatment of PCa to improve survival in the early stages of the disease and to control the disease in more severe cases [5,6]. ADT is achieved by surgical castration or, more commonly, by the administration of luteinizing hormone releasing hormone agonists or antiandrogen drugs that block androgen receptors, or both [6]. However, ADT is associated with a series of adverse reactions. Studies have shown that a rapid change in body composition occurs 1 year after ADT, with a 7%-10% increase in fat mass (FM) and a 2%-4% decrease in lean body mass (LBM) [7], and these effects persist for two years after cessation [8]. Patients have decreased muscle strength and bone mineral density (BMD) and increased risk of type 2 diabetes [9]. These side effects are clinically important because they may impair physical function and reduce independence and quality of life [10].
Some results suggest that physical exercise has a beneficial effect on these treatment-related toxics in men currently undergoing androgen suppression, thereby improving overall physical function and quality of life [11,12]. Strength training is an effective treatment that can improve insulin sensitivity [13], prevent sarcopenia [14], and increase muscle strength, and physical performance [15]. The health-related benefits of strength training in patients with PCa treated with ADT prevent functional decline, their risk of treatmentrelated co-morbidity and vulnerability, dependence and long-term care [16,17]. Strength training improves aerobic fitness and reduces FM percentage in this population after six months of training [18,19]. Thorsen et al. [20] developed a strength training program three times a week, supervised by a qualified instructor. In each session, they performed one to three sets of 6-10 repetitions (RM). The authors note that this high-load training may represent a breakthrough in scientific knowledge about the type of training best suited to ADT populations. A recent systematic review by Stene et al. [21] showed that strength training significantly improved patients' quality of life statistically compared with aerobic training, as measured by PORPUS (patient-oriented Prostate Utility Scale), and was greater than aerobic exercise. Winters-Stone et al. [22] showed that resistance exercise (RE; chest compressions and leg compressions) increased muscle strength, improved physical function, and reduced disability in ADT PCa survivors compared with a placebo group that underwent stretching exercise one year after intervention [23].
Several studies have shown the effects of RE on body composition and body function. Jacqueline K et al. [24] reported after RE intervention, the LBM, Appendicular skeletal mass (AKM), and body Fat rate (BFR) received significant improvements in body composition, however, Nilsen et al. [25] reported that RE will only improve LBM and AKM but not BFR. One study showed that stair climbing improved significantly after RE [25], but Jacqueline et al. [24] suggested that there was no significant improvement in this functional performance. Given this series of conflicting findings and the dramatic increase in high-quality randomized controlled trials in recent years, it is necessary to integrate these data. The purpose of this systematic review and meta-analysis was to comprehensively evaluate the effect of RE on body composition and function in PCa patients receiving ADT.
In addition, this study evaluated the effects of different intensity and duration of RE on LBM, Body FM (BFM) and BFR, as well as the effects of the time to start RE after ADT on the three indicators. This may provide reference and help for the formulation of resistance exercise plan.

Search strategy
We searched the electronic databases of Pubmed, Embase, Cochrane and web of science. Published studies have been collected from these databases. Search terms include resistance training, strength training, RE, androgen suppression therapy, androgen deprivation therapy, and PCa, with a deadline of 31 March 2022. The protocol for this systematic review was registered on INPLASY (ID ¼ INPLASY202280019) and is available in full on the implasy.com (https://doi.org/10.37766/inplasy2022.8.0019).

Selection criteria
The inclusion criteria were based on the Population, Intervention, Comparison, Outcomes, and Study framework. First, all participants were adult men diagnosed with PCa, and were currently receiving ADT during the intervention, regardless of whether they had received chemotherapy, radiotherapy or other therapy. Second, the interventions included RE. Third, the report should describe at least one relevant outcome. Fourth, reports of RCTs and studies were considered appropriate if they were published in English. The exclusion criteria were: (1) studies that did not provide ADT to all patients and (2) studies that involved interventions that combined exercise and diet, nutrition, or other lifestyle.

Data extraction and quality assessment
Relevant data included study-related information (first author name, publication year, study location, participant characteristics, and details of the intervention), quality assessment information, sample size, and outcomes data. The outcomes of intragroup differences in the exercise and control groups were selected as priority data. Second, the outcomes at baseline and postintervention were selected in the exercise and control groups, and then calculated the intragroup differences using formulas. The data were presented by mean and standard deviation. If the standard deviation was not originally reported, it was calculated based on related data (e.g. quartiles and 95% confidence intervals, CIs) using the relevant formulas. The Cochrane risk of bias tool was used for the quality assessment, which assigns high, low, or unclear risks for selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias.

Data analysis
The statistical analyses were performed using RevMan software (version 5.3) and Stata software (version 12.0). Absolute net differences between the intervention and control groups were used to estimate merger effects. Outcomes were expressed as the weighted mean difference (MD) and its 95% CI. Random effect models were used given the heterogeneity of interventions.

Study selection and characteristics
The search of the four databases revealed 656 potentially relevant reports, although 253 duplicates were removed using EndNote software. After screening the titles and abstracts, an additional 388 reports were removed and 15 full-text reports were ultimately assessed for eligibility ( Figure 1).
The primary analysis included five randomized controlled trials involving 181 participants (mean age 64-72 years) with PCa, 86 in the experimental group and 95 in the control group. Studies were conducted in North America, Europe and Australia. Four of the studies were conducted under the supervision of a clinic or sports club, and one study was conducted under unsupervised conditions at home ( Table 1).
The exercise intervention in all five studies was RE at 3, 4, 6 and 12 months, respectively. In the control intervention group, stretching was used in two studies and usual care was used in the remaining three studies (Table 2).

Quality assessment and publication bias
Overall, there was a low risk of bias in included studies ( Figure 2). All reports clearly described the randomization of patients, and four of five (80%) studies reports allocation concealment. All studies were free of incomplete outcome and selective reporting. However, there was no study reported blinding of the participants and personnel to treatment allocation. In addition, blinded outcome assessment was reported in three of five studies (60%). The above high risk of bias can be acceptable because it is difficult to blind an exercise intervention. Moreover, due to the small number of included literatures, we did not conduct publication bias analysis.

Sensitivity analysis
The sensitivity analysis of all results was conducted by one-by-one elimination method. The results of LBM, BFM, AKM, Leg Press were stable, while the results of BFR were unstable, and more studies were needed to verify the stability of experimental results.

Physical function
Changes in leg press were assessed in three studies with 104 participants. Exercise intervention significantly increased leg press compared with control group (MD: 77.95, 95% CI: 38.90-117.00, p < 0.001; Figure 7(A)). Changes in 400 m walk were assessed in  two studies with 43 participants. Relative to the control group, the exercise intervention did not significantly reduce the time of 400 m walk (MD: -21.74, 95% CI: À 45.53 to 2.05, p > 0.05; Figure 7(B)). Changes in stair climb were assessed in three studies with 98 participants. Exercise intervention significantly decreased the time of stair climb compared with control group (MD: -0.30, 95% CI: À 0.49 to À 0.12, p < 0.01; Figure 7(C)). Changes in times up and go were assessed in two studies with 45 participants. Relative to the control group, the exercise intervention did not significantly reduce times up and go (MD: -0.50, 95% CI: À 1.03 to 0.03, p > 0.05; Figure 7(D)).

Discussion
This systematic review and meta-analysis evaluated data from recent RCTS to determine whether RE interventions affect the adverse effects of ADT on body composition and physical function in men with PCa. The results showed that RE had effects on LBM, BFR, AKM, leg pressure, and stair climbing, but had no significant effects on BFM, 400 m walk and Times up and go. RE was significantly more effective than other forms of exercise in improving ADT side effects, and Segal et al. [26,27] reported that although both the control and aerobic training groups showed a reduction in LBM over 24 weeks, RE successfully prevented this loss. This may be because RE activates the mTORC1 signaling pathway and upregulation of mTOR signaling pathway, which is responsible for the adaptation of skeletal muscle hypertrophy, improves LBM [28] A significant increase in LBM after RE, which is usually accompanied by a decrease in FM percentage and an increase in strength, but RE alone appears to have less effect on BFM. The improvement of BFM may require joint exercise to achieve significant improvement. Shao et al. [29] reported that RE alone is not the best exercise type to decrease BFM. Their subgroup analyses of this review showed that resistance combined with other exercises had a higher effect size on BFM.
Subgroup analysis showed that body composition was significantly affected by RE intensity, training duration, and duration of ADT. Low intensity in the RE (8-12 RM) has a great impact on body composition, at the same time considering the patients received ADT, physical function and sports ability is low and most for elderly patients with older age, lower strength RE seems to be a better choice, can make patients under the body within the scope of rehabilitation training. For the duration of RE, subgroup analysis showed that training for � 6 months had a greater impact on body composition than training for < 6 months, and the meta-analysis by Gao et al. [30] showed that RE for � 6 months had a greater impact on BMI. Therefore, prolonging the duration of exercise intervention can effectively improve the side effects caused by ADT, but the upper limit of the intervention time needs to be further studied in the future. For time to exercise after ADT, subgroup analysis showed that exercise immediately after ADT had a greater effect on body composition, although studies on exercise immediately after ADT are relatively few and the results may be volatile. But Taaffe et al. [31] reported important findings from a 1-year comparison of immediate (first 6 months) exercise with delayed (second 6 months) exercise in PCa patients starting ADT: Initiation of exercise at the onset of ADT, including impact loading, resistance, and aerobic training, largely preserves spinal BMD as well as whole-body LM, ASM, and muscle density. In the future, there will be more studies on the effect of exercise immediately after ADT on body composition, which can verify the stability of the results and serve as evidence to prove that exercise immediately after ADT has a greater impact on the improvement of body composition of patients.
ADT is associated with decreased function, impaired homeostasis, and decreased strength, affecting the risk of falls and activities of daily living (ADL). Therefore, maintaining basic physical functions is very important for PCa. Stair climbing ability and lower limb strength were closely related to patients' quality of daily life. The combined results showed that RE significantly improved stair climbing ability and LEG press. Nilsen et al. [25] reported that after 16 weeks of sitting machine RE, the patient's stair climbing ability significantly improved. Leg Press indicators reflect lower extremity muscle strength levels, and Jacqueline et al. [24] reported significant improvement in lower extremity strength after RE intervention in the exercise group. Increased muscle strength in the lower extremities implies an increased margin of safety before the disability threshold and may help reduce the risk of morbidity, such as the risk of falls and fractures [32,33] and mortality [34]. A reduced risk of death was also associated with performance on stair climbing tests [35]. Therefore, the improvement of Leg Press and STAIR Climb is of great significance in improving the adverse effects of ADT.
Notably, the combined results of the 400-m walk time test and the Times Up and GO test showed an improvement in RE, but not a significant one. For Times up and go, muscle weakness and reduced gait speed are strong predictors of developing functional disability, resulting in immobility [36,37] and limited ADL [38]. Some limitations in the ability to deal with ADL may also lead to higher mortality [39]. Times up and GO are usually used to evaluate the corresponding functional parameters in geriatric care as sensitive predictors of recurrent falls [40]. As an important parameter of physical function, times up and go is closely related to the daily life of ADT patients. Therefore, the improvement of times up and go is of great significance for the improvement of physical function of ADT patients. For 400-m walking capacity, aerobic walking capacity, as measured by 400-m walking, has been shown to be a strong predictor of mortality, cardiovascular disease, and mobility limitation in older adults. The combined results of this study were not significant, which may be caused by the small combined sample size. The exercise test results of Segal et al. [19] showed that the aerobic capacity of PCa patients was improved after RE, and the improvement of aerobic capacity was of great significance for improving the 400 M walking ability of patients. It is also possible that RE combined with aerobic exercise would lead to a significant improvement in 400 M walking capacity. Cormie et al. [41] reported that 400m walking significantly improved after a 12-week combination of machine resistance and aerobic exercise, but aerobic exercise may be necessary to improve the functional performance of PCa patients in ADT. Therefore, in the future, more trials are needed to verify the stability of the results that RE has a significant effect on the improvement of 400 M walking ability, and can be compared with the combined results of combined exercise to develop a more effective RE program for patients with ADT.
At present, complete androgen suppression by ADT remains an effective first-line treatment for advanced PCa, but the clinical evidence increasingly does not consider testosterone as a linear mechanistic cause of PCa growth [42]. An androgen-androgen receptor (AR) saturation model has been proposed, suggesting that changes in serum testosterone concentration below the maximum androgen-AR binding point may substantially affect the progression of PCa. Conversely, once maximum androgen-AR binding is achieved, the presence of additional androgens has little further effect [43]. Testosterone plays an important role in maintaining male sexual function and in regulating BMD, muscle mass and function, FM, and cardiovascular health [44]. Abnormal testosterone levels can lead to benign prostate hyperplasia and even PCa. Clinical observations have shown that low serum testosterone concentration is associated with high-grade PCa. Elderly and obese people account for a large proportion of patients with BPH and PCa. Some studies have shown that PCa aggression is associated with age and Body Mass Index (BMI) increase [45]. The treatment of PCa in the elderly is a major public health concern, so better application of specific screening tools and comprehensive geriatric assessment is warranted [46]. Obesity is a risk factor for benign prostatic hyperplasia (BPH) and PCa. Obese BPH patients have the highest risk of LT, and the prevalence of LT increases with the increase of BMI [44]. M. F. Duarte et al. observed that changes in the hormonal axis co-exist with sex hormones and BMI in PCa patients, and obesity-related hormones and cytokines are responsible for volume expansion and hyperplasia of adipocytes and tumor cells [45]. After ADT treatment, the testosterone level of PCa patients decreased, but they still had a higher risk of castration-resistant PCa and other poor prognosis [42]. Norelia Torrealba et al. demonstrated the activation of TGF-b/PI3K/AKT/mTOR/NF-jB transduction pathway in PCa and proposed that TGFBR1 and PI3K can be used as useful biomarkers for early diagnosis and prognosis of biochemical recurrence after radical prostatectomy [47]. In addition, with the deepening of people's understanding of the negative health effects of testosterone deficiency or male hypogonadism and poor quality of life, the research paradigm of testosterone as a PCa inducer has changed. Ozan Efesoy et al. proved that after 1 year of treatment of hypogonadism patients with testosterone replacement therapy (TRT), there was no significant change in the prostate tissue of the patients, that is, TRT would not lead to the risk of PCa development [43]. Some people put forward a new view that bipolar androgen therapy can promote the differentiation of castration-resistant PCa cells through high levels of testosterone, restore their sensitivity to ADT, and effectively inhibit castration resistant PCa cells [42]. Therefore, it is necessary to increase the testosterone level after ADT to improve the prognosis of patients.
The results of this systematic review and meta-analysis show that RE is effective compared with other exercise methods. RE after ADT can improve the testosterone level, improve the body composition and function decline caused by testosterone deficiency, and improve the quality of life of patients after ADT. Selecting the RE intensity of 8-12 RM, appropriately extending the RE time and starting RE immediately after ADT have a very important impact on the improvement of body composition of patients. At the same time, RE can effectively improve physical function and help reduce the risk of falls and fractures in patients. Therefore, RE can improve the adverse effects of ADT treatment, and provide support and guarantee for the rehabilitation and quality of life of PCa patients after ADT treatment.

Conclusion
In the current meta-analysis, we were able to determine that RE is an effective way to improve physical function and body composition in men undergoing androgen deprivation therapy for PCa. ADT is the mainstream effective method for the treatment of PCa, while RE can offset the adverse side effects of ADT, and provide guarantee for the treatment of PCa patients and postoperative rehabilitation care. However, continued research to further determine the optimal regimen of RE for postoperative rehabilitation care of ADT is an important part of future research in this area.

Disclaimers
I statement that the views expressed in the submitted article is my own and not an official position of the institution or funder.

Disclosure statement
No potential conflict of interest was reported by the author(s).