Introduction

During the last two decades, the perception of physical exercise interventions in cancer patients has gone through a significant change process. Therefore, the recommendation of regular physical activity is a rather new option for cancer patients [1, 2].

Especially in prostate cancer patients (PCaPs) receiving androgen deprivation therapy (ADT), the treatment side effects often have massive negative implications on the well-being and quality of life of the patients [3, 4]. Overcoming these side effects is of major interest for both the attending health care team and their patients. Many PCaPs are undergoing long-term ADT, and therefore, its side effects unfold over a long period of time [5].

Known ADT side effects including loss of muscle mass [6, 7] and strength [7], increased fat mass [6–8], alterations both in the lipolytic profile [9, 11] and the insulin metabolism [8, 10, 11], together with an increased arterial stiffness [10, 11] lead to an increased risk of developing type II diabetes [12] and an enhanced cardiovascular risk [11, 12]. A decrease in bone mineral density leads to osteoporosis and to fracture risk [7, 13], whereas the loss of muscular strength, physical performance, and sexual functioning has substantial effects on QoL and is often considered to be a considerable contributor in the development of mental disorders like anxiety or depression [14, 15].

Many of those side effects and especially the predictors of QoL are positively affected by actively participating in exercise programs [2–4, 11, 16–21]. The majority of the exercise intervention studies up to the present primarily focused on the question if exercise is a safe option with beneficial effects on PCaPs receiving ADT. Only a few studies focused on the specific effects of different types of exercise.

The aim of this systematic review was to determine of how resistance exercise (RE) specifically impacts PCaPs—referring primarily to the management of treatment-related side effects.

Methods

A systematic review of the existing scientific literature was performed including the following databases: PubMed, EMBASE, MEDLINE, SCOPUS, and Cochrane Library.

The search strategy included the terms and key words “resistance training,” “resistance exercise,” “strength training,” “prostate cancer,” “androgen deprivation therapy,” “androgen suppression therapy,” and their possible variations.

A total of 945 studies were found and screened for eligibility by title and abstract. Eight hundred ninety-three studies did not meet the criteria due to a lack in inclusion criteria [including insufficient representation of RE in the intervention branch, inapplicable type of cancer (non-PCa), unsuitable type of study (review, study protocol, conference abstracts, etc.), or being represented multiple times]. After this, 52 studies were selected for full-text analysis, of which 13 met the study inclusion criteria [22, 24–32, 34–36]. Of the full text publications analyzed, only six studies focused only on RE [22, 24–27, 30] and another seven included combined RE and other exercise modalities [28, 29, 31, 32, 34–36].

Of the reported six studies that provided adequate data to evaluate the effect of the RE intervention alone in PCaPs [22, 24–27, 30], Galvao et al. [22] and Hanson et al. [24] lacked of a control group and therefore are graded to be of evidence level IIb.

The four very high-quality randomized controlled trials (RCTs) with evidence level Ib, of Segal et al. [26, 27], Santa Mina [25], as well as of Cormie [30] remain in this field of expertise. Unfortunately, the latter have some weaknesses, e.g., they were either suffering from a high dropout rate [25] or a small sample size and therefore limited power [30]. In addition, Santa Mina et al. [25] had no inactive control group. These facts lead us to modify the inclusion criteria and to include both, papers of lesser quality [22, 24] and papers with RE combined with other exercise modalities [28, 29, 31, 32, 34–36]. Furthermore, the results of eight later additional publications [23, 33, 37–42]—all based on previously published studies [22, 25–27, 32, 36]—were included. An overview of the whole selection process is shown in Fig. 1.

Fig. 1
figure 1

Flowchart of the systematic literature research and the selection process. PCaPs prostate cancer patients, RE resistance exercise

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Furthermore, the methodological quality of the included articles was rated by using the validated Downs and Black [43] checklist. This checklist consists of 27 items which help to examine reporting, external validity, bias, confounding, and power [43].

Results

After the described selection process, 13 studies [22, 24–32, 34–36] were considered eligible for elucidating the effects of resistance exercise on PCaPs (Table 1). A total of 876 PCaPs were included in these exercise intervention studies, 441 assigned to RE intervention groups, and 435 assigned to various control groups (Fig. 2).

Table 1 Level of evidence, type of exercise, and risk of bias assessment total score
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Fig. 2
figure 2

Summary of the allocation of all included participants. PCaPs prostate cancer patients, RE resistance exercise, AE aerobic exercise

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A short summary of the main results is given subsequently, while the complete display of the characteristics and key findings of all the included studies and the additional articles are summarized in Tables 3 and 4.

Methodological quality

The detailed rating of the quality of included articles is presented in Table 2. The scores of the rated studies ranged from 23 to 30 of a maximum of 32 points. A weakness of all included studies is that the study subjects could not be blinded to the interventions (Table 2, item 14). Furthermore, in 7 of the 13 studies, no attempt was made to blind those measuring the main outcomes of the intervention (Table 2, item 15).

Table 2 Extended analyses from risk of bias assessment [4, 43]
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Furthermore, some potentially limiting factors concerning the test results were found in a number of studies [22, 28–30, 32]. Galvao et al. [32]—a multicenter study—performed the strength testing with the participants only in one study center (n = 57 of 100). Cormie et al. [30] comprised two potentially limiting factors. On the one hand, contrary to the rest of the included studies, they investigated the effect of RE on PCaPs with established metastases, a condition which was an exclusion criterion in the rest of the included papers. On the other hand, they only tested a very small group of 20 participants. Galvao et al. [22] as well as Bourke et al. [28, 29] assessed only the body mass index (BMI) and therefore are not able to provide qualitative information towards changes in muscle and fat mass [44].

Physical performance

Nine studies assessed cardiovascular fitness and endurance capacity [22, 25, 27–32, 34]. Galvao et al. [22], Santa Mina et al. [25], Segal et al. [27] and Cormie et al. [30] studied the effects of RE on cardiovascular performance, and four of them [22, 25, 27, 30] were able to show a significant increase in cardiorespiratory fitness at least at one time point.

Eleven studies assessed muscle strength [22, 24–28, 30–32, 34, 35]. Galvao et al. [22], Hanson et al. [24], Cormie et al. [30], as well as Segal et al. [26, 27] studied the isolated effects of RE on muscle strength and consistently found significant increases in muscle strength and muscular endurance capacity.

Assessment of functional performance by Galvao et al. [22, 32] as well as Hanson et al. [24] showed significant improvements in almost all functional tests after the exercise interventions (Table 3).

Table 3 Study characteristics and main outcomes of the 13 included studies
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Body composition

In most of the studies, a body composition assessment was performed [22, 24, 25, 27–35]. Such a specific assessment was conducted in seven studies [24, 25, 27, 30–32, 34], where positive effects of exercise on body composition—whether through RE only [24, 25, 27, 30], aerobic exercise (AE) only [25], or combined training [31, 32, 34]—have been shown (Table 3).

Fatigue and quality of life

Eleven studies [24–35] assessed fatigue, QoL, and mental health. Nine [24–32] assessed the development of fatigue either in a RE only [24, 26, 30], a combined RE + AE [28, 29, 31, 32] or a RE versus AE [25, 27] setting. All except Santa Mina et al. [25] and Cormie et al. [30] reported significant improvements in the exercise intervention branch (Table 3).

Cormie et al. [30] showed no effects of a RE intervention on QoL, fatigue, or psychological distress in PCaPs with metastatic bone disease, however, this study had a very small sample size resulting in low power [30].

Prostate-specific antigen

Eight studies [22, 26–29, 31, 32, 34] assessed prostate-specific antigen (PSA) levels either in a setting of RE only [22, 26], RE versus AE [27], or in combination with other exercise methods [28, 29, 31–33]. No one reported any changes in PSA levels (Tables 3 and 4).

Table 4 Results of the 8 Additional Articles
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Endocrine anabolic indicators

Six studies reported data of testosterone levels and resistance training interventions [22, 24, 26, 28, 32, 33]. In patients receiving ADT, RE only [22, 24, 26] or a combined RE program [28, 32, 33] had no impact on testosterone levels in any of the studies (Tables 3 and 4).

Mina et al. [41] found several significant changes in insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) in their additional article of Santa Mina et al. [25] (Table 4).

The effects of RE on human growth hormone (hGH) in PCaPs receiving ADT remain inconclusive [22, 23].

Blood lipids (total cholesterol, LDL and HDL cholesterol, triglycerides)

Cormie et al. [31], Galvao et al. [32, 33, 34], as well as Segal et al. [27] investigated the effects of combined resistance and endurance exercise on blood lipid levels. They showed both none [31, 32], beneficial [27, 34], and detrimental [27, 33] changes (Table 3).

Bone mineral density

Cormie et al. [31], Galvao et al. [22], and Winters-Stone et al. [36] investigated the effects of RE on BMD in PCaPs. Neither combined RE and AE [31], nor RE only [22], nor combined RE and impact training [36] lead to changes in bone mineral density (BMD). Only Winters-Stone et al. [36] reported a significantly better preserved BMD at one measurement site (L4) compared to a stretching exercise routine (Table 3).

Discussion

To our knowledge, this is the first systematic review about the influence of RE on prostate cancer. Previous reviews either focused on general exercise with PCaPs and not specifically on RE [4, 19], or—if RE was the only reviewed training method—the review was not limited to PCaPs [45].

Physical performance is the key outcome in training intervention studies and is a major contributor to health-related QoL in cancer patients [4, 46, 47]. AE is associated with cardiovascular improvements, while RE is associated primarily with an increase in strength and muscle mass in the healthy population. Almost half of the PCaPs receive ADT at some point in their therapy [48–50], either as the single therapy, adjuvant with radical prostatectomy, or adjuvant with radiation therapy [50]. As testosterone levels seem to have a great impact on prevention of the loss of muscle mass [51, 52], the side effects of ADT on body composition—namely a loss of muscle mass and a gain of body fat—are substantial [4, 5, 53]. Therefore, RE obtrudes itself as the most logical type of physical therapy to counteract the negative changes in body composition in PCaPs.

The question to what extend PCaPs are actually trainable seems to be rarely discussed in the literature. Bourke et al. concluded that a supervised exercise program in combination with dietary advice is feasible for men with advanced PCa receiving ADT [28]. However, all studies experienced dropouts in the exercise intervention groups due to individual reasons (Table 5), but not a single dropout was related to the exercise program. Therefore, PCaPs seem to be well trainable with RE stimuli of different intensities and modalities. Nevertheless, for patients suffering from metastatic bone disease, affected bone regions need to be excluded from RE.

Table 5 Dropout analysis
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Segal et al. [26] were the first to explore the effects of RE only on PCaPs receiving ADT. They found significant improvements in fatigue, QoL, and muscular fitness but no effect on body composition. Segal et al. [27] verified and extended these findings when they performed nearly the same RE protocol a few years later with PCaPs scheduled to receive radiotherapy, and they demonstrated significant improvements not just in fatigue, QoL, and muscular strength but this time also in body fat percentage, triglycerides and unexpectedly even in maximal oxygen uptake (VO2max).

Segal et al. [22, 27] performed their progressive RE program three times per week with two sets of 8–12 repetitions at 60–70 % of the estimated 1RM. The only difference was the number of exercises and the duration of the training intervention with Segal et al. [22] performing nine exercises in a 12-week training program and Segal et al. [27] ten exercises in a 24-week training intervention. Considering these results, it can be concluded that this kind of training intervention leads to positive adaption in PCaPs and a longer similar training intervention leads to further positive adaptations. These results therefore lead to the question until which duration further improvements could be accomplished with this training regimen?

Santa Mina et al. [25, 41] compared a 24-week long individualized home based AE to a home-based RE program performed with resistance bands, stability ball, and exercise mat. Their main focus was to explore the relationships between training and body composition [25] as well as adipokines and the IGF axis [41]. They concluded that home-based exercise is correlated with positive changes in adipokine levels as well as the IGF axis [41]. Although the exact impact in the prostate cancer environment is still indefinite, positive changes in the IGF axis might be seen as indicators for a lowered prostate cancer risk [41, 54]. RE seemed to be slightly more beneficial on adipokine levels than AE, although they did not detect significant changes in body composition in both groups [41]. They mentioned that, contrary to home based RE, AE in a home-based environment seems to be easier to perform than RE, which in comparison is much more difficult to perform without supervision [25]. They also noted the social importance for cancer patients of being able to share the training experience with a partner, friend, or family member [25].

Galvao et al. [22] performed a supervised high-intensity progressive RE program over 20 weeks. In the initial 10 weeks, an introductory resistance exercise program (consisting of 12 concentric exercises) by using hydraulic resistance training machines was performed by the participants. In the following 10 weeks, the exercise program was altered to isotonic RE, which provided concentric and eccentric muscle contractions using similar exercises on different apparatus. After the intervention, a significant increase in muscle strength and endurance, balance, and surprisingly also in cardiorespiratory fitness was reported. The results of some functional tests (sit-to-stand, 6-m walk, 6-m backward walk, stair climb) also significantly improved, whereas further outcomes like body composition, BMD, and 6-m fast walk remained despite ADT stable. Therefore, the authors concluded that progressive RE should be considered to preserve body composition and reduce treatment side effects of ADT.

Beneficial effects on body composition with RE only were reported by Hanson et al. [24]. Seventeen black PCaPs receiving ADT performed a high-intensity strength exercise program consisting of only six exercises (details in Table 3) using Keiser air-powered machines (Keiser Corporation Inc., Fresno, CA). The participants performed exercise three times per week, only a single set per exercise although at a very high intensity. They performed 15 repetitions at their individual five repetition maximum, so they completed the first four to five repetitions until muscular fatigue, then the weight was slightly lowered so that they could complete the next one to two repetitions. This process was repeated until completion of all of the 15 repetitions of the training set. The training weight was progressively altered to reflect the strength gains. The improvements of muscle strength, endurance, and muscle mass indicated that the used exercise program might prevent the loss of muscle mass, strength, and power commonly observed during ADT [24]. Such an exercise program was already shown to improve muscle strength, power, and mass as well as physical performance in healthy sedentary elderly [55]. The fact that these kinds of multiple beneficial responses to high-intensity RE already showed after 12 weeks of supervised training [24] leads to the question if this intervention was superior to the other RE protocols [22, 25–27]. Further investigation into the impact of this kind of exercise intervention is needed.

The importance of muscle strength and its influence on functional performance was shown by Buffart et al. [37] and Holviala et al. [56]. Buffart et al. [37] conducted a study in order to identify mediators of a combined RE and AE program on perceived physical and general health in patients with ADT. The authors concluded that an improvement in physical health was mediated by upper body muscle strength and walking speed while an improvement in general health was mediated by walking speed and fatigue. Holviala et al. [56] stated that both RE and combined strength and aerobic training produce significant improvements in walking speed in aging men, so therefore should be beneficial for both physical and general health. They found out that moderate but significant relationships were observed between muscle strength and walking speed, whereas AE did not show any effect on walking speed [56].

This would explain why the patients of Mina et al. [41] improved their VO2peak in the RE group, while those of the AE group did not. During an aerobic capacity test on an inclined treadmill, PCaPs on ADT might be primarily limited due to their muscular weakness and not because of their limited endurance capacity.

Winters-Stone et al. [36] investigated a combined resistance and impact exercise program with PCaPs. Although they did not report any significant increases in BMD, they found that this exercise program was able to preserve the BMD in the L4 region of the lumbar spine compared to a placebo stretching group [36]. Before, the same exercise program was investigated regarding its effects on BMD in older women and breast cancer survivors [57–59]. Because the lower lumbar spine bears most of the weight when performing RE with free weights or jumping with weighted vests, the question emerges, if resistance and impact exercise with higher loads would have led to preservation of BMD at more skeletal regions. Nevertheless, Winters-Stone et al. [36] showed promising findings, namely that the right mode of RE might lead to positive bone adaptations even in androgen-depleted PCaPs.

When planning exercise and lifestyle interventions for PCaPs, it seems important to notice that education alone does not lead to a healthier behavior [60].

Although, for the moment, a combination of AE and RE seems to be the best treatment modality of ADT side effects in PCaPs, there is still not enough existing knowledge about the effects of different exercise parameters and interventions on some essential parameters like endocrine anabolic indicators (e.g., IGF-1, IGFBP-3, hGH, dehydroepiandrosterone), blood lipids (e.g., triglycerides, cholesterol), markers of the immune system (e.g., C-reactive protein, interleukins, tumor necrosis factor-α), or BMD.

Furthermore, the effects of additional exercise and training interventions like sensorimotor training and/or flexibility exercise on QoL of PCaPs have to be studied.

Therefore, on the one hand, there is great need for further research, namely prospective RCTs, focusing on the effects of various RE parameters and stimuli. Interventions comparing different RE intensities, volumes, frequencies, or durations are needed for being able to identify the most effective and feasible resistance training stimulus for PCaPs fighting their ADT side effects. Because there are not many high-quality RCTs referring to the aim of this systematic review and because of the heterogeneity of the exercise interventions and the outcome measures of the included articles, we did not perform a meta-analysis, which can be seen as a limitation of the present study. Nevertheless, we suggest that a minimum of about 20 high-quality RCTs would be necessary in total for being able to conduct a thorough meta-analysis. After this, a meta-analysis should be performed to support the conclusions of the present study.

Furthermore, on the other hand, at the moment, a combination of various lifestyle interventions [1, 61] seems to be beneficial of attenuating the side effects of ADT, and therefore, a leading role for the so-called clinical comparative research should be considered [62]. This due to the fact that many different lifestyle and treatment factors affect and interfere with outcomes of PCa rehabilitation interventions. Practice-based evidence (PBE) studies designed to collect data as part of the clinical daily routine are able to include and describe the effects of different interventions in a combined rehabilitation plan [62], and to analyze complex rehabilitation interventions “en bloc” and therefore might play an important role in establishing best practice guidelines for PCaPs receiving ADT.

In conclusion, AE seems to be an effective and safe treatment modality to counteract cardiovascular risk factors in PCaPs on ADT, while RE might be the equivalent for the prevention and therapy of weakness, fatigue, loss of muscle mass, and QoL.

For future purposes, an international research group “Exercise interventions in the treatment and rehabilitation of prostate cancer” should be established to increase the number of high quality RCTs in this field, which would be essential for the conduction of a meta-analysis. This future research could increase knowledge and benefit for PCaPs fighting their ADT side effects.