Football training improves lean body mass in men with prostate cancer undergoing androgen deprivation therapy

Prostate cancer (PCa) is the second most frequent malignancy in European men and the most common noncutaneous cancer in Danish men (The Danish Cancer Registry, 2012; Ferlay et al., 2013). PCa growth depends on androgen stimulation, and androgen deprivation therapy (ADT) has become a cornerstone in PCa management, with 50% of patients receiving ADT (Gregory et al., 2001; Meng et al., 2002). ADT reduces serum testosterone to castrate levels via surgery (orchiectomy) or pharmaceuticals, i.e., luteinizing hormone-releasing hormone-agonists (LHRHa; Sharifi et al., 2005). ADT reduces tumor growth and is associated with an array of adverse effects including loss of lean body mass (LBM; 2–4%), increases in fat mass (FM; 2–11%), reduced bone mineral density (BMD), increased risk of fractures, and declines in physical ability and quality of life (Lubeck et al., 2001; Galvao et al., 2008; Alibhai et al., 2010; Haseen et al., 2010).

Exercise has been suggested as a possible means to counteract the adverse effects of ADT. Previous studies have provided evidence that exercise may improve LBM, cardiorespiratory fitness, and functional task performance in patients undergoing ADT (Gardner et al., 2014). While these findings are encouraging, a low level of physical activity in this patient group remains a challenge. A recent study found that only 41% of a PCa population met the official physical activity guidelines and those treated with ADT were significantly less physical active than those treated with radiotherapy alone (Chipperfield et al., 2013). Thus, the introduction of innovative interventions reflecting male cancer survivors' need for action-orientated activities likely to stimulate long-term adherence is of importance (Adamsen et al., 2001). Recent studies have shown that recreational football induces beneficial and sustainable musculo-skeletal, metabolic and cardiovascular adaptations in healthy untrained young men (Krustrup et al., 2009), middle-aged men with hypertension (Andersen et al., 2010; Krustrup et al., 2013), middle-aged men with type 2 diabetes (Schmidt et al., 2013), and elderly untrained men (Helge, 2014).

Accordingly, we designed the “FC Prostate” randomized controlled trial (RCT) to evaluate the effects of 12 weeks of football training on body composition, cardiovascular risk profile, bone health, glucose tolerance, physical performance, and patient reported outcomes in men with PCa managed with ADT (Uth et al., 2013). In the present paper, we present data on the effect on LBM (primary outcome), body fat percentage, maximal oxygen uptake (VO_2max), muscle strength, and sit-to-stand performance. Analyses of additional measurements included in the study are ongoing and the results will be published elsewhere.

Methods

Study design and population

The present study was an RCT in men with advanced or locally advanced PCa allocated to a football intervention group or a usual care waiting list control group. The overall design and methodology have been described in details previously (Uth et al., 2013). In brief, patients presenting at Copenhagen Prostate Cancer Center, Copenhagen University Hospital, Rigshospitalet, or the Department of Urology, Frederiksberg Hospital, Denmark aged < 76 years managed with ADT, i.e., LHRHa, or surgical castration, for at least 6 months were eligible. Main criteria for exclusion were cardiovascular disorders, osteoporosis, and activity limiting pain from bone metastases. The study was approved by the Danish National Committee on Biomedical Research Ethics for the Capital Region (registration number H-3-2011-131) and written informed consent was obtained from all participants before any study procedures were undertaken. The study flow is presented in Fig. 1.

Results

HR response during football training sessions

Mean HR during football training based on four training sessions in weeks 2–3 and weeks 11–12 was 137.7 (SD 13.7) bpm corresponding to 84.6 (SD 3.9) % of individual maximal HR. The time spent in HR zones < 70%, 70–80%, 80–90%, and 90–100% was 4.6% (SD 4.3), 20.0% (SD 14.9), 48.7% (SD 13.8), and 26.8% (SD 22.2) of total training times, respectively. There was no difference in mean HR in weeks 2–3 compared with mean HR in weeks 11–12 [137.6 (SD 14.5) and 137.8 (SD 13.8) bpm; P = 0.89]. Likewise, there were no significant differences in the HR distribution for the football training in the first and last phase of the intervention period (Fig. 2).

Primary outcome

The difference in change scores in total LBM at 12 weeks was 0.7 kg (95% CI 0.1 to 1.2; P = 0.02) in favor of FG (Fig. 3(a)).

Secondary outcomes

Body composition

There was no difference in changes between FG and CON for hip-to-waist ratio (P = 0.56), android FM (P = 0.20) or gynoid FM (P = 0.64) but a trend was seen for fat percentage (mean difference −0.7; 95%CI −1.5 to 0.2; P = 0.08; Fig. 3(b)). Table 2 lists body composition end points.

Table 2. Body composition and functional capacity absolute values and changes after the 12-week intervention

	Baseline		12 Weeks		Change score			Group difference in mean change score (FG vs CON)
Variable	Mean	SD	Mean	SD	Mean	95% CI	P	Mean	95% CI	P
Lean mass, kg
Football	53.1	5.9	54.0	5.2	0.5	0.1 to 0.9	0.02	0.7	0.1 to 1.2	0.02
Control	56.7	5.5	56.8	5.1	−0.2	−0.6 to 0.2	0.38
Fat mass, kg
Football	27.6	7.5	26.3	7.0	−0.6	−1.4 to 0.1	0.08	−0.6	−1.5 to 0.2	0.14
Control	30.0	7.7	29.7	6.2	0.0	−0.5 to 0.5	0.95
Fat mass, %
Football	32.6	5.8	31.7	5.6	−0.7	−1.3 to 0.0	0.06	−0.7	−1.5 to 0.2	0.08
Control	32.9	5.2	32.9	4.0	0.1	−0.4 to 0.5	0.78
1 RM (kg)
Football	62.8	15.0	71.7	18.8	8.9	6.0 to 11.8	< 0.001	6.7	2.8 to 10.7	< 0.001
Control	71.7	16.9	73.9	16.0	2.2	−0.7 to 5.0	0.13
Sit-to-stand (repetitions)
Football	20.0	6.0	21.5	6.3	1.4	0.4 to 2.5	0.01	1.2	−0.3 to 2.8	0.11
Control	22.1	4.9	22.3	5.5	0.2	−0.9 to 1.3	0.72
VO2max (mL O2/kg/min)
Football	27.2	4.6	28.7	5.2	1.0	0.2 to 1.9	0.02	0.7	−0.6 to 2.0	0.29
Control	26.4	3.4	26.9	3.0	0.3	−0.7 to 1.4	0.50

• Mean (SD) at both time points are based on available data. Mean change is based on 12-week score minus baseline score and may not precisely reflect this difference given that mean change is calculated only on data from participants assessed at both time points.
• 1RM, one repetition maximum; CI, confidence interval; SD, standard deviation; VO_2max, maximal oxygen uptake.

Physical performance

Muscle strength for knee extensors (1RM) increased in FG (P < 0.001) with no change in CON (P = 0.13) and a mean difference of 6.7 kg (95% CI 2.8–10.7; P < 0.001) in favor of FG (Fig. 4(a)). In FG, an improvement was observed in the sit-to-stand test score (1.4 repetitions; 95% CI 0.36–2.50; P = 0.01) and VO_2max (1.0 mL/kg/min; 95% CI 0.2–1.9; P = 0.02) but these changes were not significantly different from CON (Fig. 4(b)). Table 2 lists physical capacity end points.

Adverse events

In FG, two participants had a fracture of the fibula bone (session 1 and 16, respectively). Also, one participant had a partial rupture of an Achilles tendon (session 3), and one participant had an ankle sprain in training session 16. All four recovered fully from these injuries after conservative treatment. Additionally, one participant withdrew from the study after a quadriceps muscle strain. In one of the participants who had a fibula fracture, a diagnosis of peripheral neuropathy was revealed in the medical treatment following the fracture and the participant was therefore excluded from the intervention but re-tested at 12 weeks and the data were included in the analysis. Three of the injured participants resumed football training after appropriate recovery time.

Discussion

This is the first randomized controlled study to evaluate the effects of football training compared with standard care in men with PCa managed with ADT for > 6 months. The most important findings were that the 12-week intervention resulted in an improved LBM in the football group compared with the usual care controls, in combination with an increase in knee-extensor muscle strength. These results emphasize that PCa patients managed with ADT can obtain positive adaptations in body composition and muscle strength after a short-term football intervention.

The present study showed a high attendance rate and revealed a high exercise intensity during football training for the PCa patients. The HR recordings collected over several training sessions during the intervention period revealed average HRs of 85% of individual HR_max and more than 25% of the training time with HRs above 90% of HR_max. Another 25% of the time was spent with HRs below 80% of HR_max. These HR values are similar to values obtained during football training for healthy 70-year-old men with and without prior experience with football as well as middle-aged untrained men with hypertension and type 2 diabetes (Krustrup et al., 2013; Schmidt et al., 2013; Andersen et al., 2014), which emphasizes that football training is an intense interval activity also for PCa patients managed with ADT. Considering that mean and peak HRs were around 140 and 160 bpm, respectively, during football training but only around 100 bpm during physical activities that are usually performed in everyday life, like walking at 4.5 km/h and cycling at 40W (data not shown), it is clear that the football training constitutes an extraordinary training stimulus for the participants.

The observation of an increase in LBM is accordance with the findings of Galvão et al. (2010), who reported that a combination of resistance and aerobic exercise reversed loss of LBM after 12-week intervention in men with PCa receiving ADT for > 2 months. Similarly, Alberga et al. (2012) found that a 24-week resistance exercise intervention preserved LBM in men receiving ADT while decreases were seen in both an aerobic exercise group and a control group. A recently published randomized pilot study indicated that resistance exercise may also be well tolerated and improved LBM in men with bone-metastatic PCa (Cormie et al., 2013). Loss of LBM during ADT has been widely reported (Haseen et al., 2010) and has been linked to reduced mobility and function (Clay et al., 2007). We therefore believe that the improvement in LBM resulting from the present football intervention may be clinically important. In direct relation to the increase in LBM, the football group participants had a marked increase in knee-extensor muscle strength compared with the control subjects. Likewise, a within-group improvement was observed in functional capacity as evaluated by the sit-to-stand test. These training adaptations can benefit the PCa patients during everyday life activities as well as during physical training.

Also of importance, VO_2max improved significantly from baseline to 12 weeks in the football group, although this was not significantly different from the changes in the control group. However, even modest improvements in oxygen uptake may be of importance since better peak oxygen uptake is a strong independent predictor of survival in healthy adults (Kodama et al., 2009) and PCa patients undergoing ADT have previously been shown to have reduced aerobic capacity (Galvao et al., 2008). Moreover, football training resulted in a borderline reduction in fat percentage compared with usual care. This finding is in line with findings by Segal et al., which indicated that resistance training prevented an increase in body fat (Segal et al., 2009). Since adiposity is a common adverse effect related to ADT (Hamilton et al., 2011) causing secondary morbidity, e.g., cardiovascular disease and type 2 diabetes (Keating et al., 2006), we consider this finding to be of potential clinical relevance. It is, however, essential for the preservation of the favorable effects that the men maintain the activity long term. So far, a qualitative investigation (Bruun et al., 2014) from the present study suggests that the participants regarded football training as a welcome opportunity to regain control and acquire a sense of responsibility for own health without assuming the patient role.

Three serious adverse events occurred during football training, i.e., two fibula fractures and one partial Achilles tendon rupture. These injuries were managed with conservative treatment and the participants recovered fully. As no bone metastases were present in the fractured bones, these injuries are regarded as accidental and unrelated to metastatic disease. While serious injuries are a source of great concern, the potential debilitating effects of physical inactivity on body composition, physical capacity, and subsequent risk of morbidity must be weighed against potential training related hazards. In order to prevent musculo-skeletal events, future interventions offering football training to men with prostate cancer undergoing ADT should consider an adaption period of combined strength-, balance-, and football skill training prior to actual football games, such as the FIFA 11+ exercises (Junge et al., 2011). However, given the nature of the football activity involving physical contact between players, an uneven playing surface, and unexpected moves by teammates, opponents, and the ball, the risk of injuries related to training is not completely avoidable.

The present study has several important limitations including unblinded assessment personnel and a lower than expected recruitment rate. Furthermore, the study population was relatively heterogeneous regarding age and treatment duration and there was possibly a case of selection bias, as the present study appealed to participants motivated for exercise. It should also be noted that the football group, on average, had received ADT for approximately 6 months less than the control group. Although this was not statistically significant and both groups had received treatment for more than a year, the football group may have been subject to further deterioration during the intervention period compared with the control group. Strengths of the study include the novelty of football as a cancer rehabilitation modality, assessment of clinically relevant outcomes with validated measures, and inclusion of patients with a substantial disease burden underrepresented in exercise trials.

In summary, 12 weeks of football training is an effective intervention to improve lean body mass and muscle strength in men with prostate cancer during androgen deprivation therapy.

Perspectives

Accumulating evidence suggests that exercise may ameliorate adverse effects related to androgen deprivation treatment of PCa (Gardner et al., 2014). The present study adds to existing knowledge by showing that football training improves clinically relevant outcomes and thus may be considered as a recommendable alternative to traditional rehabilitation interventions. However, pragmatic studies devoted to the examination of the effectiveness of football training in a natural setting (i.e., community-based, local football clubs) are warranted in order to establish the generalizability and dissemination potential of football in prostate cancer survivorship care.