Effects of exercise therapy in cancer patients undergoing radiotherapy treatment: a narrative review

Description of intervention

Nine studies have addressed the effects of exercise training in BC patients undergoing RT.^36–44 The detailed characteristics of the BC studies are shown in Table 1. Drouin et al. (2006) is a secondary analysis of data from Drouin et al. (2005); they are therefore considered in the following analysis as a single article.^36,37 Four studies include sample of the same population and perform the same type of intervention (BEST study); ⁴⁵ these interventions are described only one time.^40–43 All BC patients, except those in the study by Yang et al., ⁴⁴ which did not mention the information, underwent surgery followed by RT.^36–43 Time since surgery varies from 45 to 70 days.^40–43 Four studies are randomized controlled trials (RCTs)^36–43 and one is a non-RCT. ⁴⁴ The intervention groups (IGs) are compared to stretching,^36,37 relaxation^40–43 or usual care control groups.^38,39,44 The delivered total RT dose varies from 45 to 50 Gy in 2 Gy per fraction.^36–39

Four studies provide a supervised outpatient hospital-based programme^38–44 and one provides a home-based programme with a weekly phone call.^36,37 Exercise interventions comprised either aerobic training,^36,37,39,44 resistance training^40–43 or a combination of the two. ³⁸ Frequency of the intervention varied from two to five times a week over 5–12 weeks.^36–44 During the aerobic training, patients walked^36–38,44 or cycled^38,39 for 20–45 min at mild to moderate intensity, defined by a maximal heart rate (HR_max) of 40%–70%^36–39,44 or a rating of perceived exertion (RPE) of 10–12. ⁴⁴ During the resistance training, patients in the BEST study protocol performed three sets of 8 to 12 repetitions at 60%–80% of repetition maximum (RM).^40–43 The remaining study worked at 50%–70% HR_max but did not mention the volume. ³⁸

Effects of intervention

Three studies reported minor adverse events (difficulty in breathing, fatigue and dizziness during aerobic training, ⁴⁴ and shoulder tendonitis),^36,37 but it is important to note that no study reported the onset or increased severity of lymphoedema following exercise during RT, even in resistance training targeting the upper limbs. This is in agreement with the literature beyond the scope of RT, which states that resistance training does not cause or increase the severity of lymphoedema. ⁴⁶

Fatigue was evaluated in four studies.^37,38,40,44 Improvement in overall fatigue was found in the IGs including resistance training, ⁴⁰ aerobic training ⁴⁴ or a combination of the two. ³⁸ In the remaining study, the aerobic intervention did not significantly improve fatigue symptoms in the IG in comparison to the control group (CG), although a trend towards improvement in fatigue total score was observed in the IG. ³⁷ However, patients in the IG significantly improved the affective meaning domain of fatigue, while the cognitive/mood domain of fatigue improved significantly and the sensory domain significantly worsened in the CG. ³⁷ A recent meta-analysis including nine RCTs has investigated the effect of exercise on fatigue in BC patients undergoing RT and shows a significant reduction in fatigue in favour of the IG compared to the CG (standardised mean difference (SMD): –0.46, 95% confidence interval (CI) –0.79 to –0.14). ⁴⁷ Subgroup analyses reported that supervised combined aerobic and resistance training was more effective for fatigue than home-based, aerobic or resistance interventions. ⁴⁷ Nevertheless, robust conclusions cannot be drawn because some results are based on a small amount of data or a small number of studies. ⁴⁷

Diverse biological mechanisms have been proposed to explain CRF during RT, including inflammatory biomarkers. ⁴⁸ The potential benefits of resistance training on inflammatory parameters were explored by measuring interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra). ⁴³ The IL-6 and IL-6/IL-1ra ratio significantly increased from baseline to the end of RT in the CG, while inflammatory parameters remained unchanged throughout RT in the IG, where resistance training counteracted the increase in these parameters. ⁴³ Increased levels of IL-6 and IL-6/IL-1ra were significantly associated with increased physical fatigue at the end of RT and 6 weeks later. These inflammatory parameters seem to mediate the positive effect of resistance training on physical fatigue during RT, but there are probably other biological mechanisms involved. ⁴³

Another potential mechanism proposed to explain CRF is anaemia, ⁴⁸ especially with concomitant chemotherapy, because the relationship between anaemia and CRF in BC patients undergoing only RT is controversial.^49,50 A walking intervention showed beneficial effects for anaemia, with a slight non-significant increase in haemoglobin, haematocrit and red blood cell counts in the IG, whereas the CG experienced a significant decline in these three variables and all differences between groups were statistically significant. ³⁶ These findings show that performing a walking endurance training in BC patients during RT may prevent a decrease in erythrocyte levels. A positive correlation was also observed between the change in peak oxygen uptake (VO₂) and the post-intervention erythrocyte measures, supporting the relationship between erythrocyte levels and physical fitness during this period. However, these results need to be confirmed, due to the small sample size and the lack of information about dietary intake that may have an influence on erythrocyte levels. ³⁶

QoL is frequently reduced due to cancer and treatment-related side effects in BC patients. ⁷ The benefits of exercise to improve QoL during cancer treatment are evident, as reported by a Cochrane review. ³¹ During RT, the benefits are less convincing. A recent meta-analysis investigating the effect of RT on QoL in BC patients showed a medium-sized but non-significant increase in QoL in favour of the IG with large statistical heterogeneity (SMD: 0.46, 95% CI –0.01 to 0.93). ⁴⁷ However, this meta-analysis included studies with large heterogeneity in terms of exercise prescription (low-intensity mind-body exercises, resistance and/or aerobic training) and planned treatment (RT and/or chemotherapy). Among the studies included in our narrative review, one reports improvement in overall QoL in the IG and decreased QoL in the CG, the differences between groups being significant. ³⁸ Another shows a significant improvement in overall cancer-specific QoL in IG after a 12-week resistance programme. ⁴⁰ Comparison between groups demonstrated that the further perspective domain increased significantly more in the CG than in the IG, while the role function and pain domains were improved in the IG compared to the CG. ⁴⁰ This positive result regarding pain is particularly interesting to note because pain is a factor mentioned by patients to explain the decrease in physical activity levels during treatment. ⁵¹ Patients are also often worried about worsening their pain with exercise. ⁴⁰ This pain reduction is supported by another study that observes a significant decrease in pain in the IG compared to the CG. ³⁸

The results of exercise capacity and exercise functional capacity are reported in three studies in which a moderate aerobic intervention showed an increase in exercise capacity (peak VO₂: +6.3%) ³⁷ and functional exercise capacity (6-min walk test: +24 m) ³⁹ in the IG, while no change in exercise capacity was reported after resistance training. ⁴⁰

Isometric and isokinetic muscle strength in knee flexion and shoulder internal and external rotation were improved significantly in the resistance training group compared to the CG. ⁴² The patients pretreated with chemotherapy showed better benefits performing a resistance training than patients without previous chemotherapy. Concerning surgery-related aspects, strength gain in the upper limb on the operated side improved more than in the upper limb on the non-operated side. ⁴²

Another symptom frequently reported by women with BC during treatment is sleep disturbance. ⁵² The side effects of RT such as fatigue, pain, depression and impaired physical functioning have been shown to play a role in the worsening of sleep disorders. ⁵³ Steindorf et al. compared the effects of a supervised resistance training to relaxation on sleep disturbance in BC patients receiving RT. At the end of the RT and prolonged intervention, sleep problems decreased significantly in the IG compared to the CG. ⁴¹ Twelve months after the end of the treatment, a difference was still observed between groups but was not statistically significant. Previous chemotherapy, depressive symptoms, previous hysterectomy, higher body mass index (BMI), degenerative disorders and thyroid disorders have been identified as determinants of sleep problems at baseline. ⁴¹

Psychological impairments are frequently observed in BC patients who undergo RT. Some improvements in the Profile of Mood States, a psychological questionnaire assessing mood and affective states, occurred after a 7-week moderate walking programme. ³⁷ Although the total score did not show any significant difference, the IG showed significant improvement in the domains of depression–dejection and anger–hostility, while the CG improved significantly in the confusion–bewilderment domain from pre- to post-RT assessments. ³⁷

Summary

In conclusion, initiating an intervention exercise throughout RT in BC patients is feasible and safe based on the results of all the nine studies. This intervention may be helpful for CRF,^38,40,44 exercise capacity, ³⁷ exercise functional capacity, ³⁹ muscle strength, ⁴² sleep disturbance, ⁴¹ pain ³⁸ and QoL.^38,40 An aerobic training may prevent a decrease in erythrocyte levels, ³⁶ while a resistance programme seems to counteract the increase in inflammatory cytokines, ⁴³ which play a crucial role in cancer-related cachexia. ⁵⁴ Regular exercise training performed during RT may therefore alleviate treatment-related side effects and should be initiated at the same time as the RT-based treatment modality.

A supervised intervention seems to be more effective to reduce fatigue than a home-based setting, as does combined aerobic and resistance training compared to isolated aerobic or resistance training. ⁴⁷ However, further research is needed to confirm these results, because they are based on a small amount of data (home-based: n < 50) and a small number of studies (one study with resistance training). Future RCTs should also determine the optimal type, frequency and timing of exercise to achieve the greatest benefit in this context.

Description of intervention

Five prospective^60–64 studies and one retrospective ⁶⁵ study performed exercise programmes with PCa patients during RT. Kapur et al. ⁶⁵ retrospectively analysed patient data from the study by Windsor et al.; ⁶⁰ these are therefore considered as a single article in the following description of the exercise intervention. The detailed characteristics of the prostate studies are shown in Table 1. Three studies included PCa patients undergoing RT with or without ADT;^60,62,63,65 one included PCa patients undergoing RT, all of whom were currently receiving ADT; ⁶⁴ and one included patients undergoing RT without ADT. ⁶¹ The delivered total RT dose varies from 50 to 76 Gy in 20–38 fractions.^{60,61,63–65} Four studies were two-armed, comparing an aerobic training group^60,61,63,65 or an aerobic and a resistance training group ⁶⁴ to a CG. The remaining study compared three groups: an aerobic, a resistance and a CG. ⁶² Three of the studies were outpatient hospital-based programmes and supervised,^61,62,64 while the other two were home-based.^60,63,65 The length of the intervention ranged from 4 to 24 weeks. Training frequency was three times per week in four studies at moderate intensity^60–63,65 and five times per week in one study. ⁶⁴ These sessions lasted between 15 and 55 min.

Effects of intervention

Exercise was associated with high adherence (82%–100%)^60–64 and satisfaction ⁶³ and was safe with no adverse events reported, except in one study that mentioned three adverse events related to exercise, including one serious (acute myocardial infarction) during an aerobic session. ⁶²

Fatigue was the most measured variable among studies, being evaluated in five studies.^60–64 A significant increase in fatigue was observed in the CG after intervention compared to baseline in all studies,^60–64 whereas the fatigue score of the IG showed no change over time in four studies^60,62–64 and a decrease in one study. ⁶¹ Comparison of 24 weeks of aerobic or resistance training to the CG showed that both IGs mitigated fatigue in the short term, and these improvements were clinically relevant. Resistance training also generated longer-term improvements (at 24 weeks) in fatigue. ⁶² These findings were confirmed by a pooled analysis of five studies with seven different interventions that showed a significant fatigue reduction in favour of the IGs. ⁶⁶ Interestingly, physically active patients showed lower levels of fatigue compared with patients physically inactive before, during and after RT. ⁶⁰

It has previously been demonstrated that RT may alter cytokine responses, this being associated with radiation toxicity. ⁶⁷ Moderate-intensity aerobic and resistance training decreased levels of inflammatory markers after RT in PCa patients. ⁶⁴ Indeed, results have shown that an increase in IL-6 levels related to the RT and ADT is significantly reduced in the IG compared to the CG. This emphasizes the crucial role of physical exercise to reduce pro-inflammatory cytokines such as IL-6, which mediate cancer cachexia. ⁶⁴

QoL was reported in four studies.^61–64 A difference between groups in overall cancer-specific-QoL favoured the IG after 12 and 24 weeks of resistance training ⁶² and 8 weeks of a combination of the two. ⁶⁴ PCa-specific QoL score improved after 8 weeks of aerobic training ⁶¹ while a significant decline was observed after 12 weeks of aerobic or resistance training with a return to baseline after 24 weeks. ⁶² In contrast to these results, a recent meta-analysis investigated the effects of an exercise programme during RT for PCa on QoL. The pooled results of three studies did not report significant improvement in QoL in favour of the exercise, possibly due to the large heterogeneity between studies. ⁶⁶

Concerning the effects on physical fitness of exercise intervention during RT, four studies report enhancement of at least one component of it.^60–62,64 Improvement in exercise capacity and exercise functional capacity was shown after a moderate walking aerobic training (mean shuttle test distance: +67.5 m (IG) vs –11.5 m (CG) ⁶⁰ and metabolic syndrome (METS): +2.6 (IG) vs –0.2 (CG)) ⁶¹ and a programme combining aerobic and resistance training ⁶⁴ (6-min walk test: +30 m (IG) vs –24 m (CG)) in the IG compared to the CG. In Segal et al., the resistance group showed significant benefits for cardiovascular fitness compared to the CG. Surprisingly, resistance training preserved aerobic fitness as much as the aerobic training. ⁶² The authors hypothesize that this unexpected result may be because eight participants in the resistance group performed vigorous aerobic training in addition to their resistance training. ⁶² In addition, after an 8-week supervised walking programme, differences between groups post-intervention were reported in muscle strength and flexibility in favour of the IG. ⁶¹ Muscle strength and body fat percentage also improved after resistance training compared to the CG. ⁶²

Exercise training does not appear to prevent the reduction of blood parameters in men with PCa undergoing RT. Indeed, one study reported a significant decrease in red blood cells, white blood cells, haemoglobin and lymphocytes for the IG and the CG after treatment, ⁶⁴ and another showed a significant reduction in haemoglobin levels in the middle (12 weeks) and at the end of the intervention (24 weeks) in all groups (aerobic, resistance and CG). ⁶² Similarly, haemoglobin and haematocrit levels declined for both groups after 4 weeks of RT. ⁶⁰

Bladder and rectum toxicities are common treatment-related symptoms in PCa receiving RT and may be disabling for patients, negatively affecting their QoL. A retrospective analysis of toxicity data from a previously published study ⁶⁰ examined the potential effect of a 4-week aerobic training on the reported acute bladder and rectal toxicities in localized PCa patients undergoing RT. ⁶⁵ The authors report a difference in rectal toxicity score over RT between groups, with lower rectal toxicity in the IG, suggesting that an aerobic programme may reduce the severity of rectal toxicity in PCa patients undergoing RT. The non-significant effect of exercise on bladder toxicity could be explained by the fact that urinary symptoms were present due to the PCa itself at the start of the RT. Therefore, the urinary symptoms measured were the consequence not only of the RT treatment, but probably also of the PCa itself. ⁶⁵

Summary

An exercise programme performed during RT in PCa patients is associated with high adherence,^60–64 satisfaction ⁶³ and seems globally safe. A worsening in CRF, one of the most common side effects reported in PCa patients, is prevented with exercise,^60–64 and the level of fatigue reported was inversely associated with the physical activity level. ⁶⁰ Exercise training also improved exercise capacity, ⁶¹ exercise functional capacity,^60,64 and muscle strength,^61,62 and decreased levels of pro-inflammatory cytokines. ⁶⁴ Its effect on QoL has not yet been established. Exercise training may also reduce the severity of rectal toxicity, but further research is needed to confirm these results. ⁶⁵ Therefore, performing an exercise training with PCa patients undergoing RT appears to minimize treatment-related side effects and facilitate effective recovery.

Description of intervention

Five studies have investigated the feasibility and preliminary efficacy of exercise intervention during and after NACRT.^73–77 The detailed characteristics of the rectal studies are shown in Table 1. Four were prospective studies with a single group design,^73–75,77 and one study was an RCT comparing an IG to a CG. ⁷⁶ Intervention started at the beginning of the NACRT and is sometimes prolonged between treatment completion and the surgery.^74–77 The delivered total RT dose varies from 45 to 54 Gy in 25–30 fractions.^74–76 Four studies provided a supervised outpatient hospital-based programme^73–75,77 and one provided a home-based programme with follow-up telephone calls. ⁷⁶ Exercise interventions combined aerobic and resistance training in three studies^73,75,77 and included only aerobic training in two studies.^74,76 Supervised exercise sessions were performed two to three times a week for 10–16 weeks.^73–75,77 During the aerobic training, patients performed walking, running, cycling, rowing or elliptical training for 20–40 min at moderate intensity, defined by HRmax^73,75,77 at 50%–80%, by volume of VO₂ reserve at 40%–60% ⁷⁴ or by an RPE of 13–14. ⁷⁵ During the resistance training, patients performed two to four sets per exercise at 6–12 RM intensity^73,77 or three sets of 15 repetitions per exercise at 40% 1-RM. ⁷⁵ The home-based intervention was composed of aerobic training based on targeted step counts (1500–3000 daily steps accumulated above baseline). ⁷⁶

Effects of intervention

Results show that performing exercise training during and after NACRT is feasible, with good recruitment and retention rates.^73–77 Patients reported a high level of satisfaction with the walking home-based programme during and after NACRT and would recommend it to other patients diagnosed with rectal cancer. ⁷⁶ Exercise adherence was good to excellent (74%–96%). It was shown that adherence to supervised aerobic training during NACRT was better for patients who were women, younger, married, with better mental health, fewer diarrhoea symptoms, and higher anticipated enjoyment, support and motivation, although the results were not statistically significant. ⁷⁸ Another study investigated perceived barriers to exercise during and after NACRT. ⁷⁹ The most common perceived barriers were side effects from NACRT (88%), fatigue (76%) and diarrhoea (71%) during NACRT, and lack of motivation (79%), fatigue (57%) and feeling sick (50%) post-NACRT. ⁷⁹ No major adverse events related to exercise were reported. Nevertheless, Singh et al. observed bowel activation due to exercise in some patients after the radiation session. ⁷³ They decreased the intensity during the aerobic training to reduce the bowel activation. Other studies did not report this side effect.

After an aerobic training, a small decrease in VO₂max (–1.3 mL/kg/min) was observed from pre- to post-NACRT. ⁷⁴ This suggests that aerobic training during NACRT may prevent a decline in cardiorespiratory fitness. ⁷⁴ Indeed, a greater decrease in cardiorespiratory fitness (–2.5 mL/kg/min) was noticed without an exercise programme during NACRT in rectal cancer patients. ⁷⁰ Similarly, a clinically significant increase in functional exercise capacity was shown in two other studies (+46 m to the 6-min walk test ⁷⁵ and –27.5 s to the 400-m walk test) ⁷⁷ after exercise intervention. After a walking programme, a non-significant reduction in daily step count from pre- to post-treatment was reported for both groups, but the reduction was less in the IG. ⁷⁶

A significant improvement in leg and arm muscle strength (+39.2% and +34.9%, respectively) was shown after 10 weeks of aerobic and resistance training (during and after NACRT), ⁷⁵ while an increase in muscle strength and endurance was reported only in the lower limbs after a 10-week aerobic and resistance training. ⁷³ Although not statistically significant, a 16-week intervention also improved muscle strength by 9%–29% and preserved LM at pre-surgery. ⁷⁷

Total QoL and fatigue scores did not change throughout the intervention in three studies, suggesting a conservation of these parameters in rectal cancer patients undergoing NACRT.^73,75,77

Summary

The current findings show that initiating an exercise intervention during and after NACRT is feasible, safe and well tolerated.^73–77 It improves muscle strength and physical performance and prevents a decline in cardiovascular fitness, LM, QoL and fatigue.^73–75,77 It is important to point out these findings because patients with better physical fitness could reduce their risk of poor post-operative outcomes and increase recovery. However, it is necessary to remain cautious in view of these results, because four studies were a single group design with a small sample (ranging from 9 to 18). Future RCTs are warranted to determine the efficacy of an exercise training during NACRT.

Description of intervention

Eight trials evaluated the effects of an exercise programme in HNC patients during RT with or without chemotherapy.^85–92 The characteristics of these studies are summarized in Table 1. The delivered total RT dose varies from 60 to 70 Gy.^{86,87,90–92} One study was a single group, ⁹⁰ while seven studies were two-armed, comparing an IG to a CG during RT in five studies^{85–87,91,92} and comparing IGs exercising either during or after RT in two studies.^88,89 Exercise training was delivered in hospital and supervised in four studies;^86,89–91 in one study, half of the training sessions were in hospital and the other half home-based; ⁸⁸ and in three studies, exercise training was in hospital during RT and home-based during follow-up.^85,87,92 The exercise intervention consisted of combined aerobic and resistance training in three studies,^86,87,92 and resistance training alone in five studies.^85,88–91 In addition to the resistance training, a nutritional intervention was added in two studies,^85,89 and the intervention in Capozzi et al. was a lifestyle intervention consisting of four other components, including physician referral and clinic support, health education, behaviour change support and social support. ⁸⁸ The frequency of exercise training ranged from two to five times over 6–14 weeks. Aerobic training consisted of walking between 15 and 30 min at a moderate intensity at 11–13 RPE or 3–5 RPE, as measured by the original and modified Borg scales, respectively.^86,87,92 Resistance training targeted major muscle groups in five studies^{85,87,88,90,91} and upper and lower limb muscle groups in three studies.^86,89,92 Patients performed between two and four sets of 8–15 repetitions per exercise. Four trials utilized RPE,^86,87,91,92 three studies used the RM, ranging from 6 to 15,^88–90 and one study used resistance bands to prescribe intensity. ⁸⁵

Effects of intervention

Exercise training during RT with or without chemotherapy in HNC patients is safe, well tolerated and feasible,^85,89,93 even in cachectic HNC patients. ⁹¹ No exercise-related adverse events were reported.^{85,86,90–92} Adherence to exercise sessions ranged from 45% to 83% during RT and from 49% to 62% after RT. Results of the different studies are described below,^{85–87,90–92} except for the two studies^88,89 comparing groups practising exercise during (intervention during treatment (IDT)) and after radiation therapy (intervention after treatment (IAT)), which are described later in the review.

LM was one of the most evaluated variables.^85,87,90,91 A pilot study, in which 12 patients carried out a 12-week resistance programme, demonstrated a significant decrease of 5.1 kg in LM after 6 weeks of RT, as well as a decrease in body weight and fat mass. Patients then started to regain LM while they continued to lose total body weight and fat mass, but despite this LM gain, change in LM from baseline to 13 weeks was still significant. ⁹⁰ Unfortunately, in the absence of a CG, it is difficult to know if this increase in LM was due to the resistance training. The three remaining studies did not find a significant difference in LM at RT completion or at the end of the intervention in either group.^85,87,91

Regarding the six studies that assessed functional exercise performance, the 6-min walk test was used in four studies.^86,87,91,92 A 6-week combined aerobic and resistance training during RT significantly improved the walking distance by 42 m in the IG after intervention, while a significant decrease of 96 m was observed in the CG. ⁸⁶ The authors of this pilot study recently confirmed these results by performing a similar intervention over 11 weeks. The IG reported a significant improvement in functional exercise capacity compared to the CG (+37 m vs –73 m, respectively). ⁹² In addition to the 6-min walk test, functional performance was assessed using other tests (see Supplementary Appendix 1), but with no significant results.^85,87,88,90

Muscle strength and endurance were evaluated using a dynamometer,^85,87,91 the 1-RM test, ⁹⁰ and the sit-to-stand test.^85,90 A 12-week resistance training showed that upper muscle strength measured by 1-RM decreased significantly after intervention, while lower muscle strength remained almost the same. ⁹⁰ Similarly, knee extension strength was maintained in the IG for all 14 weeks of intervention, while the CG declined significantly at 7 and 14 weeks. ⁸⁷ No group difference was observed in upper limb strength. ⁸⁷

Fatigue was evaluated in three studies.^85,91,92 Aerobic and resistance training prevented increased fatigue in the IG compared to the CG. ⁹² Likewise, after 6 weeks of resistance training, an increase in fatigue was observed in the CG, ⁸⁵ and the difference between groups (Total Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score: CG: –8.0 and IG: –3.4 at 6 and 12 weeks) exceeds the minimal clinical importance difference of 3. ⁹⁴ Conversely, one study with cachectic HNC patients found no difference after 7 and 15 weeks of resistance training. ⁹¹

QoL was assessed in six studies.^{85–87,90–92} Among them, four studies showed some significant improvements in QoL with exercise intervention in HNC patients undergoing RT.^85–87,92 Using the Short-Form (SF)-36 scale, the mental component score demonstrated an improvement (+12%) in the IG, while the CG showed a decrease (–75%). The physical component score remained unchanged in the IG and decreased non-significantly in the CG. ⁸⁶ A few years later, the same authors showed that changes in physical and mental components were statistically significant between groups in favour of the IG after 11 weeks of aerobic and resistance training. ⁹² In addition, a difference between groups favoured the IG in the mental health subscale and vitality. ⁸⁷ Using the Functional Assessment of Cancer Therapy scale, a small to medium effect size improvement was found, favouring the IG over the CG, for overall QoL, physical wellbeing, emotional wellbeing and functional wellbeing. ⁸⁵ Surprisingly, the IG reported greater HNC-specific symptoms compared to the CG. This result may be explained by the fact that three of the four patients receiving concurrent chemotherapy were assigned to the IG. ⁸⁵

Muscle biopsies and proteomic evaluation were performed in a pilot study. ⁹⁰ Along with LM and muscle strength, sarcomeric protein levels declined during the 6-week CRT and thereafter increased during the remaining 6-week intervention, suggesting that structural changes may cause changes in LM and muscle strength. ⁹⁰ Better quality studies are needed to confirm these results.

Two studies investigated the ideal time to perform an exercise programme by comparing groups practising during or after RT.^88,89 Capozzi et al. compared a 12-week lifestyle intervention including resistance training either IDT or IAT. Greater adherence was reported for the IAT (IDT = 45% vs IAT = 62%). The authors showed a significant decline in LM after RT in both groups (–4.9 cm²/m² for IDT vs –5.4 cm²/m² for IAT) that remained at 24 weeks (–4.5 cm²/m² for IDT vs –4.4 cm²/m² for IAT). ⁸⁸ They also observed a decline in the distance walked in both groups during the first 12 weeks (–13 m for IDT and –35 m for ADT) that increased by 43 and 18 m, respectively, compared to baseline scores at 24 weeks. It is important to note that this increase from baseline to 24 weeks was not statistically significant, but it was clinically important for the IDT. ⁸⁸ Concerning muscle strength, the authors showed a significant decline in handgrip strength in both groups through the first 12 weeks (–3 kg for IDT vs –6.7 kg for IAT) with a return to baseline at 24 weeks (+0.2 for IDT and –1.3 for IAT). ⁸⁸ Both groups maintained functional lower body strength between 0 and 12 weeks, which increased significantly by 24 weeks. ⁸⁸ Finally, they demonstrated a decrease in the cancer-specific QoL score across the first 12 weeks in both groups that returned to baseline by 24 weeks. ⁸⁸ The authors suggest that patients should receive education before RT treatment and start the IAT completion. However, this study is limited by the lack of a CG, a resistance programme not physiologically demanding enough, and a small sample size. In addition, another study compared a group performing IDT (2×/week for 6 weeks) versus IAT (3×/week for 3 weeks). Adherence to the resistance programme was higher when exercise was performed during RT (IDT = 74% vs IAT = 49%). The authors explain this difference by the fact that the exercise training probably started too quickly after the end of the treatment (2–4 weeks after RT completion), not allowing the patient time to recover; furthermore, patients took at least 2 h to get to the rehabilitation centre post-treatment and spent the weekdays there. ⁸⁹ After RT, both groups showed a significant decline of LM, but the decrease was less pronounced in the IDT (–1.7 cm²/m² vs –4.0 cm²/m²; ES = 0.79 in favour of IDT). These results suggest that resistance training during RT may be an effective way to limit muscle mass loss. However, the change in LM from week 6 to week 14 showed a trend towards mitigating LM loss, with a medium effect size in favour of IAT. Therefore, the authors suggested that to minimize the muscle mass loss in HNC patients undergoing RT, exercise training should be initiated at the start of treatment and continue after treatment. Two studies failed to demonstrate such a difference in LM in the IG and the CG either at RT completion or at the end of the intervention.^85,87

Summary

Exercise training during CRT in HNC patients is feasible and well tolerated, and no exercise-related adverse events were reported, even in cachectic HNC patients.^{85,86,90–92} Improvement was shown for functional exercise capacity^86,92 and some domains of QoL.^85–87,92 Exercise training may also prevent a decline in lower muscle strength ⁸⁷ and an increase in fatigue.^85,92 Concerning the preservation of LM, which is a major challenge for these patients during and after RT, the current findings are not strong enough to affirm the benefit of resistance training to maintain or increase LM. Futures RCTs should be conducted to determine the optimal type and intensity of exercise to counteract the side effects of RT, especially in relation to LM, in HNC cancer patients.

The current studies do not highlight the optimal timing (during or after RT) to initiate an exercise programme, especially for maintaining or increasing LM, and future RCTs should be conducted to determine the optimal timing.

Description of intervention

A recent randomized controlled feasibility study focuses on pre-RT daily exercise training in locally advanced NSCLC. ⁹⁵ All patients received the same total dose of 66 Gy in 33 fractions. Fifteen patients were randomized either in the CG or in the IG. The exercise programme consisted of 20 min moderate- to high-intensity aerobic interval training on a cycle ergometer over a 7-week period. Each session was supervised and performed daily prior to RT.

Effects of intervention

The study demonstrates that daily moderate- to high-intensity aerobic exercise is feasible, safe and well tolerated in patients with locally advanced NSCLC undergoing concurrent CRT. ⁹⁵ The recruitment rate was 44% and the overall attendance rate to exercise was 90%, with an adherence rate to full exercise participation of 88%. No adverse event was observed during the exercise sessions. No secondary outcomes, including VO_2peak, functional exercise capacity, pulmonary function and psychological parameters, demonstrated statistical differences. These results might be explained by the small sample size or by the fact that although the CG did not receive any exercise programme, it performed more steps per day (7572 ± 2445 steps), monitored by an activity tracker, than the IG (6254 ± 2337 steps).

Summary

Moderate- to high-intensity exercise training is feasible, safe and well tolerated in NSCLC patients undergoing RT. ⁹⁵ Due to the limited number of studies available, more studies are needed to determine the safety and effectiveness of exercise training during RT.