The effect of training during treatment with chemotherapy on muscle strength and endurance capacity: A systematic review.

Background Treatment of cancer with chemotherapy decreases endurance capacity and muscle strength. Training during chemotherapy might prevent this. There are no clear guidelines concerning which type of training and which training dose are effective. This review aims to gain insight into the different training modalities during chemotherapy and the effects of such training to improve endurance capacity and muscle strength in order to obtain the knowledge to compose a future training program which trains cancer patients in the most effective way. Material and methods A systematic search of PubMed was carried out. In total, 809 studies of randomized controlled trials studying the effects of training during chemotherapy on endurance capacity and muscle strength were considered. Only 14 studies met all the inclusion criteria. The studies were assessed on methodological quality by using Cochrane criteria for randomized controlled trials. Results The quality of the studies was generally poor and the study populations varied considerably as the training programs were very heterogeneous. Variables of endurance capacity reported beneficial effects in 10 groups (59%). Increases due to training ranged from 8% to 31%. Endurance capacity decreased in nine of 13 control groups (69%), which ranged from 1% to 32%. Muscle strength improved significantly in 17 of 18 intervention groups (94%), ranging from 2% to 38%. Muscle strength also improved in 11 of 14 control groups (79%), but this increase was only minimal, ranging from 1.3% to 6.5%. Conclusions This review indicates that training during chemotherapy may help in preventing the decrease in muscle strength and endurance capacity. It is important to know which training intensity and duration is the most effective in training cancer patients, to provide a training program suitable for every cancer patient. Training should be based on good research and should be implemented into international guidelines and daily practice. More research is needed.

Ferlay et al. estimated 3.45 million new cases and 1.75 million deaths from cancer in Europe in 2012. In combination, cancers of the female breast, colorectal, prostate and lung represent almost half of the overall burden of cancer in Europe [1]. The survival rates have increased during recent years -nowadays 61% of the cancer patients will survive [2]. All these numbers show a future increase of the number of cancer survivors who have to deal with the side effects of cancer therapy.
A considerable number of cancer patients receive chemotherapy or radiotherapy. Side effects include both physical as well as psychological complications and have a huge impact on daily life. A frequently reported side effect from chemotherapy and radiation is cancer-related fatigue [3,4]. One study found that up to 82% of breast cancer patients experienced fatigue after their first chemotherapy cycle [5]. Cancer-related fatigue has a negative effect on muscle strength, endurance capacity, quality of life and return to work [6][7][8][9].
Chemotherapy may be myelotoxic, leading to anemia, which decreases the oxygen transport to the muscles [10]. In addition chemotherapy, particularly anthracyclines and irradiation of the mediastinum may result in myocardial damage and can therefore lead to a decrease in cardiac output or damage to the lungs [10]. Immunosuppressive agents may cause a marked loss of muscle mass [10]. Furthermore, anorexia and nausea caused by chemotherapy result in a reduced protein and calorie intake [10]. All these side effects may impair the physical performance in cancer patients [3,4]. Moreover, inactivity related to disease and/or treatment may cause deconditioning [5]. One study showed that in cancer patients, a maximum oxygen uptake (VO2max) of 14 ml/kg/min is not uncommon, which is even below the level of 15 ml/kg/min, which is the limit for activities for daily life [11,12].
In the past, patients were advised to rest and avoid physical effort. However, it is now well established that a decrease in physical activity results in severe deconditioning [10]. Physical exercise may have beneficial effects on reducing cancer-related fatigue, both during and following the administration of adjuvant therapies [7,[13][14][15][16]. Research has shown that physical activity after chemotherapy increases muscle strength, quality of life and return to work. Furthermore, it decreases cancerrelated fatigue. Physical activity is generally well tolerated and only a few adverse events, such as shoulder tendonitis, knee injury and syncope, during training occur [7,15,16].
The American College of Sports Medicine (ACSM) identifies types of exercise in their document 'General Principles of Exercise Prescription'. The types of exercise can be, among others, divided into aerobic exercise training and muscle exercise training. Aerobic exercise training improves body composition and cardiorespiratory fitness, while muscle exercise training improves muscle strength and muscle endurance. Any activity that uses large muscle groups can be maintained continuously and is rhythmical in nature can be regarded as an aerobic exercise. Muscle strengthening exercises enable muscles to do more work than they are accustomed. The aerobic intensity (training dose) can be expressed as a percentage of a person's VO2max/aerobic capacity or as a percentage of a person's maximum heart rate (HRmax), which could be measured by exercise tests. Moderate exercise is performed at 65-75% of HRmax and vigorous exercise is performed at 75-95% of HRmax. To approximate the appropriate limb-specific weight loads for resistance exercise (training dose), one can determine the one-repetition maximum (i.e. 1-RM) -the greatest resistance/weight that can be moved through the full range of motion for a single repetition in a controlled manner and then lift a defined percentage of that amount during each set of the exercise (i.e. % 1-RM) [17]. The ACSM advises a combination of aerobic training and progressive resistance training on moderate intensity for people training after chemotherapy. In concordance with the most recent literature the ACSM [18] also advises training during treatment with chemotherapy. Unfortunately, there is no guideline concerning which type of training and which training dose are effective.

Objectives
There is a lot of evidence that training after chemotherapy is very effective. There are guidelines providing training prescription after chemotherapy. Up to now it is not known what training program is the most effective in training patients during chemotherapy. The purpose of this paper is to gain insight in the different training modalities during chemotherapy, focusing on the most effective way to improve endurance capacity and muscle strength, using objectively measurable outcomes in order to compose a training program which trains cancer patients in the most effective way.
(2) Studies involving adult patients (418 years), diagnosed for malignancy and receiving chemotherapy. (3) Articles prescribing a physical exercise program, regardless of which type of exercise was prescribed. (4) Studies prescribing training during chemotherapy. (5) Studies using objective measurements of muscle strength or endurance capacity.

Exclusion criteria
(1) Reviews, case reports, study protocols and animal studies.
(2) Studies with patients treated with palliative intention, for this is a very heterogeneous group of patients.

Database search
A database search of PubMed up to and including January 2015 was performed, limited to studies in English, German and Dutch languages. Also the reference lists of relevant papers were searched for additional articles. The search was performed using the following terms: neoplasms OR neoplasm* OR cancer OR tumor OR tumors OR tumor* AND chemotherapy OR chemotherap* AND exercise therapy OR exercise.
The effects of the studies were graded according to the best evidence of Steultjens et al. [19]. The quality of the evidence was categorized into strong evidence, moderate evidence, limited evidence, indicative findings or no evidence [19,20].

Methodological quality
Study quality was assessed based on ''The Dutch Cochrane form for the assessment of randomized controlled trials'' [21]. However, two of the three criteria for blinding procedures could not be rated, because in physical activity interventions it is impossible to blind patients and care providers to the treatment assignment. Therefore the following seven criteria were applied and were rated as follows: yes (+), no (-), partially (+/-) or unclear (?).
(1) Were subjects randomly allocated? (2) Was allocation concealed? (3) Was there blinding of outcome assessors? (4) Were the groups similar at baseline? (5) Is loss to follow-up less than 80%? (6) Is an intention-to-treat analysis done? (7) Were the two groups treated equally, except for the intervention?

Study selection
The search resulted into 809 papers. The papers were screened for title and abstract by OH and CvM. In case of disagreement a third author was consulted. Twelve articles were selected for eligibility testing. Hand searching of the reference list of relevant reviews resulted in three additional articles. One article was excluded because it used the same data as another study, and focused mainly on hemoglobin changes during training [22]. In total 14 articles were included.

Quality assessment
Ratings of different quality criteria varied considerably (Table I).
The median score for quality was 4.25, ranging from 1 to 7.
Only one study met all the criteria. Only five studies (38%) had adequate allocation concealment. Blinding of the outcome assessors was fulfilled only in three studies. In most studies both study groups did not differ on baseline characteristic. Only a few studies took the drop-outs into account in their analyses and did an intention-to-treat analysis. In five studies the quality was very low, only scoring 1-3.5 of a maximum of seven criteria of the Cochrane Library Assessment forms. In these studies, besides the criteria mentioned in Table I, the outcome assessment was of low quality, the reasons for lossto-follow-up were not mentioned [23], people trained in the control groups as well [24,25], or the training program was of very long duration [24].

Subjects
Eight (46%) studies involved a total number of 595 breast cancer patients. Six studies (46%) involved patients with hematologic malignancies, resulting in a total number of 317 patients. Four studies selected cancer patient receiving stem cell transplantations. Three studies involved a heterogeneous group of cancer patients (Table II). The fitness level of the participants varied among the different studies. In the studies by Al-Majid, Hornsby and Campbell relatively young and fit breast cancer patients were recruited [26][27][28]. While Oechsle, Dimeo and Chang recruited relatively unfit patients, with hematological cancer types and Eastern Cooperative Oncology Group performance scores ranging from 0 to 3 [29][30][31]. Adherence among the different articles ranged from 66% to 82%.
The duration of the programs ranged from 3 to 52 weeks, with a median of 13.5 weeks. The frequency of the training sessions ranged from two to seven times per week, with a median of 5.5 sessions per week. Ten studies (71%) provided a supervised training program, three studies (23%) provided a home-based program and one study provided both (Table III).
In six studies (43%) a combination of resistance and aerobic training was applied. Six studies only focused on aerobic training. Only nine studies were accurate in describing the intensity of the training or the number of sets and repetitions. In the resistance exercises the intensity varied from 40% to 100% of 1-RM, and was mostly between 60% and 70% of 1-RM. All programs focused on large muscle groups and two studies used theraband exercises as training.

Endurance capacity
Variables of endurance capacity were assessed in 17 different intervention groups (14 articles) and reported beneficial effects in 10 groups (59%). Direct measurement of VO2max, which is the gold standard for measuring endurance capacity, was assessed in five intervention groups [25,27,31,32,34], indirect measurement of VO2max was measured in two intervention groups [27,28] (Table V). The studies reported significant increases due to training, which ranged from 8% to 31%. Endurance capacity decreased in nine of 13 control groups (69%), which ranged from 1% to 32% (Table VI). Effect sizes were very high in the papers of Al-Majid, and Campbell, 2, 7 and 2.3, respectively [26,28]. An effect size around 1 was calculated in the papers of Schwartz, Hornsby and Coleman [23,24,27] (Table IV).  ?

Muscle strength
strength (chest press) and lower body strength (leg press) were measured in nine intervention groups [24,[33][34][35], and showed an increase in eight groups. The increase on the leg press ranged from 4% to 33% and the increase in chest press ranged from 12% to 38%. Muscle strength also improved in 11 of 14 control groups (79%), but this increase was only minimal, ranging from 1.3% to 6.5%. An effect size of 0.3-0.8 was calculated in the papers of Courneya, Adamsen and Schwartz [24,33,34].

Summary of evidence
This paper gains insight into the different training modalities during cancer treatment with chemotherapy and focuses on the most effective way to improve physical fitness and muscle strength. The objective was to compose a training program in which people undergoing chemotherapy could be trained in the most effective way. In total 14 papers could be identified in which a training program during chemotherapy was compared to a control group. In addition to earlier reported improvements in cancer-related fatigue [16] these papers provide evidence to suggest that an exercise intervention during treatment with chemotherapy is associated with significant improvements in muscle strength as well as endurance capacity. Although the purpose of this study was to find the most effective way to improve endurance capacity and muscle strength, the papers were too heterogeneous to draw a distinct conclusion. Also, there was a lack in a consistent methodological approach in the dose of the training.

Limitations
This review is based on a small number of papers (n ¼ 14), their poor methodological quality suggests that not much research on this specific topic has been done so far. Most research has been done on quality of life or cancer-related fatigue [7,[13][14][15][16]. Furthermore, there was a large diversity in the study populations which ranged from very fit to unfit patients. There was also a considerable heterogeneity in tumor types, tumor stage and outcome measures.  The participation level in most papers was low. This suggests that only motivated patients participated in the studies. This is an important finding, it may have influenced the results, but is also a point of concern for future training programs, as unmotivated patients should be more encouraged and involved into training programs. As a result of the heterogeneity on several topics it was not possible to provide a meta-analysis. This was also the case in other reviews, focusing on the specific outcomes of objectively measured improvements in aerobic capacity and muscle strength [36,37]. Another limitation is the fact that only PubMed was searched, limiting the number of articles. Furthermore, we had to exclude some studies, e.g. a randomized controlled trial by Courneya et al. [38] in which no difference could be made between patients during and off treatment with chemotherapy.

Endurance capacity
Our review showed a general increase in endurance capacity. In people receiving chemotherapy for the treatment of lymphomas while not training, Vermaete et al. found a decrease of 7.8% in endurance capacity (VO2max) [39]. The magnitude of the improvement in our review, however, was inconsistent among the different groups. The improvement ranged from 4% to 33%. The greatest increase was seen in the study by Campbell et al. [26], which showed a 31% improvement on the 12-minute walking test after a follow-up of 12 weeks. Unfortunately, the sample size in this study was very small and the methodological quality was moderate. The calculated effect sizes were the highest in the papers by Campbell and Al-Majid, suggesting that the most effective training intensity ranges from 60% to 80% of maximum heart rate. The subjects in these papers were relatively fit breast cancer patients. In the paper by Courneya et al., lymphoma patients were provided with aerobic exercise training for 12 weeks. At post-intervention, the aerobic exercise training group was superior to the usual care group on all indicators of physical fitness, including VO2max [38]. This is comparable to the results of this review.

Muscle strength
Chemotherapy normally causes a severe decrease in muscle strength, especially in striated muscles [40]. Vermaete et al. showed a decrease of 5.6-14.6% in muscle strength in people not training and receiving chemotherapy for lymphoma [39]. In our review the muscle strength improved in the intervention groups as well as in the control groups, although the increase in the control groups was only minimal. A reason for the increase could be the high level of contamination. Many people in the control groups did a lot of training by themselves. This may have influenced the results. The calculated effect sizes were the highest in the papers of Courneya, Adamsen and Schwartz, the patients in these papers trained in 60-100% of 1-RM, in 2-3 sets of 5-12 repetitions. This suggests that the most effective training intensity is in that range. This is in concordance with De Backer et al., in which patients were trained after receiving chemotherapy. The patients trained at an intensity level of 65-80% of 1-RM in two sets of 10 repetitions, with an effect size of 1.3-2.7 [7]. This paper also showed long-term effects of a maintained muscle strength and quicker return to work [8].
Recent research suggests that cancer survivors experience participation in exercise-based rehabilitation as a means to fulfil their mental, social and physical well being independent of disease status [41]. Other papers suggest associations between lifetime and recent pre-diagnosis recreational physical activity and risk of all-cause death [42]. We continually need to raise awareness among health professionals to continue to suggest modifications to impact on fatigue and physical performance at all stages of cancer treatment and into survivorship and late effects [43].
It is important to know which training intensity and duration is the most effective in training cancer patients in order to provide a training program suitable for every cancer patient. Training should be based on good research and implemented  into international guidelines. Furthermore, it should be implemented into daily practice.

Conclusion
This literature review focuses specifically on the objectively assessed outcome measures muscle strength and endurance capacity in training programs during chemotherapy. It shows that training during chemotherapy is an effective way to improve muscle strength and endurance capacity in cancer patients. The overall positive results of training may warrant a more active approach to incorporate training in standard care. Given the limited availability of studies and the lack of standardization it is currently still unclear what training modalities are the best way to improve muscle strength and physical fitness. Future research should specifically focus on finding the most effective exercise intensity with the aim to gain insight into the most effective way to improve both muscle strength and endurance capacity in different patient groups.

Suggestions for future research
Future research should use valid and reliable physical outcome measures, such as VO2peak and upper-and lower body strength measures (1-RM). Furthermore, it is important to blind the outcome assessors. Also, a detailed prescription of the exercise intervention in terms of duration, intensity and frequency should be provided.
Although it is important to compare an intervention group to a control group, the high level of contamination suggests that this is difficult in daily practice. Patients participating in a study who are allocated to a control group tend to start training by themselves. A fair approach is to use a different method of research, such as clinical comparative research which is more practice based and combines implementation of effective intervention with research aiming to optimize these interventions [44].