Article Text

Download PDFPDF

Exercise interventions in metastatic cancer disease: a literature review and a brief discussion on current and future perspectives
Free
  1. Michal Wilk1,
  2. Jaroslaw Kepski2,
  3. Justyna Kepska2,
  4. Stephen Casselli3 and
  5. Sebastian Szmit2
  1. 1 Department of Oncology, Centre of Postgraduate Medical Education, European Health Centre, Otwock, Poland
  2. 2 Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre, Otwock, Poland
  3. 3 International Cardio-Oncology Society, Tampa, Florida, USA
  1. Correspondence to Dr Jaroslaw Kepski, Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre Otwock, Otwock, Poland; jaroslaw.kepski{at}gmail.com

Abstract

Exercise is a well-established factor which improves outcomes of oncological patients during curative treatment as well as in cancer survivors. However, the role of physical activity in metastatic disease, due to the deficiency of high-level evidence from prospective clinical trials, remains a partially unexplored field of research. Additionally, no specific guidelines related to exercise for persons with advanced cancer have been developed so far. Unfortunately, this research deficit may effectively prevent physicians from prescribing adequate and safe recommendations on physical activity to their patients. In an attempt to fill this gap in clinical practice, we present here an up-to-date review of potential benefits of exercise interventions in relation to the survival, quality of life and supportive care for patients with metastatic cancer. We also review the data on the safety of physical activity with special emphasis on elderly populations or individuals with bone metastases. Finally, we discuss the most relevant clinical factors that should be considered during exercise qualification. In conclusion, physical activity is an important tool for improving the outcomes of people undergoing anticancer therapy for metastatic disease. However, the training should be tailored individually to the patient’s functional status, comorbidities and preferences. Physical activity should become a standard component of every metastatic cancer care plan.

  • clinical assessment
  • quality of life
  • rehabilitation
  • supportive care
  • cancer

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Introduction

Exercise is a well-established factor which has a beneficial role on the course in numerous chronic disorders, for example, heart failure, chronic obstructive pulmonary disease or diabetes.1 Recently, more attention has been brought to the impact of exercise on cancer disease. Exercise interventions may potentially modulate the immune response and gene expression, reduce systemic inflammation and oxidative stress, or change tumour vascularisation.2 The supportive role of physical activity in patients undergoing curative oncological treatment or in cancer survivors is undeniable, as it has been confirmed in numerous clinical trials and meta-analyses. In these populations, exercise reduces anxiety, depressive symptoms and fatigue during or after anticancer therapy. It can additionally improve health-related quality of life (QoL), bone health and one’s overall physical condition.3 There is also strong evidence that patients with early cancer who achieve better results in a cardiopulmonary exercise test (CPET; with higher peak oxygen uptake—VO2peak) have a better prognosis.4 However, in most clinical trials that demonstrate such benefits, metastatic patients were excluded or were vastly underrepresented. Moreover, no specific guidelines for physical activity dedicated to patients with an incurable stage of the disease have been developed so far. Therefore, more attention should be given to this field of clinical research, especially in terms of adequate exercise qualification and its safety.

We hereby present a literature review that summarises the evidence for the impact of exercise on the course of incurable cancer disease and indicates the rationale for implementing movement interventions in every cancer care plan. We also discuss the most relevant factors that should be considered during the exercise qualification of patients with metastatic cancer.

Materials and methods

A search using the PubMed database was conducted to identify existing, published randomised clinical trials, reviews, systematic reviews and meta-analyses. Search terms were formulated using the PICO structure,5 that is, participants (P) included adults (>18 years old) with solid tumours who were considered to have metastatic cancer or were receiving palliative care. Intervention (I) included any form of exercise or physical activity. Comparisons (C) were restricted to exercise interventions versus none (we did not include studies with two or more simultaneous interferences, eg, exercise and nutrition counselling). Outcomes (O) involved survival, QoL or supportive gains such as improvements in physical function, fatigue, body composition, psychosocial aspects, sleep quality and so on. Combinations of the search terms: ‘cancer OR neoplasm’ and ‘advanced OR metastatic OR palliative’ and ‘exercise OR physical activity OR training’ AND ‘quality of life’ OR ‘safety’ OR ‘supportive care’ were used to screen titles and abstracts for potentially relevant studies. The search was limited to articles available in English. Figure 1 presents the Preferred Reporting Items for Systematic Reviews and a Meta-Analyses flow diagram.6

Figure 1

Preferred reporting items for systematic reviews and meta-analyses flow diagram.

Eventually, 25 articles were considered for the review. On the basis of the data from the aforementioned articles, we summarised the rationales for exercise interventions in patients with metastatic cancer. The eligibility criteria of each randomised clinical trial which reported safety outcomes were included in the discussion regarding the exercise qualification process.

Rationales for exercise interventions in patients with advanced cancer

Currently, there is increasing evidence that strongly supports the thesis that exercise interventions are beneficial not only for patients with early cancer but also for those with an incurable disease as well. Physical activity can positively affect survival and QoL, as well as play a significant role in supportive care.

Physical activity and survival

Until recently, there was no scientific evidence for a direct link between the intensity of physical activity and overall survival (OS) in patients with advanced cancer. The first evidence of this effect was reported by Jones et al. They demonstrated that women with metastatic breast cancer (n=52) who achieved VO2peak of <1.09 L/min had a median OS of 16 months vs 36 months for those who reported more than 1.09 L/min in CPET.7 Patients with advanced breast cancer were also a target population for Palesh et al. In a group of 103 patients, the median daily energy expenditure (MET/day) was 35.4. In the group of patients performing physical activity higher than that, the risk of mortality was lower (HR=0.90, 95% CI 0.84–0.97; p<0.01). In addition, engaging in one additional hour per day of moderate activity reduced the hazard of subsequent mortality by 23% (HR=0.77, 95% CI 0.65–0.92; p<0.01).8 Similar conclusions were presented by Guercio et al in a study of 1218 patients with metastatic colorectal cancer. Greater physical activity was associated with significantly longer progression-free survival. Patients undergoing physical training (18 or more MET hours/week) were characterised by a lower overall mortality rate, compared with a group with less than 3 MET hours/week (HR=0.85, 95% CI 0.71–1.02; p=0.06). In this unadjusted model, greater physical activity was associated with longer OS.9

In light of the research presented, it seems that aerobic physical training with adequate frequency and intensity, resulting in achieving high VO2peak, can have a positive effect on survival in patients with advanced cancer.

Physical activity, QoL and supportive care

Oncological treatment (systemic chemotherapy, radiotherapy, surgical or supportive treatment, eg, steroid therapy) may be associated with damage to the body at the molecular, cellular and organ levels, resulting in impaired function of, for example, the cardiovascular system.10 Exercise intolerance and low performance resulting from advanced cancer and comorbidities (including cardiovascular disease) are often a barrier to the inclusion of cancer therapy. The decrease in physical fitness and depletion of body reserves may also result in a worse response to oncological treatment and an increased incidence of side effects (eg, fatigue), which eventually may lead to inferior survival outcomes or deterioration of QoL. Maintaining good QoL during anticancer treatment is essential because as research shows, patients with metastatic cancer can value QoL even more than OS.11

In the last two decades, there has been a growing interest in using physical activity as a potential factor that could improve the QoL or play a role as supportive intervention in patients with an incurable disease. One of the first systematic reviews of the efficacy and beneficial effects of physical activity in patients with metastatic cancer was published in 2017 by Dittus et al. Their analysis reported an improvement of aerobic fitness, strength and physical function among those who exercised. However, the benefits of exercise interventions for reducing fatigue and improving QoL were less clear. Their findings suggested that QoL improved in more than half of the participants, but fatigue improved in less than half of those included in the analysis.12 In 2018, a systematic review (25 studies, 1188 participants) was published by Heywood et al. The authors concluded that most studies reported significant between-group and/or within-group improvements in physical function, QoL, fatigue, body composition, psychosocial function and sleep quality in patients with advanced cancer.13 In 2020, Chen et al presented the results of their systematic review regarding the impact of exercise on QoL and other cancer-related symptoms. Compared with routine care, the exercise served as an effective intervention to improve QoL and alleviate fatigue, insomnia, dyspnoea, physical and social functions for patients with metastatic cancer.14 In addition, Guercio et al demonstrated the positive impact of physical activity on reducing the frequency of chemotherapy complications (eg, neutropenia, anaemia, diarrhoea, dehydration, vomiting, nausea, cachexia and neuropathy) in patients with advanced colorectal cancer.9 In contrast to these encouraging data, Peddle-McIntyre et al performed a meta-analysis of randomised controlled trials, which compared exercise training vs no exercise training in adults with metastatic lung cancer only. QoL in the exercise group was significantly higher than in the group with no intervention. They found no significant effects of exercise training on dyspnoea, fatigue, feelings of anxiety and depression.15 Nevertheless, such discordance in the literature is an important subject for debate and a strong reason for further research on the influence of exercise on the course of advanced cancer disease.

The summary of exercise benefits in patients with metastatic cancer is presented in table 1.

Table 1

Summary of the evidence on exercise interventions among patients with metastatic cancer

Rationale for exercise qualification protocols in patients with advanced cancer

Despite the many benefits of exercise, only a handful of patients with cancer receive recommendations on how and how much to exercise. There are several potential barriers that account for this situation, however, the issue of safety is one of the most important.16 Metastatic patients are exposed to a variety of factors that increase the total risk of exercise complications, such as bone metastases or treatment toxicity (eg, low blood counts, polyneuropathy or cardiotoxicity). In addition, those patients can have multiple comorbidities that are, in themselves, contraindications to exercise.

Another important barrier is an insufficient level of experience among many medical professionals in exercise qualification for individuals with advanced cancer, especially in terms of selecting the right patient for the appropriate type of physical activity. Ideally, clinicians should perform an easily accessible, simple and safe test for assessing the performance of patients with cancer and reliably determining their physical fitness. In clinical practice, CPET is considered to be the gold standard for assessing exercise performance and differential diagnosis of exertional dyspnoea.17 CPET enables the clinician to exclude cardiovascular reasons for exercise intolerance. It is also a relatively safe and feasible assessment tool to objectively evaluate physical functioning in select patients with advanced cancer.18 Nevertheless, due to limited access to CPET in oncology departments, other possible assessment tools for exercise qualification for metastatic patients are awaiting development.

Special considerations for exercise in advanced cancer disease

Every patient with metastatic disease should be encouraged to exercise. However, before that, all relevant medical history for an exercise candidate should be evaluated, for example, age, body mass index, comorbidities (cardiovascular, pulmonary and musculoskeletal disorders), actual symptoms and exercise preferences. Due to the fact that numerous anticancer therapies have a hypertensive potential, blood pressure should always be evaluated.19 Patients ≥65 years old should undergo geriatric screening (using validated tools, eg, G-8 or VES-1320) and if found to be abnormal, then they should be referred to a geriatrician. The symptoms of greatest importance are dyspnoea, peripheral neuropathy, incontinence or bowel/bladder symptoms or pain. The presence of ostomy or the need of movement assisting devices should be noted. These, when present, should determine specific types of exercise interventions. The results of laboratory tests should also be taken into account, especially a complete blood count. Performing CPET and assessing physical fitness is highly recommended if available. This is particularly important in patients with a history of heart failure and suffering from dyspnoea or fatigue. Ideally, every patient should also undergo a cardio-oncologic evaluation as it may reveal important cardiovascular impairments.21 22

This information allows for the exclusion of important contraindications to exercise which are listed in table 2.

Table 2

Contraindications to exercise in patients with advanced cancer

The patient’s performance status is also a very important factor for safe qualification to exercise. The ECOG (Estern Cooperative Oncology Group) scale is used worldwide to describe a patient’s level of functioning in terms of their ability to care for themselves, daily activity and physical ability (table 3).23 Intensive exercise interventions should be mostly restricted to patients with an ECOG performance status of ‘0’ and ‘1’, as their functional reserves are enough to cope with increased body overload during physical activity. Patients with grade ≥2 should be encouraged to be active; however, they require a cautious and individualised approach, as they are at higher risk for exercise complications.

Table 3

ECOG (Estern Cooperative Oncology Group) performance status

Before exercise initiation, important characteristics of cancer such as the type or metastases’ localisation with a particular concern for bone involvement should also be noted. Current and prior oncological treatment should also be defined and thus, the probability of its most common complications can be anticipated. Therefore, a more carefully adjusted exercise schedule and its intensity can be planned.

Patients with bone metastases are at the highest risk for serious complications from exercise, with spinal cord compression being one of the most severe. However, many individuals with skeletal involvement are still candidates for physical activity. Careful assessment plays a key role here. It should consist of evaluating the location of metastases, estimating the risk of fractures and finally establishing a training plan that avoids exercise overload in metastatic sites (table 4).24 25 Nevertheless, it must be noted that these recommendations are based on results from small population clinical trials and they should be followed with caution.

Table 4

Precautions in resistance training for patients with prostate cancer and with bone metastases (based on Cormie et al 24 and Cheville et al 25)

For the assessment of long bones’ fracture risk, Mirel’s classification is worth mentioning (table 5).26 For patients with vertebral column metastases, for example, from breast cancer, an alternative non-invasive approach was introduced by Snyder et al. 27

Table 5

Mirel’s classification

In Mirel’s classification, scores of 7 or less represent a low risk of fracture and such patients should be encouraged at most to increase their daily physical activity.

The year 2020 brought very important progress in terms of exercise qualifications of patients with bone involvement. For the first time, exercise expert panels formed screening recommendations dedicated exclusively to individuals with skeletal metastases. Key consensus points highlighted the role of communication between a referencing physician and exercise professionals, for example, information regarding patient’s characteristics, bone scan results or current pain intensity and the history of its treatment. Such conscientious prescreening will be included in future guidelines of the International Bone Metastases Exercise Working Group.28

Several cancers (eg, brain) can impair gait or balance, therefore, an assistive device during exercise is strongly recommended. Stationary aerobic training or resistance band exercises are preferred.29 This is also a recommendation for patients with peripheral neuropathy. Patients with an ostomy should not be disqualified from physical activity; however, several safety issues should be taken into consideration. First, an ostomy bag should be emptied before engaging in exercise. Patients should then be encouraged to participate in weight training and muscle strengthening programmes. Contact sports and exercises that increase intra-abdominal pressure are not absolutely contraindicated; however, they should be supervised by trained personnel. Swimming is also an option but infection precautions are recommended.30

Evaluating basic information and the performance status of the patient and determining key characteristics of cancer help to develop a preliminary plan of physical activity. The aim is to fulfil exercise recommendations for cancer survivors or those with non-metastatic disease. According to the National Comprehensive Cancer Network, at least 150–300 min/week of moderate-intensity activity, or 75 min/week of vigorous-intensity activity, and two to three sessions of resistance training and stretching per week are recommended.31 Individual exercise, or supervised exercise programmes, or classes can be considered. Patients should be advised to start with light to moderate-intensity exercise (eg, walking) 1–3 days per week for 20 min per session, with incremental increases in time spent in physical activity, or in the intensity of activity as may be tolerated.

The main goal of implementing an exercise plan is to share the benefits of physical activity among persons with metastatic cancer. However, clinicians should be aware that unfortunately, many of their patients will not be able to reach the recommended intensity of exercise due to health or physical limits. Periodic evaluation (depending on treatment schedule) and additional evaluations on every disease progression is obligatory.

Summary

With increasing evidence supporting the safety and efficacy of exercise training, it has become an important field of clinical research in oncology. The benefits of physical activity can not only be seen in patients with early cancer, but also in metastatic populations. Individual exercise plans can improve both the prognosis and QoL for patients with advanced cancer and can also play a significant role as a supportive care tool. Therefore, physical activity should become a standard component of every cancer care plan. Despite the current deficiency of dedicated guidelines for physical activity for metastatic cancer populations, the positive trend can be seen as more national and international medical societies are trying to form more adequate recommendations. Clinicians should be provided with instructions that enable safe qualification for exercise interventions as there are numerous relevant factors which should be considered during this process. With a personalised approach and good communication between oncology specialists and exercise experts, the risks of complications from increased physical activity can be kept to a minimum.

Acknowledgments

The authors would like to thank Associate Professor Prue Cormie and Mark Trevaskis from Exercise and Nutrition Research Programme, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne for the permission to use the components of their original article which are shown in table 4.

References

Footnotes

  • Twitter @oncology_cardio

  • Contributors MW: conception or design of the work. MW, JaK and JuK: data collection; data analysis and interpretation. MW, SC and SS: drafting the article. MW, JaK, JuK, SC and SS: critical revision of the article; final approval of the version to be published.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.