Exercise rehabilitation in patients with cancer

Abstract

Emerging evidence indicates that patients with cancer have considerable impairments in cardiorespiratory fitness, which is likely to be a result of the direct toxic effects of anticancer therapy as well as the indirect consequences secondary to therapy (for example, deconditioning). This reduced cardiorespiratory fitness is associated with heightened symptoms, functional dependence, and possibly with an increased risk of cardiovascular morbidity and mortality. Current understanding of the complex interaction between the effects of the tumour and cancer-associated therapies on the organ components that govern cardiorespiratory fitness, and the effects of exercise training on these parameters is limited; further research will be critical for further progress of exercise-based rehabilitation in the oncology setting. We assess the current evidence regarding the level, mechanisms, and clinical importance of diminished cardiorespiratory fitness in patients with cancer. The efficacy and adaptations to exercise training to prevent and/or mitigate dysfunction in conjunction with exercise prescription considerations for clinical use are also discussed.

Introduction

Structured exercise training is established as the cornerstone of primary and secondary disease prevention in multiple clinical settings.¹ In stark contrast, the role of exercise following a diagnosis of cancer has, until recently, received comparably less attention.² The precise reasons for this are unknown but likely stem from the prevailing dogma that a cancer diagnosis is associated with poor prognosis, immune deficiency, and other severe debilitating side effects that preclude participation in, and benefit from, exercise training. Modern cancer management typically involves aggressive and prolonged combination locoregional and/or systemic therapy that causes a plethora of acute and long-term toxic effects leading to considerable functional morbidity and an increased risk of mortality from non-cancer-related causes.² Exercise training is a pleiotropic therapeutic strategy with the capacity to act across multiple organ systems³ to facilitate attenuation and/or prevention of cancer therapy-associated morbidity as well as improve clinical outcomes in patients with cancer.⁴ The purpose of this article is to review the current evidence regarding the level, mechanisms, and clinical importance of diminished cardiorespiratory fitness in patients with cancer. In addition, we also discuss the efficacy and mechanisms of exercise training to prevent and/or mitigate the adverse effects of therapy as well as provide exercise prescription guidelines for clinical practice.

Cardiorespiratory fitness

Definition of cardiorespiratory fitness

Cardiorespiratory fitness is determined by the transport and use of oxygen from the environment to the skeletal muscle mitochondria; therefore, it is governed by the integrative capacity of several organ components including the pulmonary and cardiovascular systems, the vasculature, blood, and skeletal muscle.⁵ Oxygen transport and use occurs via a series of convective and diffusive steps involving a sequential reduction in the partial pressure of oxygen, commonly termed the oxygen cascade.⁶ In this article, we use the oxygen cascade as a central framework to explain the factors contributing to reduced cardiorespiratory fitness and efficacy of exercise training to augment cardiorespiratory fitness.

Cardiorespiratory fitness measurement

In current oncology practice and clinical trials, the physiological status of patients is typically assessed through subjective performance status scoring systems (for example, Karnofsky Performance Status [KPS]) or evaluation of individual cardiac and/or pulmonary function at rest via echocardiography or spirometry, respectively. By contrast, an evaluation of cardiorespiratory fitness provides an assessment of the integrative capacity of the cardiovascular, haematopoietic, and musculoskeletal systems during stress (that is, aerobic exercise).⁷ There are several methods available that provide an objective determination of cardiorespiratory fitness (Table 1), and international guidelines on the proper conduct of cardiorespiratory fitness testing are available.^7–10 An incremental cardiopulmonary exercise test with gas exchange measurement, to assess peak oxygen consumption (VO_2peak), provides the gold standard assessment of cardiorespiratory fitness.

Table 1.

Cardiorespiratory fitness testing modalities

Characteristic	Maximal		Submaximal
	Cardiopulmonary exercise testing	Stress test	Age-predicted HR test	6 or 12 min walk test
Direct measurement of VO2	Yes	No	No	No
Estimated measurement of VO2	No	Yes—estimated from highest workload achieved during the test	Yes—estimated from the workload achieved at a predefined HR (70–85% HRmax)	Yes—estimated from BP and HR response during test
Equipment	Expired gas measurement system Electronically-braked cycle ergometer or motorised treadmill 12-lead ECG Pulse oximeter BP monitoring	Electronically-braked cycle ergometer or motorised treadmill 12-lead ECG Pulse oximeter BP monitoring	Electronically-braked cycle ergometer or motorised treadmill HR monitor Pulse oximeter BP monitoring 12-lead ECG (optional but recommended) Stop watch	30m corridor HR monitor Pulse oximeter Stop watch
Duration	8–12min	8–20min	8–20min	6 or 12 min
Description	Incremental exercise with expired gas analysis until volitional exhaustion or symptom limitation	Incremental exercise until volitional exhaustion or symptom limitation	Incremental exercise until predefined HR (70–85% HRmax) achieved	Participant asked to walk as far as possible in 6 or 12 min
Purpose	Intervention Non-intervention Exercise limitation Diagnosis (CVD) Prognosis Measurement of cardiorespiratory fitness	Intervention Non-intervention Diagnosis (CVD) Measurement of cardiorespiratory fitness	Non-intervention	Intervention Non-intervention Prognosis
Patient population	Operable (early stage) Inoperable (advanced stage) Undergoing therapy Off therapy Pre-surgery Pre-BMT	Operable (early stage) Inoperable (advanced stage) Undergoing therapy Off therapy	Operable (early stage)	Inoperable (advanced stage) Undergoing therapy Frail, elderly

Abbreviations: BMT, bone-marrow transplantation; BP, blood pressure; CVD, cardiovascular disease; ECG, echocardiogram; HR, heart rate; HR_max, heart rate maximum; VO₂, oxygen consumption.

Evidence of impaired fitness

Persuasive evidence is emerging showing that cancer patients have significant impairments in cardiorespiratory fitness; for instance, Loewen et al.¹¹ found that the mean VO_2peak in 346 presurgical patients with non-small-cell lung cancer (NSCLC) was 15.8 ± 0.43 ml/kg per min, which is equivalent to 36% below the mean VO_2peak for age-matched and sex-matched normative data for sedentary individuals. There is also evidence of significant impairment in cancer patient populations that are considered, in general, to have good functional status. For example, in a cohort of 130 patients with operable breast cancer with ‘good’ performance status (KPS ≥70) and normal cardiac function (that is, resting left ventricular ejection fraction ≥50%), 27 months following the completion of primary adjuvant therapy the mean VO_2peak was 22% below that of age-matched sedentary healthy women (L. W. Jones, personal communication). Evidence from randomised trials suggests that the observed marked impairment in VO_2peak in patients following the completion of therapy may be primarily sustained during adjuvant therapy; for example, 12 weeks of conventional anthracycline–cyclophosphamide neoadjuvant chemotherapy causes a 1.6 ml/kg per min (9.7%) decrease in VO_2peak in women with operable breast cancer.¹² In healthy women, VO_2peak typically declines 10% every decade.¹³ It is noteworthy that in addition to systemic adjuvant therapy, cancer patients with early stage disease also receive concomitant supportive medications (such as dexamethasone and antiemetics), and these agents may also contribute to observed declines in VO_2peak.¹⁴

Mechanisms of impairment

In non-cancer clinical populations, the causes of reduced cardiorespiratory fitness are often multifactorial with no single organ component of oxygen transport or use being identified as solely responsible.⁴ In brief, the causes of exercise intolerance can be classified into three major categories: first, pulmonary limitation (ventilatory and gas exchange limitations); second, cardiovascular limitation (impairment in cardiac and systemic circulation, and haematological parameters); and third, peripheral limitation (abnormalities impacting oxygen conductance and use, and skeletal muscle contraction).⁷ Patients diagnosed with cancer are the personification of a clinical population in which multifactorial causes are responsible for reduced cardiorespiratory fitness. Patients with cancer are often older than the general population and commonly present with a diverse range of pulmonary, cardiovascular, and/or musculoskeletal complications that limit exercise tolerance. Furthermore, prior and current treatment with anticancer and/or supportive-care therapies combined with tumour burden, when applicable, is expected to simultaneously impact several organ components in the oxygen cascade.⁴ Finally, indirect effects such as increased physical inactivity (deconditioning) will further contribute to marked reductions in cardiorespiratory fitness.¹⁵

Here we review the potential causes of reduced cardiorespiratory fitness in patients with cancer as organised by the organ components of the oxygen cascade (Table 2). An extensive discussion of the adverse impact of all anticancer and supportive-care therapies in the oncology setting is beyond the scope of this article; therefore, we focus on the effects of conventional cancer therapy (that is, surgery, combination chemotherapy, radiotherapy, and hormone therapy). To date, a paucity of studies has directly investigated the mechanisms of reduced cardiorespiratory fitness in cancer patients; thus, we also draw evidence from clinical studies with extrapolation to the postulated implications on mechanisms governing cardiorespiratory fitness.

Table 2.

Proposed mechanisms of impaired cardiorespiratory fitness in patients with cancer

Organ component of oxygen system	Oxygen transport component	Tumour and/or cancer therapy-associated impairment					At-risk cancer patient population
		Tumour presence	Surgery	Chemotherapy	Radiation	Hormone suppression
Pulmonary	Reduced diffusion capacity Increased alveolar hypoventilation Pulmonary vascular damage, remodelling, and fibrosis	Primary or secondary lung cancer (↑↑↑)	Thoracic surgery (↑↑↑)	Platinum-based chemotherapy (↑) Other classes (unknown)	Thoracic radiation (↑↑)	Unknown	Primary or secondary thoracic malignancies Presenting with concomitant respiratory disease Any population receiving thoracic or total-body irradiation
Cardiac	Left ventricular systolic dysfunction Reduced left ventricular relaxation Reliance on late rather than early filling Reduced ventricular compliance Reduced stroke volume Reduced cardiac output Reduced chronotropic reserve Reduced myocardial perfusion	NA	NA	Anthracycline-based chemotherapy (↑↑↑) Other classes (↑↑)	Thoracic radiation (↑↑)	ADT (↑) Endocrine therapy (unknown)	Any population receiving chemotherapy particularly anthracycline-containing regimens Presenting with concomitant cardiovascular disease or cardiovascular risk factors Any population receiving thoracic or total-body irradiation Elderly patients (>65 years)
Blood	Reduced haemoglobin concentration	Haematological malignancy (↑↑↑) Extensive bone metastases (↑↑)	Extensive surgery (↑↑↑)	All classes (↑↑↑)	Femur exposure (↑)	Unknown	The majority of cancer patients receiving any type of anticancer therapy
Vascular function	Impaired vasodilatory response to hyperaemia (that is, endothelial dysfunction) Increased arterial stiffness Increased reactive oxygen species or decreased anti-inflammatory expression	NA	NA	Anthracycline-based chemotherapy (↑) Other classes (unknown)	Thoracic radiation (↑)	Unknown	Any population receiving chemotherapy particularly anthracycline-containing regimens Presenting with concomitant cardiovascular disease or cardiovascular risk factors Any population receiving thoracic or total-body irradiation
Skeletal muscle oxidative capacity	Muscle atrophy Reduced capillarisation Reduced enzymes for oxidative phosphorylation Reduced mitochondrial density Reduced myoglobin concentration Fiber type transition to more glycolytic phenotype	Advanced disease (↑↑↑)	NA	Anthracycline-based chemotherapy (↑) Other classes (unknown)	Muscle- implicated radiation (unknown)	Unknown	Any population receiving chemotherapy, particularly anthracycline-containing regimens Patients experiencing cachexia Prolonged bed-rest (for example, post BMT) Presenting with concomitant cardiovascular disease or respiratory disease

Abbreviations: ↑, weak evidence; ↑↑, moderate evidence; ↑↑↑, strong evidence; ADT, androgen deprivation therapy; BMT, bone marrow transplantation; NA, not applicable.

Pulmonary limitations

The first step in the oxygen cascade is delivery of oxygen from the environment to the pulmonary capillaries, which is achieved by increasing ventilation to ensure the maintenance of arterial oxygen and carbon dioxide content. The efficiency of the pulmonary system is governed by alveolar ventilation (involving mechanical factors [that is, respiratory muscle function and airway mechanics]) and pulmonary gas exchange (diffusion capacity). Thus, anticancer therapies that adversely impact either of these processes contribute to exercise intolerance. Clearly, the therapy that is most clearly indicated in this regard is surgical resection of lung tissue in patients presenting with thoracic malignancies, because surgery can greatly reduce the maximal alveolar ventilation and reduce surface area for diffusion. The average reduction in VO_2peak is 15–20% and 30% after lobectomy and pneumonectomy, respectively. ^16,17 However, Hsia et al.¹⁸ found that lung diffusion during peak exercise was normal and the upper limit was not approached in patients with NSCLC after pneumonectomy, suggesting that other components of oxygen transport are also responsible for reduced VO_2peak in patients with NSCLC. Nevertheless, at least 30% of patients with inoperable NSCLC present with concomitant chronic obstructive pulmonary disease (COPD),¹⁹ as well as extensive tumour burden. Together, these factors adversely impact respiratory muscle mechanics, airway resistance and gas exchange,²⁰ contributing to dyspnoea and exercise intolerance.

Lung cancer is not the only malignancy where pulmonary limitations may contribute to the reduced cardiorespiratory fitness. Incidental radiation to the lungs in patients receiving upper thoracic radiation, alone or in combination with systemic chemotherapy, for operable breast cancer causes fibrosis and a subsequent reduction in diffusion capacity.²¹ To our knowledge, no study has investigated directly the impact of thoracic radiation or chemotherapy-induced pulmonary abnormalities on cardiorespiratory fitness in cancer patients.

Cardiac limitations

Oxygen is transported in the blood to metabolically active tissues via the pumping action of the heart. In response to exercise, heart rate and stroke volume increase to augment cardiac output in an attempt to match peripheral oxygen demand. Therefore, impairments in heart rate response and systolic and/or diastolic function are important contributors to exercise intolerance. Chemotherapy, radiation, and hormone therapy may adversely impact these parameters.

The detrimental effect of different classes of chemotherapeutic agents on cardiac function has been reviewed in detail previously.²² Anthracycline-containing chemotherapy can cause significant impairments in left ventricular dysfunction, which can ultimately lead to a reduced ejection fraction and overt heart failure.^23,24 Resting left ventricular ejection fraction was a significant predictor of VO_2peak in patients with operable breast cancer following the completion of anthracycline-containing adjuvant chemotherapy.²⁵ Of importance, patients with preserved ejection fraction may have impaired diastolic relaxation and filling.²⁶ Diastolic function is a significant determinant of VO_2peak in healthy individuals²⁷ and clinical populations, ²⁸ and is also likely to contribute to diminished VO_2peak in patients treated with anthracyclines.

Incidental radiation exposure can also cause cardiac abnormalities as myocardial perfusion defects were detected in 50% of patients receiving left-sided radiation for operable breast cancer.²⁹ The adverse impact of these defects on cardiorespiratory fitness is not known. The effects of hormone suppression (androgen deprivation therapy [ADT], oestrogen receptor antagonists and aromatase inhibitors) on cardiac function and exercise tolerance are also largely unknown. In preclinical work, ADT has been shown to impair cardiac function and cause higher β-myosin heavy chain distribution,³⁰ and the marked reduction in the bioactivity of oestrogen associated with aromatase inhibitor therapy theoretically raises concerns about the adverse cardiac effects of this therapy class.

Haematological and vascular function

An adequate concentration of haemoglobin molecules in the blood is critical for the transport of oxygen to the metabolically active skeletal muscles. Aetiologies that impact either the production or destruction of red blood cells cause a proportional reduction in arterial oxygen blood content, diminished convective oxygen delivery to the muscle capillary and reduced diffusive oxygen delivery into the muscle cell; all these effects will markedly reduce cardiorespiratory fitness. To varying degrees, all conventional anticancer therapies may cause a decrease in red-blood cell and haemoglobin concentrations through various aetiologies (excessive blood loss, red blood cell destruction or deficient production). Anaemia (haemoglobin concentration <12.0 g/dl and <13.0 g/dl for women and men, respectively) is a frequent complication in the oncology setting, particularly during chemotherapy, occurring in approximately 30–100% of patients.³¹ Due to the nature of the Fick Equation,³² a reduction in haemoglobin concentration will result in a proportional reduction in VO_2peak unless there is a compensatory effect in mitochondrial respiration. In healthy individuals, a 14% reduction in haemoglobin content was associated with a 10% decline in VO_2peak.³³ Dolan et al.³⁴ found significant correlations between percent change in VO_2peak and haemoglobin levels in women receiving conventional adjuvant chemotherapy for operable breast cancer.

Vascular structure and function has a critical role in regional blood flow control and hence the matching of blood flow to oxygen demand in the working muscles. There are a large number of vasodilatory substances (including, nitric oxide [NO], prostaglandins, endothelium-derived hyperpolarizing factor, adenosine and ATP) that are known to cause arterial vasodilation³⁵ and likely contribute to exercise hyperaemia. One of the primary vasodilator regulators is NO, which is essential for maintenance of vascular tone and integrity.³⁶ NO also has a vital role in scavenging free radicals or reactive oxygen species (ROS).³⁶ Thus, an increase in ROS production can dramatically reduce the beneficial vasodilatory properties of NO, leading to local vasoconstriction or a reduced functional sympatholysis during exercise. Of relevance, locoregional radiotherapy and certain forms of chemotherapy cause a dramatic increase in ROS generation, which can lead to direct endothelial injury, endothelial dysfunction, vascular remodelling and increased arterial stiffness.³⁷ In terms of locoregional radiotherapy, Beckman et al.³⁷ found that in patients with operable breast cancer, dilatation of the axillary artery exposed to irradiation was significantly impaired compared with the contralateral, non-irradiated artery. In terms of the arterial stiffness, significant increases in aortic stiffness were observed after 4 months exposure to anthracycline-containing chemotherapy.³⁸

Skeletal muscle

The final step in the oxygen cascade is the diffusive transport of oxygen from the capillary bed into the muscle cell to the mitochondria to resynthesise ATP. The efficiency of this process is governed by blood flow in the peripheral circulation, transport of oxygen through the muscle cell via myoglobin, and skeletal muscle oxidative capacity. Deficiencies in any of these steps will result in diminished cardiorespiratory fitness, although whether these defects alter VO_2peak in cancer patients remains largely unknown. Of the conventional anticancer therapies, there is a clinical consensus that ADT causes a plethora of unfavourable changes in skeletal muscle function including muscle weakness and muscle atrophy,³⁹ but few, if any, studies have examined whether such abnormalities are associated with reductions in cardiorespiratory fitness. Preclinical work found that doxorubicin caused a reduction in maximal twitch force,⁴⁰ impaired relaxation,⁴¹ and significant alterations in gene pathways responsible for regulating skeletal muscle glycolysis and fatty acid oxidation, which was accompanied by a significant reduction in exercise capacity (L. W. Jones, personal communication). Whether these findings translate to the clinical setting has not been investigated.

Certain solid tumours (such as, NSCLC, advanced-stage colorectal cancer and pancreatic cancer) produce a wide variety of proinflammatory cytokines (for example, TNF-α, interleukins and c-reactive protein) leading to a chronic state of low-grade systemic inflammation. Chronic activation of these cytokines are implicated in the pathogenesis of skeletal muscle atrophy and inhibition of muscle regeneration.⁴² Levels of proinflammatory cytokines are inversely related to VO_2peak in advanced-stage NSCLC.⁴³

Sedentary behaviour

Physical inactivity causes maladaptive changes in all organ components of oxygen transport. For example, in the seminal Dallas Bed Rest and Training Study,⁴⁴ 3 weeks of bed rest (inactivity) caused significant reductions in cardiac output, oxidative capacity, and muscle cross-sectional area (that is, muscle atrophy), which resulted in an approximately 35% decline in VO_2peak. Most cancer patients do not adhere to national exercise recommendations⁴⁵ and can experience significant declines in physical activity levels from pre-to-post diagnosis.⁴⁶ Reduced physical activity combined with the adverse effects of anticancer therapy on all components of the oxygen cascade will markedly reduce cardiorespiratory fitness.

In summary, the evidence reviewed here indicates that in most circumstances multiple factors contribute to diminished cardiorespiratory fitness in patients with cancer. Nevertheless, even if impairment in one organ component seems to be a major contributor to exercise intolerance (in a given patient), oxygen transport is an integrative process wherein functional impairment in one organ component is offset by initial adaptive and eventual maladaptive responses in the other oxygen transport components to maintain whole-body homeostatic regulation. ⁴⁷ As a consequence, the vast majority of patients have marked reductions in cardiorespiratory fitness relative to sex-matched and age-matched normative data.

Clinical importance

A wealth of studies provide convincing evidence of the remarkable ability of cardiorespiratory fitness to predict cardiovascular disease mortality and all-cause mortality in numerous adult populations.⁴⁸ Less is known regarding the prognostic importance of cardiorespiratory fitness in patients with cancer. In two studies, in comparison with patients in the lowest fitness categories, higher VO_2peak was associated with significantly prolonged survival in patients with NSCLC and metastatic breast cancer; the prognostic value of VO_2peak remained unchanged after adjustment for age, gender, and performance status (L. W. Jones, personal communication).⁴⁹ Beyond mortality risk-prediction, cardiorespiratory fitness in cancer patients is correlated with select patient-reported outcomes (for example, quality of life and fatigue), biomarkers associated with cancer progression (including metabolic hormones and proinflammatory cytokines), and cardiovascular disease risk factors (such as, blood pressure and lipid profile).^15,25,50 Finally, with marked reductions in cardiorespiratory fitness, some patients are required to exert near maximal or maximal effort to perform normal activities of daily living (such as, climbing stairs and gardening), which impacts functional independence; this issue is becoming a critical consideration as the number of elderly patients with cancer is anticipated to drastically increase over the next two decades.⁵¹

Efficacy of exercise training

Over the past decade, there has been increased research and clinical interest in the role of exercise training and rehabilitation following a cancer diagnosis both during and following cancer therapy.^52–54

After treatment cessation

Randomised trials, mostly in women with operable breast cancer, have investigated the safety, feasibility, and efficacy of exercise training in this setting.^52,53 The putative evidence supports the conclusion that structured exercise training is safe (few adverse events), well tolerated (adherence rates >80%), and associated with 10–15% improvements in different measures of cardiorespiratory fitness in studies adopting traditional exercise prescription guidelines (3–5 days per week at 50% to 75% of baseline VO_2peak for 12–15 weeks). Patient-reported outcomes including fatigue and quality of life also improved as a result of exercise training following adjuvant therapy.^52,53

During treatment

Although less well accepted, randomised trials indicate that exercise training—following traditional exercise prescription guidelines—is safe and well tolerated during various conventional therapeutic modalities and can negate the adverse effects of therapy on cardiorespiratory fitness.^52,53 For example, in the largest trial to date,⁵⁵ supervised aerobic training or resistance training did not improve VO_2peak in women undergoing conventional adjuvant chemotherapy for operable breast cancer. Aerobic training did, however, completely abrogate the significant VO_2peak decline (0.5 ml/kg per min) observed in the patients assigned to the non-intervention control group. Similarly, Segal et al.⁵⁶ reported that although 24 weeks of supervised aerobic training or resistance training was not associated with significant improvements in VO_2peak in men with prostate cancer receiving radiation therapy with or without ADT, it did abrogate the significant decline (1.2 ml/kg per min) observed in the control group.

On the basis of available evidence, second-generation studies are currently underway investigating the optimal exercise prescription (including type, frequency and intensity recommendations) to improve cardiorespiratory fitness in patients with cancer.^57–59 First-generation studies investigating the efficacy of exercise training in cancer populations that include patients with advanced-stage disease and those receiving novel anticancer therapeutics are also warranted.

Underlying mechanisms

Aerobic exercise training is widely established as one of the most-effective therapies to improve cardiorespiratory fitness in healthy individuals. Apart from lung diffusion capacity, it improves the reserve capacity of all other components of oxygen transport and use, which collectively lead to favourable improvements in VO_2peak.⁴⁴ An overview of the demonstrated efficacy of exercise training on the organ components of oxygen transport in non-cancer clinical populations is provided in Table 3. Unfortunately, there is a paucity of data describing whether similar exercise-induced adaptations occur in patients with cancer. As an initial step, we investigated the effects and mechanisms of supervised aerobic training during neoadjuvant chemotherapy, relative to chemotherapy only, in patients with operable breast cancer.¹² Aerobic training during chemotherapy resulted in an 11.8% improvement in VO_2peak, while VO_2peak declined 9.4% in patients receiving chemotherapy only. No changes in resting left ventricular ejection fraction were observed in either group although haemoglobin concentration significantly declined (to the same extent) in both groups. Aerobic training did improve endothelial function but these favourable adaptations in vascular function are unlikely to account for all of the improvements in VO_2peak, suggesting that augmentation of skeletal muscle oxidative capacity or maximal cardiac output were likely responsible. Unfortunately, neither exercise cardiac function nor muscle oxidative capacity was evaluated in this study.¹² Clearly, further mechanistically focused investigations are critical to improve our understanding of the complex nature of exercise-induced cardiopulmonary adaptations during different classes of anticancer therapeutics—such work has tremendous promise and may lead to the prevention and/or mitigation of the emerging adverse cardiovascular and skeletal muscle effects of anticancer therapy.

Table 3.

Efficacy of exercise training to augment oxygen transport organ components in clinical populations

Oxygen transport component	Evidence in non-cancer clinical patients	Evidence in cancer patients
Pulmonary	Increased diffusion capacity (–) Reduced expiratory obstruction (–) Reduced pulmonary vascular damage, remodelling, and fibrosis (–)	Not available
Cardiac	Increased left ventricular systolic function (↑↑) Increased left ventricular relaxation (↑↑) Improvements in early filling (↑↑) Increased ventricular compliance (↑↑) Increased stroke volume (↑↑↑) Increased cardiac output (↑↑↑) Increased chronotropic reserve (↑↑) Increased myocardial perfusion (↑)	Not available
Blood	Increased haemoglobin concentration (↑↑↑)	Haemoglobin concentration (–)
Vascular function	Improved endothelial function (↑↑↑) Reduced arterial stiffness (↑↑) Reduced reactive oxygen species or increased anti-inflammatory expression (↑↑↑)	Improved endothelial function (↑) Reduced reactive oxygen species or increased anti-inflammatory activity (↑)
Skeletal muscle oxidative capacity	Increased muscle mass (↑↑↑) Increased capillarisation (↑↑↑) Increased enzymes for oxidative phosphorylation (↑↑↑) Increased mitochondrial density (↑↑↑) Increased myoglobin concentration (↑) Fibre type transition to more fatigue resistant type IIA fibre (↑↑↑)	Increased muscle mass (↑↑)

Abbreviations: –, no change; ↑, weak evidence; ↑↑, moderate evidence; ↑↑↑, strong evidence.

Exercise prescription

Exercise training for cancer patients both during and following adjuvant therapy is recommended by several agencies.^52,60 In general, these recommendations follow the standard exercise guidelines for healthy individuals— 3–5 days per week for ≥30 min per session for moderate-intensity exercise or 3 days per week for ≥20 min per session for vigorous-intensity exercise. Although general exercise prescription guidelines likely confer health benefits for all individuals with cancer, exercise should be prescribed on a patient-by-patient basis with consideration of cancer type, therapy, limitations to exercise, and other medical characteristics. To this end, Table 4 provides examples of suggested exercise prescriptions for patients presenting with one of the three major classifications of exercise intolerance. Clearly, before initiation of any exercise program, it is highly advisable for all individuals to undergo appropriate pre-exercise screening; specific tools are available in the oncology setting.⁶¹

Table 4.

Exercise prescription guidelines for cancer patients

Patient characteristics (examples)	Goal of exercise	Initial prescription	Exercise progression
General (patients following the completion of adjuvant therapy for localised disease presenting with no overt underlying comorbid disease)	To improve all components of the oxygen cascade	Frequency: 3–5 days/week Intensity:* light to moderate Type: aerobic endurance Time: 20–40min/session	Frequency: 4–6 days/week Intensity:* light to vigorous Type: aerobic endurance, interval training and resistance Time: ~30–60min/session
Cardiovascular limitation (patients presenting with chemotherapy-induced LV dysfunction and/or anaemia)	Improved LV filling and relaxation, enhanced LV compliance, improvement in endothelial function, and decreased arterial stiffness	Frequency: 3 days/week Intensity:* light to moderate Type: aerobic endurance Time: ~20–30min/session	Frequency: 3–5 days/week Intensity:* moderate Type: aerobic Time: ~20–60min/session
Respiratory limitation (patients following pulmonary resection with concomitant COPD)	Reduced ventilatory demand and dyspnoea, with favourable skeletal muscle adaptations	Frequency: 3–4 days/week Intensity:* light to moderate Type: aerobic endurance and resistance Time: >20min/session	Frequency: 4–5 days/week Intensity:* moderate to vigorous Type: aerobic endurance, interval and resistance Time: ~20–60min/session
Peripheral limitation (patients presenting with tumour and/or treatment-induced cachexia or muscle atrophy)	Increased muscle mass and aerobic enzymes, and improved fibre type transition and oxidative metabolism	Frequency: 3 days/week Intensity:‡ light to moderate Type: resistance Time: 20–30min/session	Frequency: >3 days/week Intensity:‡ moderate Type: resistance and aerobic Time: ~20–60min/session

^*Relative intensities guideline for aerobic endurance training: light (light effort, normal or slight breathing, 40–50% of measured heart rate maximum or VO_2peak); moderate (moderate effort, elevated breathing, 50–70% of measured heart rate maximum or VO_2peak); vigorous (hard effort, greater breathing, >70% of measured heart rate maximum or VO_2peak).

^‡Relative intensities guideline for resistance training: light (50–60% of measured one repetition maximum), moderate (60–80% of measured one repetition maximum), and hard (>80% of measured one repetition maximum).⁶³

Abbreviations: COPD, chronic obstructive pulmonary disease; LV, left ventricular; VO_2peak, peak oxygen consumption.

Conclusions

Although the mechanisms remain to be elucidated, emerging evidence suggests that structured exercise training may be an important adjunct for optimal recovery and possibly prevention of therapy-associated exercise intolerance. In addition, our understanding of the molecular mechanisms underlying the purported protective properties of exercise against anticancer therapy-induced cardiovascular injury is virtually non-existent. This major research gap needs to be addressed since elucidation of these complexities will be essential to inform evidence-based exercise guidelines, as well as for the identification of new therapeutic targets to facilitate optimal health, quality of life, and longevity in cancer patients.

From a practical perspective, in contrast to other areas of clinical medicine, exercise training recommendations and/or exercise-based rehabilitation programmes are not part of standard clinical management following a cancer diagnosis. Establishment of such programmes face a number of major obstacles arguably the most important of which, at least in the USA, is that a cancer diagnosis is not considered a qualifying diagnosis for exercise-based rehabilitation by most major insurance companies. Other major hurdles include the requirement to establish programmes with personnel possessing the specialised knowledge of exercise–oncology principles, limited access to specialised services in rural communities, and lack of oncologist referral and support. In terms of the latter hurdle, the initiation of more sophisticated ongoing and forthcoming second-generation exercise– oncology trials will provide further rigorous evidence. However, simply increasing the number and size of trials may be insufficient; for example, despite overwhelming evidence of benefit, referral and adherence rates to exercise- based cardiac rehabilitation programmes remains alarmingly low.⁶² To avoid similar issues in the oncology setting, effectiveness-based (implementation) and cost-effectiveness studies together with continued advocacy from the various stake holders (in parallel with efficacy-based trials) is required to ensure wide implementation and uptake of these programmes.

Key points.

• Cardiorespiratory fitness is governed by the integrative capacity of the pulmonary and cardiovascular systems and skeletal muscle to transport and use oxygen to resynthesise ATP

• Patients with cancer have marked reductions in cardiorespiratory fitness due to impairments in one or more organs in the transport or use of oxygen as a result of anticancer therapy and effects secondary to therapy

• Emerging evidence indicates that cardiorespiratory fitness might be a robust predictor of prognosis following a cancer diagnosis

• Cardiorespiratory fitness level assessment might be an important tool to assess treatment tolerability in patients prior to therapy initiation

• Randomised trials indicate that exercise training is a safe and efficacious adjunct therapy to recover and/or prevent cancer therapy induced impairments in cardiorespiratory fitness

• Exercise should be prescribed on a patient-by-patient basis with consideration for cancer type, therapy, personal limitations and other medical characteristics

Review criteria.

A comprehensive literature review using PubMed, MEDLINE, Sport Discus, and Cochrane Controlled Trials Register (1966 to January 2012) was conducted using the following MESH terms and text words: ‘exercise’, ‘cardiorespiratory fitness’, ‘exercise capacity’, ‘cardiopulmonary fitness’, ‘functional capacity’, ‘exercise test’, ‘oncology’, and ‘cancer’. Relevant reference lists were also hand-searched.