Graeme J. Koelwyn

Cancer therapy-induced autonomic dysfunction in early breast cancer: Implications for aerobic exercise training

Breast cancer is the most common malignancy affecting women and the second leading cause of cancer death in women in the United States [1]. Due to improvements in detection and adjuvant therapy, breast cancer specific mortality has decreased significantly in women with early stage disease, and the five-year relative survival rate for early stage disease has increased from 80% in 1950 to 89% today [1]. Increased breast cancer specific survival, however, is at risk of being offset by the potential late occurring cardiovascular toxic effects of oncologic therapy. Indeed, among women with early breast cancer, particularly those over age 65, cardiovascular disease (CVD) is now the predominant cause of mortality, and these women are also at increased risk of CVD compared with age-matched women without a history of breast cancer [2].

Running on Empty: Cardiovascular Reserve Capacity and Late Effects of Therapy in Cancer Survivorship

Seminal investigations by Frank 1 and Starling 2 provided thefirst evidence that the heart possesses inherent reserve capacity—a key principle that is a pillar of modern cardiology research and practice. After 150 years of research, we now understand that cardiovascular reserve capacity (CVRC) is determined by the integrative ability of cross-system mechanisms (eg, neurohormonal, central, and peripheral oxygen delivery 3 ), which collectively possess remarkable adaptive capacity. Sequential as well as concurrent pathologic perturbations to either one or more of these mechanisms are offset by initial compensatory adaptive responses in other component systems to maintain whole-body homeostatic regulation—a process termed coordinated adaptation. 4 Unfortunately, CVRC is finite, and continued insults ultimately lead to overt dysfunction (eg, acute coronary syndromes, left ventricular dysfunction). Pathologic impairments in CVRC are etiologicinmanychronicdiseaseconditionsandarethusanintegralconsiderationindailypractice.Thepurposeofthiscommentaryistoprovidean overviewoftheguidingprinciplesandapplicationofCVRCintheoncology setting using early breast cancer as an illustrative model. Measurement of CVRC

Exercise therapy as treatment for cardiovascular and oncologic disease after a diagnosis of early-stage cancer.

Advances in early detection and adjuvant therapy have led to dramatic improvements in longevity after a cancer diagnosis. As a result, there are ~13.7 million cancer survivors alive in the United States, with this figure projected to increase to 18 million in 2022. Despite improvements in the 5-year relative survival rates, cancer patients with early-stage disease not only remain at high risk of cancer recurrence but also have sufficient longevity to now be at risk for late effects of adjuvant therapy, particularly cardiovascular disease (CVD). Against this background, we review here the risk factors common to cancer and CVD as well as the extant evidence supporting the potential efficacy of exercise therapy to modify the risk of cancer-specific and CVD-specific mortality in persons with cancer. We also evaluate evidence from clinical studies investigating the effects of structured exercise therapy to modify risk factors common to cancer and CVD. Findings of this review indicate that several major biomarkers/risk factors are predictive of both recurrence as well as non-cancer mortality in persons diagnosed with cancer. Such information is important to health professionals providing disease-risk screening as well as informing effective management strategies in long-term cancer survivors. In terms of the latter, there is growing but preliminary evidence that exercise may be efficacious in lowering both recurrence and CVD risk in cancer patients.

Exercise therapy in the management of dyspnea in patients with cancer.

Purpose of reviewDyspnea is a frequent, debilitating, and understudied symptom in cancer associated with poor prognosis and reduced health-related quality of life. The purpose of this study is to review the incidence, pathophysiology, and mechanisms of dyspnea in patients diagnosed with cancer. We also discuss the existing evidence supporting the efficacy of exercise therapy to complement traditional approaches to reduce the impact of this devastating symptom in persons with cancer. Recent findingsIn other clinical populations presenting with dyspnea, such as chronic obstructive pulmonary disease, exercise therapy is demonstrated to be an efficacious strategy. In contrast, relatively few studies to date have investigated the efficacy of exercise training as a therapeutic strategy to mitigate dyspnea in patients with cancer. SummaryAlthough much more work is required, exercise therapy is a promising adjunct strategy to systematically reduce dyspnea in the oncology setting that may also provide additive efficacy when prescribed in combination with other adjunct therapies including pharmacologic interventions.

Efficacy of Exercise Therapy on Cardiorespiratory Fitness in Patients With Cancer: A Systematic Review and Meta-Analysis

Purpose To evaluate the effects of exercise therapy on cardiorespiratory fitness (CRF) in randomized controlled trials (RCTs) among patients with adult-onset cancer. Secondary objectives were to evaluate treatment effect modifiers, safety, and fidelity. Methods A systematic search of PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library was conducted to identify RCTs that compared exercise therapy to a nonexercise control group. The primary end point was change in CRF as evaluated by peak oxygen consumption (VO2peak; in mL O2 × kg-1 × min-1) from baseline to postintervention. Subgroup analyses evaluated whether treatment effects differed as a function of exercise prescription (ie, modality, schedule, length, supervision), study characteristics (ie, intervention timing, primary cancer site), and publication year. Safety was defined as report of any adverse event (AE); fidelity was evaluated by rates of attendance, adherence, and loss to follow-up. Results Forty-eight unique RCTs that represented 3,632 patients (mean standard deviation age, 55 ± 7.5 years; 68% women); 1,990 (55%) and 1,642 (45%) allocated to exercise therapy and control/usual care groups, respectively, were evaluated. Exercise therapy was associated with a significant increase in CRF (+2.80 mL O2 × kg-1 × min-1) compared with no change (+0.02 mL O2 × kg-1 × min-1) in the control group (weighted mean differences, +2.13 mL O2 × kg-1 × min-1; 95% CI, 1.58 to 2.67; I2, 20.6; P < .001). No statistical significant differences were observed on the basis of any treatment effect modifiers. Thirty trials (63%) monitored AEs; a total of 44 AEs were reported. The mean standard deviation loss to follow-up, attendance, and adherence rates were 11% ± 13%, 84% ± 12%, and 88% ± 32%, respectively. Conclusion Exercise therapy is an effective adjunctive therapy to improve CRF in patients with cancer. Our findings support the recommendation of exercise therapy for patients with adult-onset cancer.

Ventricular-Arterial Coupling in Breast Cancer Patients After Treatment With Anthracycline-Containing Adjuvant Chemotherapy

BACKGROUND Anthracycline-containing chemotherapy (Anth-C) is associated with long-term cardiovascular mortality. Although cardiovascular risk assessment has traditionally focused on the heart, evidence has demonstrated that vascular dysfunction also occurs during and up to 1 year following Anth-C. Whether vascular dysfunction persists long-term or negatively influences cardiac function remains unknown. Hence, the present study evaluated ventricular-arterial coupling, in concert with measures of vascular structure and function, in the years following Anth-C. METHODS Arterial elastance (Ea), end-systolic elastance (Ees), and ventricular-arterial coupling (Ea/Ees) were measured during rest and exercise using echocardiography. Resting vascular function (flow-mediated dilation) and structure (carotid intima-media thickness, arterial stiffness) were also measured. RESULTS Thirty breast cancer survivors (6.5 ± 3.6 years after Anth-C) with normal left ventricular ejection fraction (LVEF) (60% ± 6%) and 30 matched controls were studied. At rest, no differences were found in Ea, Ees, Ea/Ees, or LVEF between groups. The normal exercise-induced increase in Ees was attenuated in survivors at 50% and 75% of maximal workload (p < .01). Ea/Ees was also higher at all workloads in the survivors compared with the controls (p < .01). No differences in vascular structure and function were observed between the two groups (p > .05). CONCLUSION In the years after Anth-C, ventricular-arterial coupling was significantly attenuated during exercise, primarily owing to decreased LV contractility (indicated by a reduced Ees). This subclinical dysfunction appears to be isolated to the heart, as no differences in Ea were observed. The previously reported adverse effects of Anth-C on the vasculature appear to not persist in the years after treatment, as vascular structure and function were comparable to controls. IMPLICATIONS FOR PRACTICE Anthracycline-induced cardiotoxicity results in significantly impaired ventricular-arterial coupling in the years following chemotherapy, owing specifically to decreased left ventricular contractility. This subclinical dysfunction was identified only under exercise stress. A comprehensive evaluation of vascular structure and function yielded no differences between those treated with anthracyclines and controls. Combined with a stress stimulus, ventricular-arterial coupling might hold significant value beyond characterization of integrative cardiovascular function, in particular as a part of a risk-stratification strategy after anthracycline-containing chemotherapy. Although vascular function and structure were not different in this cohort, this does not undermine the importance of identifying vascular (dys)function in this population, because increases in net arterial load during exercise might amplify the effect of reductions in contractility on cardiovascular function after anthracycline-containing chemotherapy.

Ultrasonography and Tonometry for the Assessment of Human Arterial Stiffness

The structure and function of the human vasculature is integral to the efficacy of the cardiovascular system. In particular, arteries function as both a reservoir to dampen oscillations from the pumping heart, as well as a conduit to transport blood to the periphery. With age and disease, alterations in the composition of the arterial wall can occur. This can result in arteries becoming more resistant to wall deformation, referred to as arterial stiffness, which can have significant implications for the development of cardiovascular disease. Due to the emergence of arterial stiffness as a measure of cardiovascular disease risk, a number of non-invasive techniques have been developed, which include the use of ultrasonic assessment. These techniques are highly effective, reliable, and well validated, and consider stiffness both locally (most commonly measured at the carotid artery) as well as regionally (most commonly measured through the aorta) in the arterial tree. The assessment of arterial stiffness is critical to our understanding of the overall vascular health, and is the focus of this chapter.

Comparison of performance status with peak oxygen consumption in operable patients with non-small-cell lung cancer.

In this era of increasing options for treatment of ‘surgical’ lung cancer patients, preoperative physiologic assessment of accurate patient selection is becoming more important. The variability in an objective measure of cardiorespiratory fitness (peak oxygen consumption (VO2peak)) across performance in operable non‐small‐cell lung cancer (NSCLC) patients enrolled in the Cancer and Leukemia Group B trial was compared.

Short of breath, short of benefit: Important considerations for the rehabilitation of IPF patients

Pulmonary rehabilitation is a multidisciplinary intervention that includes exercise training, disease specific education and behaviour modification techniques designed to reduce symptoms, improve functional capacity, enhance health-related quality of life (HRQL) and allow patients with respiratory disease to better self-manage their condition. Where pulmonary rehabilitation has been a standard of care for some time in patients with COPD, there is growing evidence to make the same recommendation for all patients with chronic lung disease. For patients with IPF, preliminary studies consistently demonstrate pulmonary rehabilitation can improve functional capacity, exertional dyspnoea and HRQL albeit to a lesser magnitude than in individuals with COPD. With all of the documented benefits of pulmonary rehabilitation for patients with chronic lung disease, it is easy to become complacent and accept that pulmonary rehabilitation is working for all patients. Closer inspection of individual responses to any pulmonary rehabilitation program identifies that many patients do not achieve minimal clinically important improvements in dyspnoea, functional capacity or HRQL. This concept was highlighted by Vagaggini et al., who demonstrated that following 8 weeks of pulmonary rehabilitation, only 45% and 53% of patients with COPD obtained the established minimally clinically important improvements in 6-minute walk distance (6MWD) 8 and HRQL (measured by the disease specific St Georges’ Respiratory Questionnaire). These findings are not unique to COPD, as a recent retrospective study reported that only a50% of patients with interstitial lung disease (approximately half of whom had IPF) demonstrated minimal clinically important improvements in Borg dyspnoea and 6MWD following 6–8 weeks of pulmonary rehabilitation. There are many factors that could impact the benefits of pulmonary rehabilitation. Previously, we reported that the magnitude of improvements in exercise tolerance following a pulmonary rehabilitation program in patients with COPD was strongly associated with the volume and intensity of exercise performed during the program. The finding that those who perform more exercise, or exercise at a higher intensity, get greater improvements is intuitive but reminds us that if exercise is not optimally prescribed or if a patient has multiple limitations to exercise, then gains could be greatly reduced. There are many factors that may contribute to a reduced ability to perform exercise for patients with IPF, including mechanical constraint to ventilation, diffusion limitation, ventilation–perfusion mismatching, cardiovascular limitation, neuromuscular disorders, and peripheral muscle dysfunction and weakness. However, the severity of exertional dyspnoea experienced by patients is often most critical in determining the type, intensity and volume of exercise that a patient can perform. In this issue of Respirology, Kozu and colleagues advance current understanding of how dyspnoea severity and the accompanying disability affects the benefits that can be gained from pulmonary rehabilitation in patients with IPF. Patients were grouped according to the Medical Research Council (MRC) dyspnoea scale, with those reporting MRC grades 2–4 performing 8 weeks of supervised comprehensive pulmonary rehabilitation twice weekly and those with the most severe disability (MRC grade 5) participating in an unsupervised, home-based program. A strength of the study was that the exercise prescriptions were individualized to each patient and progressed throughout the study in an attempt to optimize exercise, even for those exercising at home. Kozu reports improvements in 6MWD, HRQL (measured by the SF-36) and dyspnoea (transitional dyspnoea index), with those in MRC grades 2 and 3 having the greatest improvements in 6MWD and HRQL. Importantly, those in MRC grade 2 were the only group with a clinically important change in mean 6MWD for this population, suggesting that pulmonary rehabilitation may have a reduced clinical benefit for patients classified MRC grade 3–5. However, another encouraging finding of the study was the substantial reduction in the total number of hospital admissions and days in a hospital bed in the year following rehabilitation in the MRC grade 2, 3 and 4 groups, even though pulmonary rehabilitation did not greatly improve the more traditional outcomes for those in MRC grade 4. Kozu and colleagues appropriately suggest this unique finding may be related to the educational aspects of pulmonary rehabilitation improving the patient’s ability to self-manage their condition. The investigation of Kozu et al. accentuates that, although patients are referred to pulmonary rehabilitation to reduce dyspnoea, it is often the severity of breathlessness that prevents patients gaining more from pulmonary rehabilitation. This dilemma encourages us to revisit a number of questions regarding the

Preventing Cardiovascular Complications of Breast Cancer Treatment: The Utility of Effective Exercise Prescription

Advances in early detection and adjuvant therapy have led to dramatic improvements in longevity following a cancer diagnosis. As a result, approximately 3 million breast cancer survivors are alive in the US, with this figure projected to increase to 3.7 million in 2022. However, conventional breast cancer therapies (i.e., chemotherapy, radiotherapy, endocrine therapy, HER-2–directed therapies) can lead to important cardiovascular side-effects, particularly cardiovascular disease (CVD). Since adjuvant therapy for breast cancer is curative in the vast majority of scenarios, it is critical to identify strategies that permit maximum antitumor efficacy whilst minimizing acute and long-term toxicities in order to optimize long-term overall survival and quality of life. Here we overview the cardiac and vascular risk toxicities associated with breast cancer adjuvant therapy as well as the extant evidence supporting the efficacy of aerobic exercise training to modify CVD-specific mortality in women with early breast cancer. Such information is important to clinicians and exercise oncology researchers who are developing effective management strategies in long-term cancer survivors.