Cardiopulmonary exercise for management of cardiovascular toxicity

Presurgery/therapy

The presurgery or therapy setting is broadly defined as investigating the impact of exercise in the period between primary diagnosis and surgical intervention. This setting is typically characterized as (1) a period of one to six weeks without administration of any anticancer therapy or (2) a period of several months with administration of chemotherapy with or without radiation (i.e., chemoradiation) or endocrine therapy until surgical resection (known as induction or neoadjuvant therapy). In the most common presurgery clinical scenario (i.e., no concurrent treatment administration), the primary question of interest is whether short-term exercise training can augment cardiovascular (physiologic) function (e.g., CRF) to, in turn, lower complications/recovery or even impact surgical eligibility. In a meta-analysis of 14 RCTs, single arm trials, and retrospective cohort studies investigating the effects of preoperative exercise in patients with lung cancer, Garcia and colleagues reported that, in comparison to usual care, exercise decreased hospital stay (mean difference, −4.83 days; 95% CI,−5.9 to −3.76) and significantly reduced postoperative complications risk (risk ratios [RR], 0.45; 95% CI, 0.28–0.74]). The two RCTs, which assessed postoperative outcomes in cancer types other than lung, had conflicting results. Dronkers and colleagues evaluated the efficacy of two to four weeks of preoperative aerobic training (2 days/week supervised, 4 days/week unsupervised 60 minutes/session at 55% to 75% peak heart rate) in 42 patients scheduled for abdominal surgery for colorectal cancer; no differences in postoperative complications or length of hospital stay were observed between groups. In contrast, Dunne and colleagues reported that four weeks of exercise (3 days/week, 30 minutes/session alternating between 90% and 60% of CRF) led to a four-day decrease in hospital stay compared with usual care in 38 patients undergoing liver resection for colorectal liver metastasis. In studies on CRF, Stefanelli and colleagues randomized 40 patients with non-small-cell lung cancer and chronic obstructive pulmonary disease to aerobic exercise (5 days/week, 30 minutes/ session at 70% of CRF), or usual care control for three weeks. Exercise training led to, 17% in CRF compared with no change in usual care. Collectively, extant evidence indicates that presurgical exercise therapy is an effective intervention to augment CRF and reduce postoperative complications.

During adjuvant therapy

The adjuvant therapy setting is defined as investigation of exercise during any form of primary adjuvant therapy (i.e., chemotherapy, radiation, or molecularly targeted therapy, except hormone deprivation therapy) following curative-intent. Key questions in this setting relate to whether exercise can prevent and/or mitigate common toxicities (e.g., cardiovascular dysfunction, anemia). Data from at least one observational cohort study support the initial contention that exposure to exercise during or around the period of adjuvant therapy may alter chronic therapy-related outcomes. In a study of 4015 patients with primary breast cancer, exercise exposure of, 18 metabolic equivalent hours per week (MET-h/week) was associated with an adjusted 37% (95% CI, 0.43 to 0.80) lower risk of any CVD event compared with less than 2 MET-h/week after 12.7 years of follow-up. Exercise is also associated with improvements in CRF in this setting. In a meta-analysis of RCTs evaluating the effects of exercise training on CRF in patients with adult-onset cancer, Scott and colleagues reported that among 14 studies conducted during therapy, exercise training improved CRF compared with usual care (weighted mean differences [WMD], +1.37 mL O ₂ /kg/min favoring exercise training; 95% CI,0.58 to 2.16).

Few studies have assessed the effects of exercise on cardiovascular outcomes other than CRF. In a single-arm study investigating the effects of 16 weeks of supervised linear aerobic training (3 days/week, 30 to 60 minutes/session at 60% to 0% peak heart rate) on CRF and cardiac function in 17 women previously treated with anthracycline-containing chemotherapy and currently receiving trastuzumab for human epidermal growth factor receptor 2 (HER2) positive early breast cancer, Haykowsky and colleagues found no significant change in CRF, that resting and peak end diastolic and end systolic left ventricle volumes significantly increased, and that resting and peak left ventricle ejection fraction significantly decreased. In sum, short-term (12 to 26 weeks) anticancer therapy markedly decreases CRF. Structured exercise training during this period may abrogate this marked decline; however, limited evidence exists regarding the effects of exercise on other CVD risk factors, and whether an exercise-induced attenuation in CRF decline is clinically meaningful is not known.

After adjuvant therapy (survivorship)

This setting is defined as investigation of exercise after the cessation of any form of primary adjuvant therapy, where exercise is applied to prevent and/or reverse CVD-related morbidity and mortality. Three epidemiologic studies have investigated whether exposure to exercise after primary treatment cessation lowers long-term risk of cause-specific late mortality. Jones and colleagues examined the association between exercise exposure and risk of major CVD events among adult survivors of childhood Hodgkin lymphoma (n = 1187; median age, 31.2 years; median follow up, 11.9 years) and women with primary breast cancer (n = 2973; mean age, 57 years; median follow up, 8.6 years). Adherence to national exercise guidelines was associated with an adjusted 23% (breast cancer) and 51% (Hodgkin lymphoma) lowered risk of CVD events, in comparison with not meeting guidelines. In extension of this work, Scott and colleagues reported that 3 or more MET-h/wk was associated with a 19% ( P = .026), 39% ( P = .026), and 11% ( P = .17) reduction in all-cause, recurrence/progression and health-related deaths, respectively, in 15,450 adult survivors of childhood cancer after median follow up of 10 years. Increase in exercise exposure (+7.9 ± 4.4 MET-h/week) over an 8-year period was associated with a 40% reduction in all-cause mortality rate compared with maintenance of low exercise exposure (RR, 0.60; 95% CI, 0.44 to 0.82). In a meta-analysis evaluating the effects of exercise training on CRF in RCTs (outlined above), Scott and colleagues reported that among 27 studies conducted after therapy, exercise was associated with a significant increase in CRF compared with usual care (WMD, +2.45 mL O ₂ /kg/min; 95% CI, 1.71 to 3.19).

Several studies have assessed the effects of exercise on cardiovascular outcomes other than CRF. For instance, Jones and colleagues investigated the efficacy of supervised nonlinear aerobic training (5 days/week [3 supervised, 2 home-based]; 30 to 60 minutes/session at 55% to 100% of CRF for 24 weeks) compared with usual care in 50 patients with prostate cancer and found that exercise improved endothelial function (as measured by flow-mediated dilatation of brachial artery), but there were no changes in body composition (as assessed by dual-energy x-ray absorptiometry), cardiac function (resting left ventricular ejection fraction), or biochemical CVD markers (e.g., lipids, glucose). Adams and colleagues reported that, compared with usual care, 12 weeks of exercise (3 days/week, 35 minutes/session at 75% to 95% VO _2peak ) improved vascular function (adjusted mean group differences of −0.6 mm, 1.54 10 ⁻³ /kPa, and −2.02 m/s for carotid intima-media thickness, carotid distensibility, arterial stiffness, respectively), and Framingham risk score (adjusted mean group difference −0.6%) in 63 patients with testicular cancer.

Finally, in an unplanned, ancillary retrospective analysis of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) trial, Jones and colleagues reported that among 90 patients with cancer and with heart failure, the incidence of cardiovascular mortality or cardiovascular hospitalization was significantly higher in the exercise group compared with the usual care group (67% vs. 41%; HR, 1.94; 95% CI, 1.12 to 3.16). In summary, most studies support the conclusion that exercise training after therapy augments CRF and improves CVD risk factors; only one small retrospective analysis has investigated the effects of exercise on clinical end points in patients with overt CVD (e.g., cardiovascular death, all-cause mortality).

In totality, meta-analyses and systematic reviews of the extant data conclude that exercise, and particularly supervised exercise, improves CRF in a broad array of patients with cancer before, during, and after treatment. Emerging data suggest that exercise during these periods may lower the risk of death from CVD and all causes following diagnosis, although confirmatory data from RCTs are not yet available.