Whitney E. Hornsby

Cardiopulmonary Function and Age-Related Decline Across the Breast Cancer Survivorship Continuum

PURPOSE To evaluate cardiopulmonary function (as measured by peak oxygen consumption [VO(2peak)]) across the breast cancer continuum and its prognostic significance in women with metastatic disease. PATIENTS AND METHODS Patients with breast cancer representing four cross-sectional cohorts--that is, (1) before, (2) during, and (3) after adjuvant therapy for nonmetastatic disease, and (4) during therapy in metastatic disease--were studied. A cardiopulmonary exercise test (CPET) with expired gas analysis was used to assess VO(2peak). A Cox proportional hazards model was used to estimate the risk of death according to VO(2peak) category (< 15.4 v ≥ 15.4 mL · kg(-1) · min(-1)) with adjustment for clinical factors. RESULTS A total of 248 women (age, 55 ± 8 years) completed a CPET. Mean VO(2peak) was 17.8 ± a standard deviation of 4.3 mL · kg(-1) · min(-1), the equivalent of 27% ± 17% below age-matched healthy sedentary women. For the entire cohort, 32% had a VO(2peak) less than 15.4 mL · kg(-1) · min(-1)--the VO(2peak) required for functional independence. VO(2peak) was significantly different across breast cancer cohorts for relative (mL · kg(-1) · min(-1)) and absolute (L · min(-1)) VO(2peak) (P = .017 and P < .001, respectively); VO(2peak) was lowest in women with metastatic disease. In patients with metastatic disease (n = 52), compared with patients achieving a VO(2peak) ≤ 1.09 L · min(-1), the adjusted hazard ratio for death was 0.32 (95% CI, 0.16 to 0.67, P = .002) for a VO(2peak) more than 1.09 L · min(-1). CONCLUSION Patients with breast cancer have marked impairment in VO(2peak) across the entire survivorship continuum. VO(2peak) may be an independent predictor of survival in metastatic disease.

Effect of Exercise Training on Peak Oxygen Consumption in Patients with Cancer: A Meta-Analysis

BACKGROUND We conducted a meta-analysis to determine the effects of supervised exercise training on peak oxygen consumption (VO(2peak)) in adults with cancer. METHODS A literature review using Ovid MEDLINE (1950-2010), the Cochrane Central Register of Controlled Trials (1991-2010), AMED (1985-2010), Embase (1988-2010), PubMed (1966-2010), Scopus (1950-2010), and Web of Science (1950-2010) was performed to identify randomized controlled trials examining the effects of supervised exercise training on measurement of VO(2peak) (via gas exchange analysis) in adults with cancer. Studies were selected using predetermined criteria, and two independent reviewers extracted data. Weighted mean differences (WMDs) were calculated using random effect models. RESULTS Six studies evaluated VO(2peak) involving a total of 571 adult cancer patients (exercise, n = 344; usual care control, n = 227). Pooled data indicated that exercise training was associated with a statistically significant increase in VO(2peak) (WMD, 2.90 ml·kg(-1)·min(-1); 95% confidence interval [CI], 1.16-4.64); however, significant heterogeneity was evident in this estimate (I(2), 87%). Usual care (control) was associated with a significant decline in VO(2peak) from baseline to postintervention (WMD, -1.02 ml·kg(-1)·min(-1); 95% CI, -1.46 to -0.58; I(2), 22%). Sensitivity analyses indicated superior improvements in VO(2peak) for studies conducted for a shorter duration (<4 months) and following the completion of adjuvant therapy (p-values < .001). Exercise training was not associated with a higher incidence of adverse events, although safety was not rigorously monitored or reported. CONCLUSIONS Supervised exercise training is associated with significant improvements in VO(2peak) following a diagnosis of early-stage cancer, with minimal adverse events.

Prognostic significance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer

BACKGROUND To investigate the prognostic importance of functional capacity and exercise behavior in patients with metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Using a prospective design, 118 consecutive participants with histologically confirmed metastatic (inoperable) NSCLC and Eastern Cooperative Oncology group (ECOG) 0-3 completed a six-minute walk test to assess functional capacity and questionnaire that assessed self-reported exercise behavior. Cox proportional models were used to estimate the risk of all-cause mortality according to six-minute walk distance (6MWD) (<358.5m, 358.5-450 m, ≥450 m) and exercise behavior (MET-hrswk(-1)) categories with adjustment for important covariates. RESULTS Median follow-up was 26.6 months; 77 deaths were reported during this period. Functional capacity was an independent predictor of survival (P(trend)=0.003) and added incremental prognostic value beyond that provided by PS plus other traditional markers of prognosis (P(trend)=0.025). Compared with patients achieving a 6MWD <358.5m, the adjusted hazard ratio (HR) for all-cause mortality was 0.61 (95% CI, 0.34-1.07) for a 6MWD of 358.5-450 m, and 0.48 (95% CI, 0.24-0.93) for a 6MWD >450 m. In unadjusted analysis, there was a borderline significant effect of exercise behavior on survival (p=0.052). Median survival was 12.89 months (95% CI, 9.11-21.05 months) for those reporting <9MET-hrswk(-1) compared with 25.63 months (95% CI, 11.28 to ∞ months) for those reporting ≥9MET-hrswk(-1). CONCLUSIONS Functional capacity is a strong independent predictor of survival in advanced NSCLC that adds to the prediction of survival beyond traditional risk factors. This parameter may improve risk stratification and prognostication in NSCLC.

Safety and efficacy of aerobic training in operable breast cancer patients receiving neoadjuvant chemotherapy: A phase II randomized trial

Abstract Background. To evaluate the safety and efficacy of moderate-to-high intensity aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Methods. Twenty patients with stage IIB–IIIC operable breast cancer were randomly assigned to receive doxorubicin plus cyclophosphamide (AC) or AC in combination with aerobic training (AC + AET) (n = 10/group) for 12 weeks. The AC+ AET group performed three supervised aerobic cycle ergometry sessions per week at 60%–100% of exercise capacity (VO2peak). Safety outcomes included exercise testing as well as treatment- and exercise training-related adverse events (AEs), whereas efficacy outcomes included cardiopulmonary function and patient-reported outcomes (PROs) as measured by a cardiopulmonary exercise test (CPET) and Functional Assessment of Cancer Therapy-Breast (FACT-B) scale. Results. Twelve non-significant ECG abnormalities and three non-life threatening events occurred during CPET procedures. One AE was reported during aerobic training. There were no significant between group differences for clinician-documented events (e.g. pain, nausea) or hematological parameters (ps > 0.05). Attendance and adherence rates to aerobic training were 82% and 66%, respectively. Intention-to-treat analysis indicated that VO2peak increased by 2.6 ± 3.5 ml/kg/min (+ 13.3%) in the AC + AET group and decreased by 1.5 ± 2.2 ml/kg/min (−8.6%) in the AC group (between group difference, p = 0.001). FACT-B increased 11.1 points in the AC + AET group compared to a 1.5 point decrease in the AC group (between group difference, p = 0.685). Conclusion. Moderate-to-high intensity aerobic training when conducted with one-on-one supervision is a safe adjunct therapy associated with improvements in cardiopulmonary function and select PROs during neoadjuvant chemotherapy.

Exercise Behavior, Functional Capacity, and Survival in Adults With Malignant Recurrent Glioma

PURPOSE Identifying strong markers of prognosis are critical to optimize treatment and survival outcomes in patients with malignant recurrent glioma. We investigated the prognostic significance of exercise behavior and functional capacity in this population. PATIENTS AND METHODS Using a prospective design, 243 patients with WHO grades 3 to 4 recurrent malignant glioma and Karnofsky performance status (KPS) ≥ 70 completed a self-administered questionnaire that assessed exercise behavior and performed a 6-minute walk test (6MWT) to assess functional capacity. Cox proportional models were used to estimate the risk of all-cause mortality according to 6MWT distance (6MWD; < 390 meters, 390-489 meters, > 489 meters) and exercise behavior (metabolic equivalent [MET] -h/wk) adjusted for KPS and other important clinical factors. RESULTS Median follow-up was 27.43 months. During this period, 149 deaths were recorded (61% of the total sample). Exercise behavior was an independent predictor of survival (P = .0081). Median survival was 13.03 months for patients reporting < 9 MET-h/wk relative to 21.84 months for those reporting ≥ 9 MET-h/wk. Exercise behavior added incremental prognostic value beyond that provided by KPS, age, sex, grade, and number of prior progressions (P < .001). Compared with patients reporting < 9 MET-h/wk, the adjusted hazard ratio for mortality was 0.64 (95% CI, 0.46 to 0.91) for patients reporting ≥ 9 MET-h/wk. Functional capacity was not an independent predictor of prognosis. CONCLUSION Exercise behavior is a strong independent predictor of survival that provides incremental prognostic value to KPS as well as traditional markers of prognosis in malignant recurrent glioma.

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].

Effects of Nonlinear Aerobic Training on Erectile Dysfunction and Cardiovascular Function Following Radical Prostatectomy for Clinically Localized Prostate Cancer

UNLABELLED Erectile dysfunction (ED) is a major adverse effect of radical prostatectomy (RP). We conducted a randomized controlled trial to examine the efficacy of aerobic training (AT) compared with usual care (UC) on ED prevalence in 50 men (n=25 per group) after RP. AT consisted of five walking sessions per week at 55-100% of peak oxygen uptake (VO2peak) for 30-60 min per session following a nonlinear prescription. The primary outcome was change in the prevalence of ED, as measured by the International Index of Erectile Function (IIEF), from baseline to 6 mo. Secondary outcomes were brachial artery flow-mediated dilation (FMD), VO2peak, cardiovascular (CV) risk profile (eg, lipid profile, body composition), and patient-reported outcomes (PROs). The prevalence of ED (IIEF score ≤ 21) decreased by 20% in the AT group and by 24% in the UC group (difference: p=0.406). There were no significant between-group differences in any erectile function subscale (p>0.05). Significant between-group differences were observed for changes in FMD and VO2peak, favoring AT. There were no group differences in other markers of CV risk profile or PROs. In summary, nonlinear AT does not improve ED in men with localized prostate cancer in the acute period following RP. TRIAL REGISTRATION Clinicaltrials.gov identifier NCT00620932.

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.

Abstract 5024: Effects of aerobic training to improve cardiovascular function and prevent cardiac remodeling after cytotoxic therapy in early breast cancer

Background: It is well-established that doxorubicin (DOX)-containing chemotherapy causes progressive cardiomyopathy clinically manifest as decreased left ventricular ejection fraction (LVEF). The effects of DOX on the other organ components of oxygen (O2) transport and utilization that govern global aerobic reserve capacity are poorly characterized. Methods and Results: To test our research questions, we established a mouse model of DOX in which female mice were subjected to DOX (8mg.kg.wk-1) or placebo (CON) (0.9% saline) for 4 weeks. Transthoracic echocardiography was performed to assess left ventricular wall thickness, volumes and LVEF, determined from M-mode tracings at baseline and 8 weeks. As expected, LV systolic volumes were higher and fractional shortening and LVEF were lower in the DOX group compared to CON after 8 weeks (p9s Conclusions: Our findings have important implications for the identification and protection against DOX-induced acute and late-occurring injury as well as optimizing therapeutic dosing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5024. doi:10.1158/1538-7445.AM2011-5024

Quantitative Measures of Physical Functioning After Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma: A Feasibility Study

BACKGROUND The safety and feasibility of the symptom-limited cardiopulmonary exercise test (CPET) and the 6-minute walk test (6MWT) has not been rigorously tested in patients with multiple myeloma (MM) after high-dose chemotherapy with autologous stem cell transplantation (ASCT), nor have correlations with patient-reported outcomes (PROs) been explored. PATIENTS AND METHODS We undertook CPET, 6MWT, and PRO assessments using standardized measurements and questionnaires in patients with MM in remission after ASCT. RESULTS A total of 22 patients who were a median of 17 months after ASCT underwent assessment. No severe adverse events were observed. Exercise capacity, measured during CPET as the peak oxygen consumption, was 17.5 ± 5.9 mL/kg/min, the equivalent of 38% ± 18% less than that for age- and sex-predicted sedentary normative values. During the 6MWT, the mean 6-minute walk distance was 500 m, or 25% ± 13% less than the predicted values. Additional analysis using Pearsons correlation revealed no significant univariate associations between exercise or functional capacity and any PROs. CONCLUSION Patients with MM have marked and significant reductions in quantitative measures of physical function for years after the initial therapy, although that did not correlate with PROs in the present pilot study. Larger prospective studies are required to determine the clinical ramifications of these findings and to mechanistically dissect them, as well to test interventions aimed at mitigating them.