Cardiovascular Outcomes

Evaluation/characterization of the chronic and late cardiovascular effects of cancer therapy and efficacy of cardiovascular-based strategies to prevent and/or reverse dysfunction. We have several projects in this domain:

Aerobic Training during or after Adjuvant Therapy: A Randomized Trial (R01-CA164751)

Exercise training is a safe and efficacious intervention for breast cancer patients following the completion of primary therapy (such as chemotherapy and radiation). In contrast, the role of exercise during primary breast cancer therapy is less well accepted. Indeed, a perception exists that conducting scientifically rigorous exercise trials may not be possible during therapy due to poor adherence and attrition rates, elevated risk of adverse events, and significant patient selection bias. Nevertheless, a growing number of studies indicate that exercise is an effective therapy to mitigate certain cancer-related toxicities (for example, deconditioning and fatigue) with adherence and attrition rates well within conventionally accepted levels and with minimal adverse events. Although the acceptance of exercise during therapy has made significant strides over the past decade, the prevailing dogma is still that exercise should be avoided during primary therapy.

Accordingly, we are conducting a four-arm randomized controlled trial to compare the effects and safety of supervised aerobic training performed during, after, or both during and after standard primary therapy, relative to attention-control, in 160 (n=40/group) early-stage breast cancer patients.

Lung Cancer Exercise Trial (LUNGEVITY) (R01-CA138624)

Improvements in surgical techniques together with more-effective adjuvant chemotherapeutic regimens have led to significant survival benefit for individuals with non-small cell lung cancer (NSCLC). With improving prognosis, acute and long-term disease- and treatment-related morbidity (symptom control) and mortality are now recognized as issues of major clinical importance in the multidisciplinary management of operable NSCLC. Few studies have examined the efficacy of exercise training in patients with early-stage NSCLC following the completion of surgical resection. In addition, the optimal type of exercise training to improve cardiopulmonary function and patient-reported outcomes in this setting has not been investigated.

Against this background, we designed the Lung Cancer Exercise Training Study (LUNGEVITY), a randomized trial to investigate the efficacy of different types of exercise training in postoperative NSCLC patients. The fundamental rationale for this single-center trial is to identify the optimal type of exercise training to improve VO2 peak in postoperative NSCLC patients and understand the physiologic mechanisms underlying this effect.

Jones LW, Eves ND, Kraus WE, Potti A, Crawford J, Blumenthal JA, Peterson BL, Douglas PS. The lung cancer exercise training study: a randomized trial of aerobic training, resistance training or both in postsurgical lung cancer patients: rationale and design. BMC Cancer, 2010;10:155. [PMID: 20409311]

Breast Cancer Exercise Trial (EXCITE) (R01-CA142566)

Women with early-stage breast cancer have markedly reduced cardiorespiratory fitness. In a series of studies, we observed that cardiorespiratory fitness was approximately 30 percent below that of age-matched sedentary healthy women up to three years following the completion of adjuvant therapy. The precise causes of poor cardiorespiratory fitness are not known but likely are a consequence of direct cytotoxic therapy-associated injury to the cardiovascular system together with lifestyle perturbations (such as deconditioning and weight gain) that we have termed the “multiple hit” hypothesis.

A growing number of research groups have investigated the efficacy of supervised exercise training interventions (aerobic, resistance, or combination training) to counteract therapy-induced poor cardiorespiratory fitness both during and following the completion of adjuvant therapy. Although much progress has been made over the past 20 years, the format and intensity of exercise required to induce optimal improvements in cardiorespiratory fitness and other pertinent outcomes in women with breast cancer has not been investigated.

Against this background, we designed the EXCITE trial, a randomized trial comparing the effects of supervised moderate-intensity to high-intensity aerobic training in women with operable breast cancer following the completion of primary adjuvant therapy.

Jones LW, Douglas PS, Eves ND, Marcom PK, Kraus WE, Herndon JE, Inman BA, Allen JD, Peppercorn J. Rationale and design of the exercise intensity training study (EXCITE): a randomized trial comparing the effects of moderate versus high-intensity aerobic training in operable breast cancer. BMC Cancer, 2010;10:531. [PMID: 20925920]

EXTEND: Safety and Efficacy of Exercise Training in Men Receiving Enzalutamide in Combination with Conventional Androgen Deprivation Therapy for Hormone Naive Prostate Cancer (Medivation/Astellas, Inc.)

Androgen deprivation therapy (ADT) is the mainstay of treatment for advanced prostate cancer, with about 600,000 US men currently on ADT. However, despite demonstrated efficacy, ADT causes multiple deleterious metabolic and physical adverse events including muscle wasting (atrophy), decreased lean body mass (sarcopenia), increased body fat mass (obesity), and increased insulin resistance leading to a 44 percent increased risk of new onset type II diabetes and 16 percent risk of new coronary heart disease. The addition of enzalutamide, an androgen receptor antagonist, to conventional castration therapy (GnRH agonists/antagonists or orchiectomy to maintain serum testosterone <50 ng/dL) may be a highly effective approach for the treatment of hormone-naive prostate cancer but also may exacerbate the well-described adverse toxicities associated with androgen suppression.

Against this background, we designed the EXTEND trial, a two-arm, nonblinded randomized (1:1) phase II trial to determine the efficacy on aerobic capacity of the combination of enzalutamide with androgen deprivation therapy compared to the same regimen plus supervised exercise training in men with hormone-naive prostate cancer.