Exercise, chemotherapy and cardiovascular risk in ovarian cancer

Cardiovascular Medicine; Oncology (Cancer)

The proposed project will examine the effects of a novel exercise training paradigm during ovarian cancer chemotherapy to reduce or mitigate the adverse cardiovascular effects of chemotherapy.

Research Interests
  • Cardiovascular disease
  • cardiooncology
  • cancer survivorship
  • ovarian cancer

Epithelial ovarian cancer is the most lethal gynecological cancer with a 5-year survival of approximately 48% and ranks fifth in cancer deaths among women in the US.(1,2) As successful oncological treatment options have exploded over the last decade (surgical and pharmacological),survivorship has continued to improve.(1) However, these advances in treatment have been tempered by the off-target effects of chemotherapy leading to reduced quality of life, increased risk of cardiovascular disease including heart failure and stroke and increased risk of adverse clinical events including neuropathy, loss of quality of life, hospitalization and death not arising from the primary disease.(3-5)

The initial agents typically used in adjuvant and neoadjuvant chemotherapy settings for the treatment of ovarian cancer are paclitaxel and carboplatin; both of which have considerable off target cardiovascular effects. Paclitaxel and carboplatin cause demonstrable and significant endothelial dysfunction, a pathogenic sine qua non for the development of atherosclerotic cardiovascular disease.(6) This chemotherapy combination also increases the incidence of severe hypertension 10-fold especially when combined with VEGF inhibition.(7) Additionally, survivors of ovarian cancer have been shown to have lower peak oxygen uptake(V̇O2peak) as compared to controls. (8) Given that V̇O2peak is an important predictor of future cardiovascular, cancer and all-cause mortality risk this represents series of multiple “hits” to the cardiovascular system that can adversely alter prognostic trajectories. Treatments to modify or mitigate off-target effects of these chemotherapeutic agents are urgently needed. Although pharmacological treatments such as fibrates have been shown to mitigate endothelial dysfunction, no guideline directed, broad-spectrum therapies exist to mitigate this range of sequelae. (6)

Further, chemotherapy induced neuropathy can affect up to 48% of patients and paclitaxel is one of the main culprits.  Mouse models investigating a rigorous exercise program showed that exercise could partially negate paclitaxel induced axonal degeneration  and improve biomarkers for neurodegeneration.(9) Several trials in patients with recurrent colorectal cancer, breast cancer, recurrent ovarian cancer and lymphoma have shown a protective effect for exercise in terms of neuropathy and neuropathy specific quality of life but study limitations included participation of patients with recurrent disease and prior chemotherapy exposures, and reliance on questionnaires as a main endpoints. (10-14)

Exercise initiated prior to chemotherapy induction and continued through treatment has promise in terms of preserving VO2peak and mitigating the negative cardiovascular and neuropathic effects of chemotherapy. Exercise is a powerful, tissue specific antioxidant which, when initiated prior to chemotherapy induction, builds up endogenous antioxidant reserves and protects peripheral targets from chemotherapy induced oxidative stress. Preliminary data from our team have demonstrated the preservation of VO2peak in the setting of dose-dense doxorubicin based chemotherapy in women undergoing adjuvant chemotherapy for breast cancer. Further, we have demonstrated salutary effects on blood pressure and endothelial function with acute and chronic exercise. However, this paradigm remains to be tested in the setting of ovarian cancer.

In the proposed project, we plan to examine the effects of initiating exercise prior to any oncologic therapy and sustaining this exercise paradigm in newly diagnosed women with ovarian cancer who are undergoing initial surgery and chemotherapy. We plan to assess the following outcomes of interest by treatment group:

1.   Determine the extent to which exercise training initiated prior to any surgery or paclitaxel/carboplatin based chemotherapy preserves cardiovascular function compared to control. We hypothesize that exercise preconditioning will preserve V̇O2peak,endothelial function and resting/exercise blood pressure compared to attention-controls who will be given standard physical activity advice. Further, we will examine changes in serum markers of cardiovascular and cancer risk namely, serum lipids, glucose/insulin, NTproBNP, pentraxin-3 and CA125.

2.   Estimate the effects of exercise training on inflammation, peripheral neuropathy and related symptoms for both treatment groups. We will explore changes in C-reactive protein and neuropathy as compared to those randomized to attention-controls who will be given standard physical activity advice.

3.   Examine the effects of exercise training on overall quality of life (SF-12) as well as disease and neuropathy specific quality of life as characterized by the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity –Ovarian (FACT-GOG-NTX). We will explore changes in overall quality of life and disease specific quality of life in the exercise group compared to attention-controls who will be given standard physical activity advice.

The goal of these aims is to generate preliminary effect sizes and pilot data for submission to the NIH.

Preliminary Data related to the proposed design and outcomes are presented below:

·  Evidence to support greater improvement in VO2peak and diastolic function with high-intensity exercise training. We have completed a randomized controlled trial examining the effects of a short (4-week long) exercise training program on VO2peak and diastolic dysfunction in older heart failure patients randomized to either high-intensity interval training, as described in this proposal, or moderate-intensity continuous exercise. (15,16) Findings from this study show that high-intensity interval exercise training significantly improved VO2peak and diastolic function in heart failure patients whereas no improvements were facilitated by moderate-intensity exercise training. These data indicate that high-intensity exercise presents a greater stimulus to preserve VO2peak and diastolic function vs. traditional, moderate-intensity exercise.

·  Evidence that high intensity exercise preserves VO2peak, ejection fraction, and left ventricular global longitudinal strain during chemotherapy. We recently performed a pilot study in 8 breast cancer patients being treated with anthracycline/ cyclophosphamide-containing chemotherapy (4 bi-weekly cycles). Similar to this proposal, five subjects initiated high-intensity exercise 1-week prior to chemotherapy treatment and continued throughout treatment whereas three subjects were randomized to control during treatment. Notably, the high-intensity exercise group showed better preservation / improvement in the outcomes. Results are summarized in the bullets below.

o VO2peak was reduced by 16% in the control group, whereas VO2peak was preserved (5% increase) in the high-intensity exercise group. Notably, VO2peak was reduced in every subject in the control group, while only one subject in the high-intensity exercise group experienced a reduction, and this reduction was smaller than any of the subjects in the control group.

o Ejection fraction was reduced by 6% in the control group, whereas it was preserved (3% increase) in the high-intensity exercise group.

o Left ventricular global longitudinal strain worsened (↑8%) in the control group and improved(↓8%) in the high-intensity exercise group.

Evidence that exercise may result in decreased neuropathy:  Overall, a meta-analysis of 31 studies showed a baseline chemotherapy induced neuropathy prevalence of 48% 17.  Exercise has been shown to potentially mitigate neuropathy effects but the only trial in ovarian cancer patients to date was limited by the fact that it was in recurrent patients, lacked a control group, and relied only on questionnaire assessment.  Our group has previously demonstrated the ability to recruit patients and conduct an exercise trial in cancer survivors(including 23 ovarian cancer patients). (18) 

Subject Characteristics. The target sample size for this study is  24 patients diagnosed with ovarian cancer. Subjects will be enrolled in the Gynecologic Oncology clinic of the Emily Couric Clinical Cancer Center with support from Dr. Modesitt (Co-PI). The Gynecologic Oncology division sees about 5-10 new ovarian cancer patients per month who would potentially qualify for the proposed research based on our inclusion/exclusion criteria.  The Gynecologic Oncology division has an extremely well-developed clinical research infrastructure and over the last 12 months, the division enrolled the highest number of patients onto therapeutic clinical cancer trials in the entire cancer center and accounted for 20% of the entire cancer center accruals so we are well positioned to enroll patients in this trial.

Screening: After carefully explaining procedures and risks, signed informed consent will be obtained from all subjects. Eligibility will be assessed with medical history charts, physical activity and health history exam, and laboratory tests. All medications will be recorded for all subjects throughout study participation.

·  Inclusion criteria: Age 18 years or over with a diagnosis of ovarian cancer and a planned chemotherapy regimen of a taxane and carboplatin with or without VEGF inhibition with physician clearance for exercise training.

·  Exclusion criteria: Cancer recurrence; previous treatment with chemotherapy in the last 5-years;medical/orthopedic co-morbidities that preclude exercise training; significant heart, liver, kidney, blood, or respiratory disease precluding exercise participation; peripheral vascular disease; acute infectious disease or history of chronic infections; malnutrition (BMI < 20 kg/m2, and/or hypotransferrinemia).

Randomization: Qualified subjects will be randomized to one of two experimental groups (using a 2:1 ratio):

1.               High-Intensity Exercise training (16 patients) 

2.               Attention Control (physical activity education + physical activity monitor) (8 patients).

Balance between treatment groups will be maintained by use of randomly permutated blocks with unequal block sizes of 3 and 6.

Study Design: Each group will be evaluated before surgery, prior to chemotherapy initiation and then following conclusion of chemotherapy treatment: Pre-surgical, pre-chemotherapy and post-treatment testing will be identical for each group and will consist of three separate testing days. We will assess VO2peak (and maximal heart rate), body weight and composition (DEXA), and cardiovascular performance (2D echo, flow-mediated dilation [FMD], pulse wave velocity), skeletal muscle strength (isokinetic dynamometer, hand grip) and quality of life.

1)    Pre-Surgery.  7-21 days prior to surgery

2)    Pre-chemotherapy:7-14 days prior to the initial chemotherapy dose 

3)    Post-treatment:  Patients will undergo 2 initial training sessions at the exercise physiology core lab. All exercise will consist of stationary cycling to avoid discomfort associated with abdominal surgery as well as stress to the incision and help reduce fall risk .All exercise will be appropriately and safely supervised. Subjects will then perform this exercise training at their own homes using exercise bikes provided by the investigators for that purpose. Study investigators will check in weekly with participants and remotely track exercise data and compliance via the Fitbit app. This exercise protocol that involves loaning exercise and mHealth equipment is not without precedent at UVA and we have successfully carried out similar studies that involve the provision of exercise equipment to patients. We have also demonstrated that this exercise is well-tolerated by patients with heart failure with preserved ejection fraction with no significant cardiovascular or musculoskeletal events reported. (15,16) Further compliance rates with exercise were ~95%.

·  Patients in the control group (physical activity education and physical activity monitoring) will receive counseling regarding the benefits of physical activity during chemotherapy treatment. During the intervention, participants will receive a twice weekly phone call to discuss their physical activity and remind them to engage in physical activity. Patients will be given a goal of  working up to 30 minutes of exercise daily. Subjects will be urged to increase daily step counts by 250-500 steps/day. Physical activity will be objectively assessed and made available to the participant using an accelerometer (Fitbit Flex 2).

 Sample size: The target sample size is 21 participants, randomized 2:1 to high-intensity exercise and attention control, respectively. The primary aim of the study is to assess change in cardiovascular function measured by change in V̇O2peak, assessed prior to surgery and after treatment. Preliminary data from 8 participants (5 receiving high-intensity exercise and 3 receiving control) provide estimates for the sample standard deviation of 0.1 for change in V̇O2peak. The target sample size of 21 participants provides 80% power to reject the null hypothesis of equal change in V̇O2peak between the two intervention groups when the difference in population averages of change in V̇O2peak between interventions arms is 0.17.This calculation assumes a type I error rate of 0.05 and a sample standard deviation of the change in V̇O2peak of 0.1 for both treatment groups. Maximum target sample size is 24 participants, with 16 randomized to the high-intensity exercise arm and 8 randomized to the attention control arm, which allows for a10% drop out adjustment.

Analysis plans: Standard descriptive statistics will be used to summarize covariates of interest by treatment group. The goal of these aims is to generate preliminary effect sizes and pilot data for submission to the NIH.

Measures of interest include:

1.   Change in cardiovascular function

a.   V̇O2peak,endothelial function (brachial artery flow-mediated dilation), and blood pressure at rest and during exercise

b.   Serum markers of cardiovascular and cancer risk, including serum lipids, glucose/insulin, NTproBNP, pentraxin-3, and CA125

2.   Change in C-reactive protein, peripheral neuropathy, and related symptoms (such as )

3.   Change in quality of life:

a.   Overall quality of life will be assessed using the SF-12

b.   Disease specific and neuropathy specific quality of life will be assessed using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group – Neurotoxicity –Ovarian (FACT-GOG-NTX)

 

Expected Outcomes & Interpretations: We expect high-intensity exercise preconditioning will hasten a return to baseline function following surgery and then preserve or even improve VO2peak, whereas we expect a 15-20%reduction in VO2peak in the control group.(22) We would expect a preservation of peripheral nerve function as measured by the FACT-NTX and objective measures compared to a 25-50% decline in the control group.  We also expect that high-intensity exercise preconditioning will demonstrate preservation or even reduction in body weight and fat mass, whereas we expect increased body weight and fat mass in the control group.(23) If our expectations are met, we will consider our hypothesis to be correct and we will conclude that high-intensity exercise preconditioning is a powerful, adjunctive therapy that can be implemented into the clinical care of ovarian cancer patients undergoing surgery and chemotherapy. Future research will focus on developing approaches to implement exercise training into this patient population, including supervised and non-supervised (e.g., at home) strategies. Examining adherence and compliance to the exercise program and relating these findings to our measured outcomes will provide an additional layer of data to identify whether any dose-response relationship exists between exercise and acute health and functional impairments

Potential Problems & Alternative Strategies: We have assembled a strong collaborative team including a physician that works directly with the proposed patient population both during treatment and following treatment (Dr. Modesitt). One potential problem is adherence/compliance to the exercise program, however, exercise during chemotherapy treatment has been previously documented in the literature. (24-27) Direct observations from members of the research team (Drs. Modesitt and Horton) also indicate that the proposed patient population is very capable of performing exercise. Our prior work with this patient population revealed that one of the main barriers to exercise was lack of a place to walk or perform exercise and we are planning to overcome that but doing either supervised exercise at our institution or providing a home exercise bike with tele-coaching as an option for patients living too far away to travel. Further, we have demonstrated >95% compliance of this exercise protocol in a breast cancer patients (see preliminary data) and >90% compliance in a cohort of heart failure patients. (16) We have had no dropouts from the breast cancer exercise group during our pilot work.

Investigative team: The investigative team will consist principally of Siddhartha Angadi, PhD (cardiovascular exercise physiology), Susan Modesitt, MD(Gynecological oncosurgeon) and Bethany Horton, PhD (Public health sciences). Dr. Angadi has extensive experience in exercise prescription and testing in clinical populations including those with cancer, heart failure and end-stage renal disease and has utilized this exercise model in women with breast cancer. Drs. Modesitt and Horton have previously used a model of physical activity and exercise in ovarian cancer survivors (long after completion of chemotherapy). All three PIs have never previously applied to this funding mechanism. All testing will be carried out in the clinical research unit and the exercise physiology core lab (Director - Arthur Weltman, PhD) who will provide additional support.

Future Directions: Data from this grant will be used for an NIH R01 application that is specifically focused on cardio-oncology outcomes in ovarian cancer survivors (PA-19-112 - Improving Outcomes in Cancer Treatment-Related Cardiotoxicity).


 

References

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Desired outcomes

The ultimate goal of this project is to generate important preliminary data to support a future NIH proposal that is focused on cardio-oncological outcomes in patients with ovarian cancer (PA-19-112 - Improving Outcomes in Cancer Treatment-RelatedCardiotoxicity).