EXercise Training for the Prevention of Cancer Thrombosis (EXPECT) Pilot Trial (EXPECT)

Patients with lymphoma or cancer who are receiving chemotherapy in the outpatient setting are at risk for blood clots which form in the veins. The occurrence of blood clots has major implications on personal health including the need for blood thinners and monitoring, potential bleeding, and complications related to blood clots on cardiovascular health. The goal of this study is to determine whether aerobic exercise training is a therapeutic strategy to offset risk of blood clots and improve quality of life among cancer patients during chemotherapy.

Activation of the blood coagulation system is a common manifestation in cancer associated with premature death from venous thromboembolism (VTE).(1-5) Ambulatory cancer patients undergoing chemotherapy for lymphoma or cancers such as lung, ovarian, stomach, bladder, and pancreas confer a 12.6% absolute rate of VTE at 1-year compared to similarly age-sex matched controls, with nearly 50% of VTE events occurring within the first 3 months of treatment.(6) Further, cancer patients who develop VTE have a 2.5-fold higher mortality risk compared to cancer patients who do not experience a VTE.(3) Therapies to offset VTE risk, such as low-molecular weight heparin or vitamin K antagonists, are not currently recommended by the American Society of Clinical Oncology Guidelines secondary to the lack of robust clinical trial data, potential bleeding, and need for monitoring and dose adjustment.(7) As such, alternative strategies to prevent VTE during chemotherapy without adding further toxicity are urgently required. The investigators hypothesize aerobic exercise training is a therapeutic strategy to mitigate VTE risk among ambulatory cancer patients undergoing chemotherapy. Aerobic exercise training at moderate intensity has favorable effects on coagulation factors and reduces risk of VTE in healthy populations.(8-11) To date, no studies have determined whether exercise training has favorable impact on coagulation factors implicated in VTE risk. Furthermore, there is a lack of data regarding the impact of exercise training on functional performance and patient-reported outcomes among ambulatory cancer patients during chemotherapy. The focus of this grant application is to establish whether aerobic exercise training is as a potential modality to prevent VTE in ambulatory lymphoma and cancer patients during chemotherapy. To this end, investigators propose the EXercise Training for the PrEvention of Cancer Thrombosis (EXPECT) Pilot trial, a two-arm randomized controlled trial (RCT) comparing aerobic exercise training (three supervised treadmill sessions per week on nonconsecutive days for 12 weeks at moderate intensity (50-70% of baseline VO2max)), versus control among 54 subjects (27/group). Patients with high risk VTE malignancies receiving chemotherapy in the ambulatory setting will be the focus of recruitment.(2, 6, 12) The primary endpoint will be change in thrombin generation,(13) as well as other established VTE risk markers in cancer.(14, 15) We will also assess relationships between exercise training and factor Xa generation, a key modulator of thrombosis and a novel therapeutic target for VTE prevention.(16, 17) Design and Procedures: Potential participants will be identified and screened for eligibility by the study clinical research coordinator via medical record review of candidates scheduled to initiate chemotherapy at the Vermont Cancer Center. After obtaining written consent, all participants will complete the following baseline assessments: (1) fasting blood draw and (2) cardiopulmonary exercise test (CPET). Blood draws and CPET baseline assessments will be repeated at the end of the 12 week intervention. Group (Randomization): Participants will be randomly allocated, on an individual basis, to one of the two study groups prior to the initiation of chemotherapy. Randomly allocated participants will remain in the same group for the remainder of the study (i.e., no cross-over). Randomization will be stratified by cancer type to ensure balance of types between groups. Exercise Intervention: All participants will agree to participate in exercise testing, exercise logging, blood draws, and surveys pre and post intervention. The intervention, depending on randomization, will include: Group 1 - The goal of all AT groups is 3 supervised exercise sessions/week at an intensity of 50%-70% of the individually determined VO2max between 30-45 min/session for 12 weeks. The aerobic training intervention will closely mimic the standard exercise-based guidelines adopted in cardiac rehabilitation. All intervention sessions will be performed in a supervised setting with one-on-one supervision by an American College of Sports Medicine-certified exercise physiologist. Aerobic exercise training will be prescribed based on the guiding ACSM principles with the aim of improving VO2max. Walking was chosen because it is the preferred mode of exercise training in cancer patients.(51) Group 2 - Control: The 12-week program will consist of monthly phone contacts to check in with patient and review their exercise log entries for that month in order to capture physical activity done outside of the intervention setting. Study Endpoints: Markers of VTE Risk: Investigators will measure the following markers of VTE risk: thrombin, FXa, F 1+2, TAT, D-Dimer, vWF, soluble P-selectin, and C-reactive protein. Samples will be processed in the clinic with attention to issues related to coagulation activation, and plasma and serum will be stored at -80 degrees C in our laboratory. Functional Capacity: VO2peak: To determine VO2peak, an incremental treadmill test (modified Balke protocol) with 12-lead ECG monitoring (Mortara) will be performed by ACSM-certified exercise physiologists. Expired gases will be analyzed continuously by a metabolic measurement system (Sensormedics Vmax 29c). Physical Functioning will also include both subjective (i.e., SF-36) assessment as well as a 6-min walk distance test as described previously.(55) Fatigue: The Fatigue Symptom Inventory (FSI) has been tested in several cancer patient populations and will be used to assess fatigue(56) Anxiety and depression will be assessed using The Medical Outcomes Study, Short Form Health Survey (SF-36). This is a widely used and validated instrument to assess general functional and health related quality of life.(58) The SF-36 is a 36 item instrument containing eight individual scales measuring the following domains: physical functioning, role physical, bodily pain, social functioning, mental health, vitality, role emotional and general health perceptions. Exercise Experience: Individuals experience with exercise predicts participation in exercise interventions. Exercise Self-Efficacy: Self-efficacy refers to one's belief that he/she can successfully complete a given activity.(59) Adherence will be evaluated by assessing the rates of study eligibility, acceptance, and overall accrual. Safety will be evaluated by the type and prevalence of adverse events during exercise-related assessments.

This group will participate in 3 supervised exercise sessions/week at an intensity of 50%-70% of the individually determined VO2max between 30-45 min/session for 12 weeks. The aerobic training intervention will closely mimic the standard exercise-based guidelines adopted in cardiac rehabilitation. All intervention sessions will be performed in a supervised setting with one-on-one supervision by an American College of Sports Medicine-certified exercise physiologist. Aerobic exercise training will be prescribed based on the guiding ACSM principles with the aim of improving VO2max. Walking was chosen because it is the preferred mode of exercise training in cancer patients.

The 12-week program will consist of monthly phone contacts to check in with patient and review their exercise log entries for that month in order to capture physical activity done outside of the intervention setting.

Inclusion Criteria: Diagnosis of lymphoma or cancer Beginning chemotherapy regimen Patient self-report of ability to walk 10 minutes without interruption or pain Age >18 and <80 Willingness to participate in the oncology rehabilitation program at Tilley Drive South Burlington Exclusion Criteria: Presence or history of DVT or PE prior to entry Antithrombotic therapy including warfarin, dabigatran, low molecular weight heparin or unfractionated heparin which will alter levels of hemostatic factors (Off Lovenox 48 hours before first study blood draw) Medical condition that alters ability to walk for exercise

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