EXercise Training for the Prevention of Cancer Thrombosis (EXPECT) Pilot Trial
Condition: Cancer Thrombosis
MeSH terms: Thrombosis
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Supervised aerobic exercise training
Intervention type(s): Behavioral
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: Cancer; Chemotherapy; Thrombosis; Prevention; Exercise