Trial Information

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

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.