Prevention Using Exercise Rehabilitation to Offset Cardiac Toxicities Induced Via Chemotherapy

With more than 14 million cancer survivors in the United States, more patients than ever are
living well beyond their initial cancer diagnosis. However despite the tremendous progress,
cancer treatments often come with adverse side-effects, perhaps none are more serious or
devastating than chemotherapy induced heart failure.

In many patients, the clinical manifestation of heart failure may not appear until a year, or
several years, after completion of chemotherapy. While an echocardiogram is part of
standardized surveillance for patients on these drugs, current echocardiogram parameters may
not be sensitive enough to quickly detect early heart damage which, in some cases, is
irreversible.

Unfortunately, even if detected early, there is no uniformity in terms of how to best treat
patients with subclinical cardiac dysfunction who are at risk for heart failure. The use of
certain blood pressure drugs show promise, especially in patients with hypertension. However,
in addition to drug side-effects (e.g. dizziness/lightheadedness), they do not target the
underlying mechanism of chemotherapy induced cardiotoxicity.

Exercise, in various forms, has shown promise in animal studies as a potential
cardio-protective therapy to counteract drug toxicity. In general, exercise has many
pleiotropic effects for patients receiving chemotherapy (e.g. reduces fatigue, improves
endurance, reduces frailty, and enhances quality of life). Relative to DOX toxicity, research
involving animals has also shown that exercise protects against deleterious heart dysfunction
while showing an enhancement of potential mechanisms involved in chemotherapy induced heart
failure (i.e. anti-oxidant and anti-apoptosis pathways).

Patients with cancer who receive either doxorubicin (DOX) or trastuzumab will be screened by
one of two methods: 1) a strain echo or 2) a high sensitivity troponin. If either test is
positive, patients will meet with a board-certified cardiologist who will determine if the
patient may participate in the exercise trial. Under the supervision of a trained clinical
exercise physiologist patients will undergo baseline testing, which includes: a quality of
life assessment via questionaires, a body composition test, cardiopulmonary stress test and a
muscle strength test. These assessment will be performed at baseline and at 12 weeks. Also
performed at 12 weeks will be a repeat strain echo and high sensitivity troponin.

Following baseline testing patients will be randomized into exercise training versus standard
care. The exercise training will include 12 weeks of cardiac rehabilitation which can be
offered in Detroit, Livonia, or West Bloomfield. Exercise will consist of 3 days per week of
an interval training aerobic exercise on a treadmill and/or bike for 30-60 minutes and 1-2
days per week of an individualized resistance training program.

Inclusion Criteria:

- Patients with cancer who are undergoing or have completed the chemotherapy drugs
doxorubicin and/or trastuzumab.

- Have had a recent echocardiogram with a relative reduction in LV strain of >10%.

- If no recent echocardiogram, have a troponin value >0.04 ng/mL, or an increase of 0.04
ng/mL if baseline troponin is elevated.

- Age >/= 18 years.

- Eastern Cooperative Oncology Group (ECOG) scale 0-2.

- Males and females.

Exclusion Criteria:

- Patients with an Ejection Fraction <50%

- Patients not deemed appropriate by a cardiologist or oncologist

- Patients with an ECOG scale >2

- Inability to perform exercise

- Patients who already report exercising >2days per week for >29 minutes