Multimodal Treatment Strategy for Cancer Cachexia
Multimodal Treatment Strategy for Cancer Cachexia
The primary aim of this proposal is to present a novel, multimodal treatment strategy for
 increasing lean body mass in individuals with cancer who experience cachexia between baseline
 and day 29 (+/- 3 days). The strategy includes graded resistance training and aerobic
 exercise, targeted nutrient supplementation and pharmacologic intervention (melatonin).

 We postulate that this strategy, together with the simultaneous management of symptoms that
 decrease appetite (e.g. depression, pain, and nausea), will also accomplish our secondary
 objectives of improving clinical outcomes such as strength and function between baseline and
 day 29 (+/- 3 days).
The Study Drugs:

 Melatonin is a hormone that helps reduce inflammation and poor food absorption caused by
 cancer. It may also enhance the effects of ibuprofen.

 Juven is a nutritional supplement that is designed to help build muscle and slow muscle
 breakdown.

 Screening Tests:

 Before you can start treatment on this study, you will have "screening tests" to help the
 doctor decide if you are eligible to take part in this study. The following tests will be
 performed:

 -  Blood (1 to 2 tablespoons) will be drawn for routine tests. This routine blood draw will
 include a pregnancy test for women who are able to have children. To be eligible to take
 part in this study, the pregnancy test must be negative.

 -  Additional blood (1 tablespoon) will be drawn to check your thyroid function and the
 levels of two B vitamins, if these have not been checked within the past 3 months.

 -  You will have a physical exam, including measurement of vital signs (blood pressure,
 heart rate, temperature, and breathing rate).

 -  You will have an electrocardiogram (ECG -- a test that measures the electrical activity
 of the heart).

 -  Your resting energy expenditure (energy used at rest) will be measured. with a
 calorie-measuring device. For this test, you will breathe in and out through your mouth
 for about 10 minutes to allow a calorie-measuring device to measure the oxygen your body
 uses, and from this it calculates how much energy your body uses at rest.

 -  You will be asked to fill out a questionnaire to rate your overall physical well-being,
 another questionnaire to rate your level of fatigue, and a third questionnaire to rate
 your experiences with 10 common symptoms in the past 24 hours (pain, fatigue, nausea,
 depression, anxiety, drowsiness, shortness of breath, changes in appetite, sleep
 difficulty, and feeling of well being). In total, these questionnaires will take about
 30 minutes to complete.

 -  You will complete a diary entry that lists all of the food and drinks you have had in
 the last 3 days. It should take about 10 minutes to complete.

 -  Your strength and stamina will be evaluated. This is measured by hand-grip and pinch
 strength tests that are done with both hands. These tests will see how hard you can grip
 a device with your hand and pinch the pads of another device called a pinch gauge. These
 tests will be done 3 times and your best scores will be used. Your strength and stamina
 will also be checked using the Get-Up-and-Go test and the 6-minute walk test. The
 Get-Up-and-Go test measures how long it takes to get up from sitting in a chair that has
 arms, walking 10 feet, turning around and walking back to the chair, and sitting down.
 The 6-minute walk test will measure the distance you can walk in 6 minutes on a 100-foot
 loop. You will walk 50 feet and then turn and walk back to the beginning. You will do
 this at a walking speed that feels comfortable and for as many times as you can in 6
 minutes.

 -  Blood (1 to 2 tablespoons) will be drawn to check for markers of inflammation and
 nutrition status.

 Study Drug Administration:

 You will take one (1) 20mg capsule of melatonin every night. It can be taken with or without
 food. It should be taken with 8 ounces (1 cup) of water.

 You will drink 90 calories of Juven, twice a day. Juven is a powder supplement that is mixed
 into 8 ounces of water. It is available in orange or grape flavors.

 You will also be instructed to increase your daily calorie intake by at least 1,000 calories.
 To assist you in doing so, dietary advice will be given to you by a nurse or physician.

 Exercise Training:

 You will complete 2 exercise training sessions a week. The sessions will combine resistance
 and graded aerobic training.

 Resistance training (with Thera-bands) is designed to increase the muscle-building effects of
 a hormone called testosterone. Thera-bands are rubber bands that you can hold or put around
 your feet to provide resistance to your muscles when you bend and flex your arms and legs.

 You will be instructed in how to do 3 upper-body exercises (chest press, shoulder press, and
 arm pull down) and 3 lower-body exercises (leg press, leg extension, and leg flexion).

 At your first visit, a physician will educate you to make sure that all exercises are done
 correctly.

 Each repetition will take 12 seconds to complete (6 seconds to bend, then 6 seconds to
 straighten your arm or leg). When 6 repetitions are completed, the next week's set will be
 increased by 1 repetition.

 Graded aerobic exercise is a walking/running program that may help you exercise longer.

 Graded aerobic exercise involves walking or running for 3-4 minutes at 70-80% of your maximum
 predicted heart rate. There will be a 3-minute warm-up and a 3-minute cool-down before and
 after this exercise.

 During your first visit, you will be shown how to monitor your heart rate and how to exercise
 at 70-80% of your maximum heart rate.

 You will add 1 minute to your aerobic exercise at the start of each week.

 You will receive your own customized aerobic and resistance exercise program based on your
 range of motion and risk for falls, which will be evaluated by the study staff.

 If you experience chest pain, have a temperature over 100.4 °F, have a platelet count of
 lower than a certain level, have fresh bruises, or shortness of breath at rest, you will be
 advised to stop exercising until these are relieved.

 Evaluations:

 While on study, within 3 days of the days listed below, the following measurements will be
 monitored:

 -  Your lean body mass and weight will be checked at Days 15 and 29 using the Tanita
 TBF-310 body composition analyzer/scale. For measurements with the Tanita TBF 310, you
 will be asked to wear light clothes and to take off your shoes and socks when being
 weighed. You will stand on a special scale that will send an extremely low-energy,
 high-frequency electrical signal from one foot to your other foot. You should not be
 able to feel this at all.

 -  Your muscle mass (mid-arm muscle area) will be measured with a special tape.

 -  The thickness of a skin fold on your triceps (back of your upper arm) will be measured 3
 times using skin fold calipers. Calipers are a gentle clamp-like device that is used on
 the outside of your body to measure skin thickness.

 -  At Day 29, your resting energy expenditure will be measured.

 -  On Days 15 and 29 of the study cycle, you will complete the same 3 questionnaires as at
 screening.

 -  Your caloric intake will be measured on Days 15 and 29.

 -  Your strength and stamina will be evaluated on Days 15 and 29.

 -  On Day 29, blood (1 to 2 tablespoons) will be drawn to check for markers of inflammation
 and nutrition.

 -  Blood (about 1 to 2 tablespoons) will be drawn for routine tests every 15 days while you
 are on-study. You will also have a fecal occult blood test at this time.

 Length of Study:

 You will be on study for 29 days (1 cycle).

 This is an investigational study. Melatonin and Juven are commercially available nutritional
 supplements and are exempt from FDA approval. However, in patients with cancer and cachexia,
 the study treatment (resistance training, aerobic exercise, and the use of Juven, and
 melatonin) is considered experimental. At this time, it is only being used in research.

 Up to 40 patients will be enrolled on this study. Up to 30 patients will be enrolled at M.D.
 Anderson, and 10 will be enrolled at the University of Alabama-Birmingham.
Inclusion Criteria:

 1. Are referred to the Cachexia Clinic with involuntary weight loss of >5% of their
 premorbid weight within the previous 6 months.

 2. Are 18 years of age or older

 3. Have a Karnofsky performance score of 60 or higher.

 4. Can maintain oral food intake during the study

 5. Can understand the study procedures and can sign an informed consent form.

 6. Are not currently taking melatonin.

 7. Are taking megestrol acetate and continue to lose weight despite at least 2 weeks of
 therapy.

 8. Have a calculated creatinine clearance of >/= 60 cc/min.

 Exclusion Criteria:

 1. Have dementia or delirium (as determined by the palliative care specialist) at study
 entry.

 2. Are pregnant

 3. Have been taking corticosteroids for longer than 48 hours.

 4. Have pulmonary edema, ascites or pitting edema on clinical examination.

 5. Are unable to walk.

 6. Have a history of serious adverse gastrointestinal events (i.e., bleeding or
 perforation),history of a coagulopathy or current anti-coagulant use.

 7. Have an ALT/AST>3x upper limit of normal.

 8. Patients on methotrexate.

 9. Patients taking melatonin receptor agonists (such as Rozerem® [ramelteon]).