Testosterone for Treating Cachexia in Patients With Squamous Cell Carcinoma

RATIONALE: Testosterone may lessen weight loss and improve muscle size and strength in patients with cachexia caused by cancer. PURPOSE: This randomized phase I trial is studying whether testosterone administered during standard of care chemotherapy and/or radiation works by helping patients with squamous cell carcinoma to maintain their body weight and muscle size and strength during treatment.

OBJECTIVES: To determine the effect of testosterone therapy on lean body mass and muscle strength in patients with advanced or recurrent squamous cell carcinoma. To determine the testosterone therapy on inflammatory biomarkers in patients with advanced or recurrent squamous cell carcinoma. OUTLINE: Patients are stratified according to age and disease stage. Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive standard of care chemotherapy and/or radiation and placebo testosterone intramuscularly (IM) weekly for 7 weeks. Arm II: Patients receive standard of care chemotherapy and/or radiation and testosterone IM weekly for 7 weeks. Patients undergo dual energy x-ray absorptiometry, muscle strength tests, stable isotope metabolic studies, indirect calorimetry studies, and assessment of their physical activity level, and nutritional counseling. Patients also complete mood, fatigue, and quality-of-life questionnaires. Blood, muscle tissue, and urine samples are collected periodically for laboratory studies. Samples are analyzed for serum inflammatory biomarkers and inflammatory cytokines by immunoassay. After completion of study treatment, patients are followed periodically for 1 year.

stage IIB cervical cancer, stage III cervical cancer, recurrent cervical cancer, cachexia, advanced head/neck carcinoma, recurrent head/neck carcinoma

Patients receive standard of care chemotherapy and/or radiation plus placebo testosterone intramuscularly (IM) weekly for 7 weeks.

Patients receive standard of care chemotherapy and/or radiation plus testosterone (Testosterone Enanthate 100mg/ml) intramuscularly (IM) weekly for 7 weeks.

Change in Total Lean Body Mass as Measured by Dual Energy X-ray Absorptiometry (DEXA) From Baseline to 7 Weeks.

Total Lean Body Mass was measured on a GE Lunar iDEXA at baseline and 7 weeks. Percent change from baseline to 7 weeks is reported.

Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction. There was 1 set of 3 contractions at 100% force performed.

Peak isometric strength is measured on a Biodex System 4 Pro. This test is isolated to the quadricep muscle of one leg. Isometric test is performed at 90 degrees with 5 seconds of force production for each contraction. There was 1 set of 3 contractions at 100% force performed. This outcome was measured after 7 weeks of treatment with study medication.

Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion. Subjects performed concentric contractions at a fixed speed of 120 degree/sec. 1 set of 3 contractions were performed at 100% force.

Isokinetic strength (knee extension) is measured on a Biodex System Pro 4 within a 75 degree range of motion set at a fixed speed of 120 degree/sec.

Body Weight in kilograms as measured on a scale after 7 weeks of treatment with the study medication.

Energy expenditure and substrate oxidation as measured by indirect calorimetry using expired gases collected and analyzed for oxygen and carbon dioxide concentrations. 30 minutes of sampling was performed, the last 25 minutes were averaged to calculate mean Kcal/day values.

Energy expenditure and substrate oxidation as measured by indirect calorimetry using expired gases collected and analyzed for oxygen and carbon dioxide concentrations. 30 minutes of sampling was performed, the last 25 minutes were averaged to calculate mean Kcal/day values.

Concentration of Cytokine Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) in Blood as Measured by Immunoassay at Baseline

Concentration of cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Granulocyte-macrophage Colony-stimulating Factor (GM-CSF) in Blood as Measured by Immunoassay at 7 Weeks

Concentration of cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Interferon-gamma (IFN Gamma) in Blood as Measured by Immunoassay at Baseline.

Concentration of cytokine Interferon-gamma (IFN gamma) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Interferon-gamma (IFN Gamma) in Blood as Measured by Immunoassay at 7 Weeks

Concentration of cytokine Interferon-gamma (IFN gamma) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Interleukin 1 Beta (IL-1B) in Blood as Measured by Immunoassay at Baseline.

Concentration of cytokine Interleukin 1 beta (IL-1B) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 1 beta (IL-1B) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 2 (IL-2) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 2 (IL-2) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 4 (IL-4) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 4 (IL-4) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 5 (IL-5) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 5 (IL-5) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 6 (IL-6) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 6 (IL-6) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 7 (IL-7) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 7 (IL-7) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 8 (IL-8) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 8 (IL-8) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 10 (IL-10) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 10 (IL-10) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 12 (IL-12) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 12 (IL-12) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 13 (IL-13) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of cytokine Interleukin 13 (IL-13) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Tumor Necrosis Factor Alpha (TNFa) in Blood as Measured by Immunoassay at Baseline.

Concentration of cytokine tumor necrosis factor alpha (TNFa) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

Concentration of Cytokine Tumor Necrosis Factor Alpha (TNFa) in Blood as Measured by Immunoassay at 7 Weeks.

Concentration of cytokine tumor necrosis factor alpha (TNFa) in blood as measured using Millipore Multiplex Human Cytokine Panel assay.

The Medical Outcome Study - Short Form 36 (MOS-SF-36) is a questionnaire developed by RAND Health to measure patient self-reported quality of life. Data presented is a subset of the questionnaire, Scale of General Health. The range for the subset presented (General Health) is 0 - 100, with 100 being better perceived health and 0 being worst perceived health. The national average of the MOS-36 General Health Subscale is reported as 56.99.

The Medical Outcome Study - Short Form 36 (MOS-SF-36) is a questionnaire developed by RAND Health to measure patient self-reported quality of life. Data presented is a subset of the questionnaire, Scale of General Health. The range for the subset presented (General Health) is 0 - 100, with 100 being better perceived health and 0 being worst perceived health. The national average of the MOS-36 General Health Subscale is reported as 56.99

Personal Perception of Fatigue as Measured by Multidimensional Fatigue Symptom Inventory - Short Form at Baseline

Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue. There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score. The range of the total score is -24 to 96, with the higher the number meaning more fatigue.

Multidimensional Fatigue Symptom Inventory Short Form (MFSI-SF) from the Moffitt Cancer Center, University of South Florida The MFSI-SF is a 30 question assessment designed to assess the principal manifestations of fatigue. There 5 subscales used to calculate a total score. The subscales are: General Fatigue, Physical Fatigue, Emotional Fatigue, Mental Fatigue, and Vigor (an estimate of the patient's energy level). The total score is calculated with the equation: (general + physical + emotional + mental) - vigor = total score. The range of the total score is -24 to 96, with the higher the number meaning more fatigue.

Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best).

Profile of Mood States (POMS) is a questionnaire by MultiHealth Systems, that measures mood. In this 65 item questionnaire, subjects are asked to rate their feelings toward a statement from 0-4, with 0 being "not at all' and 4 being "extremely". There are 6 subscales which include, tension-anxiety, depression, anger-hostility, vigor, fatigue, and confusion. To calculate the total mood disturbance, which is what is reported here, the subscales tension-anxiety, depression, anger-hostility, fatigue and confusion are summed and vigor is subtracted. The scale range for total mood disturbance is 200 (worst) to -32 (best).

Quality of Life as Measured by Functional Assessment of Cancer Therapy - General Questionnaire at Baseline

Functional Assessment of Cancer Therapy - General (FACT-G) is a patient-reported questionnaire of quality of life. The 27 item questionnaire is separated into 4 subscales, physical well-being, social/family well-being, emotional well-being, functional well-being. These subscales are summed to calculate total score. The range for FACT-G is 0 (worst quality of life) to 108 (best quality of life).

Quality of Life as Measured by Functional Assessment of Cancer Therapy - General Questionnaire at 7 Weeks

Functional Assessment of Cancer Therapy - General (FACT-G) is a patient-reported questionnaire of quality of life. The 27 item questionnaire is separated into 4 subscales, physical well-being, social/family well-being, emotional well-being, functional well-being. These subscales are summed to calculate total score. The range for FACT-G is 0 (worst quality of life) to 108 (best quality of life).

Inclusion Criteria: Diagnosis of advanced (stage IIB, IIIA, or IIIB) or recurrent squamous cell carcinoma Eastern Cooperative Oncology Group (ECOG) performance status 0-1 Mini Mental State Examination score > 23 Exclusion Criteria: Pregnancy Evidence of hepatitis as indicated by a 3-fold increase in 2 out of 3 liver enzymes Significant liver, renal, or heart disease Diabetes mellitus or other untreated endocrine disease Polycystic ovary syndrome and/or hyperthecosis Androgen secreting tumors of the ovary and adrenal or any ovarian tumors (e.g., Sertoli- Leydig cell tumor) Non-classical adrenal hyperplasia Cushing's syndrome Glucocorticoid resistance Hyperprolactinoma or hypothyroidism Lactose intolerance Alcohol or drug abuse Recent treatment (within 3 months) with anabolic steroids Ongoing anticoagulant therapy Any other circumstance that would preclude study participation, in the opinion of the principal investigator or study physician

Scott JM, Dillon EL, Kinsky M, Chamberlain A, McCammon S, Jupiter D, Willis M, Hatch S, Richardson G, Danesi C, Randolph K, Durham W, Wright T, Urban R, Sheffield-Moore M. Effects of adjunct testosterone on cardiac morphology and function in advanced cancers: an ancillary analysis of a randomized controlled trial. BMC Cancer. 2019 Aug 7;19(1):778. doi: 10.1186/s12885-019-6006-5.