Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

All Drugs and Chemicals

Reproductive Control Agents

Estradiol

Androgens

Estrogens

Estradiol 17 beta-cypionate

Estradiol 3-benzoate

Polyestradiol phosphate

Hormones

Hormone Antagonists

Participants (n=155) receiving transdermal estradiol and androgen deprivation therapy.

Participants (n=155) receiving solely androgen deprivation therapy.

Participants (n=155) receiving transdermal estradiol for 12 months.

Transdermal estrogen

Participants (n=155) receiving solely androgen deprivation therapy for 12 months.

Active Comparator: Androgen deprivation therapy

Participants (n=30 in each arm) performing supervised resistance training for six months.

Resistance training

Heikki Seikkula, MD, Docent

Ilkka Jussila, MSc.

The goal of the clinical trial is to find out whether transdermal estradiol will reduce the adverse effects of androgen deprivation therapy in prostate cancer patients.

The primary aim of this study is to estimate the efficacy of transdermal estradiol (E2) in reducing androgen deprivation therapy induced adverse effects on sexual function. A secondary aim of this study is to estimate the utility of E2 and the combination of E2 with supervised exercise in reducing other androgen deprivation therapy related adverse effects.

Participants (n=310) will use transdermal estradiol for 12 months concomitant to androgen deprivation therapy. The use of transdermal estradiol will start at the beginning of the trial, at the same time as androgen deprivation therapy. A subgroup of participants (n=120) will also be allocated to perform six months supervised resistance training.

Researchers will compare transdermal estradiol group to control group, and resistance training groups and non-training control groups.

The current study is an open-label study examining a drug with known tolerability and safety profile (phase IIA trial). The study will recruit 310 prostate cancer patients with high-risk disease and scheduled for external beam radiation with adjuvant subcutaneous androgen deprivation therapy, leuprorelin (LHRH agonist).

Stratified randomization (n=310) will be done in a 1:1 fashion to the transdermal estradiol + androgen deprivation therapy arm or control arm (androgen deprivation therapy only). Stratified randomization will be based on two covariates, which are sexual dysfunction score and BMI. The use of the stratified randomization method will guarantee even distribution of covariates, which could likely affect the study outcomes. Additionally, a total of 120 participants who are willing to participate in the supervised resistance training program and have sufficient performance status (ECOG 0-1) will be randomized to the resistance training group or the non-training control group. A total of 30 men from each arm will be recruited to supervised training and 30 men from each arm the non-training control group. Participants of the ESTRACISE who do not participate in the exercise substudy will form a non-training group (n=95 per arm). The stratified randomization of the substudy participants in the training group or the non-training control group will be done in a 1:1 fashion before the start of the training period. Stratified randomization will be based on two main covariates, which are age and the self-reported physical activity level of the participant.

ESTRACISE participants allocated to the transdermal estradiol arm will use transdermal estradiol gel (E2) as a dose of 750 ug (EstroGel 0.6 mg/ml) in addition to androgen deprivation therapy for 12 months. Additionally, substudy participants allocated to the resistance training groups will be attending supervised group resistance training sessions twice a week for six months. The resistance training will start after six months of androgen deprivation therapy. Participants in the non-training groups are advised to stay physically active but they will do it at their own discretion.

According to the standard treatment protocol, all participants will receive androgen deprivation therapy as leuprorelin, subcutaneous injections at three months intervals for a minimum of one year, and standard external beam radiation for prostate cancer with standard clinical dosing and fractionation at the discretion of the radiation oncologist.

The research methodologies include questionnaires (expanded prostate cancer index composition 26, world health organization quality of life brief version, and patient health questionnaire), adverse event screening, medication compliance screening, computerized tomography (CT) of the thigh muscle, bioimpedance analysis (BIA), 3D-imaging of the body composition, body composition and bone mineral assessment by dual-energy x-ray absorptiometry (DXA), strength, functional capacity, physical activity measurements, and serum and plasma blood samples. In addition, muscle biopsies are collected from a subset of participants allocated in the resistance training (n=60) and non-training control groups (n=60). The primary measurement timepoints are baseline (0 months), after six months of androgen deprivation therapy, and after twelve months of androgen deprivation therapy.

Based on prior sample size estimation of primary outcome the n=310 should be more than adequate to detect statistically significant differences in the mean sexual domain score between the two study arms. The true difference in the mean is expected to be 10, with a probability (power) of 0.8, a Type 1 error probability of 0.05, and with dropout rate of 10%.

Participants are randomized in a 1:1 fashion to receive transdermal estradiol and androgen deprivation or solely androgen deprivation therapy. In addition subgroup of participants are randomized in a 1:1 fashion to perform resistance training or to be allocated in non-training control group.

Transdermal Estradiol and Exercise in Mitigating Adverse Effects of Androgen Deprivation Therapy for Prostate Cancer Radiation Therapy

Transdermal Estradiol and Exercise in Mitigating Adverse Effects of Androgen Deprivation Therapy for Prostate Cancer Radiation Therapy: A Randomized Controlled Trial

Compared between the two arms. Scores scaled from 0 - 100, higher score means better sexual function.

Compared between different groups. Assessed by CTCAE (Common Termionology Criteria for Adverse Events). Number of participants with androgen deprivation therapy related adverse events, and grading of adverse event from 1 - 5. Higher grading indicates worse adverse event.

Transdermal estradiol arm. Number and grading of adverse events from 1 - 5. Higher grading means worse adverse event.

Compared between different groups. One repetition maximum tests and maximal hand grip strength assessed as kilograms or newtons. Higher kilograms or newtons indicates higher strength.

Compared between different groups. From CMJ flight time is defined as milliseconds. Higher flight time in milliseconds represents higher jump height and explosive strength.

Compared between different groups. Walking distance and heart rate will be collected from 6-minute walk test. Higher walking distance with lower heart rate indicates better functional capacity.

Compared between different groups. Time taken to ascend and descend from 10-stair climb test. Less time taken to complete 10-stair climb test indicates better functional capacity.

Compared between different groups. More lean mass, and less fat mass indicates better body composition.

Compared between different groups. Higher bone mineral density indicates better outcome.

Compared between different groups. Higher mid-thigh muscles cross-sectional area indicates higher mid-thigh muscle mass.

Compared between different groups. Lower adipose tissue size indicates less mid-thigh fat mass.

Compared between different groups. Higher or lower hormones levels could indicate better outcome, depending on the arm of the participant, and overall status. Lower PSA concentration usually indicates better outcome.

Compared between different groups. Higher or lower concentration of biomarkers can indicate better outcome, depending on the exact biomarker.

Compared between different groups. Higher type I and II myofibers' cross-sectional area indicates improved skeletal muscle characteristics. Higher myonuclei, myonuclear domain, satellitte cell count, and androgen and myostatin content usually indicates improved cellular function.

Compared between different groups. Higher or lower concentration of proteins could indicate improved or worsen muscle cellular function, depending on the exact protein.

Compared between different groups. Subdomain scores scaled from 0 to 100. Higher overall and subdomain score in WHOQOL-BREF indicates higher quality of life.

Compared between different groups. Scores scaled from 0 to 27. Higher overall score in PHQ-9 indicates more depressive symptoms.

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