Perioperative Testosterone Replacement Therapy in Sarcopenic Male Colorectal Cancer Patients (TERESA)

Use of Perioperative Testosterone Replacement Therapy (TRT) in Sarcopenic Male Colorectal Cancer Patients - A Single Arm Open Label Feasibility Study

With increasing age and the additional impact from the bowel cancer and the chemotherapy and/ or radiotherapy it has been described that testosterone (a male hormone produced naturally in the body) levels are reduced. Testosterone has an impact on numerous body functions including the muscle mass and quality. Previous studies have identified that muscle mass is reduced as a result of ageing but also because of the deleterious effect of cancer and chemotherapy and/or radiotherapy. There is growing evidence from published studies that patients with better muscle mass and quality, do better after surgery. Mr Jenkins and his team are therefore looking at ways, the investigators can try and prevent or reduce this muscle loss and therefore improve patient outcomes.

The aim of this study is to assess whether using testosterone replacement therapy in the form of a topically applied gel daily for a total of 12 weeks, is feasible and acceptable by the patients who are diagnosed with colorectal cancer and are waiting to undergo surgery. The investigators will also collect information related to the testosterone replacement therapy such as questionnaires on the quality of life, fatigue and muscle mass, and blood biomarker changes in the blood.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer; Sarcopenia; Perioperative Care; Hypogonadism, Male; Testosterone Replacement Therapy
• Intervention / Treatment: Drug: Testosterone

• Study Type: Observational
• Enrollment (Anticipated): 30

Contacts and Locations

• Study Contact: Name: Ioanna Drami, MSc, MRCS; Phone Number: +4420 8864 3232; Email: i.drami20@imperial.ac.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • London North West University Healthcare NHS Trust
    • Contact: I Drami, MSc, MRCS
    • Principal Investigator: I Drami, MSc, MRCS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with colorectal cancer who attend to the surgical clinic, following completion of their neoadjuvant chemoradiotherapy or for initial review by the surgical team in order to proceed with surgery.

Description

Inclusion Criteria:

• Male ≥ 45 years old
• Colorectal cancer - histology confirmed
• Identified as sarcopenic on latest computerised tomography (CT) scan prior to intervention (part of initial investigations - using Martin et al (2013) criteria - 43cm2/m2 for Body Mass Index (BMI) <25, 53cm2/m2 for BMI>25)
• Documented low or normal testosterone at time of recruitment (<12 nano moles/ Litre (nmol/L)
• Eligible for operative intervention
• Capacity to consent
• Able to mobilise & able to complete the 6 Minute Walk Test (MWT)
• Post completion of chemotherapy/ chemoradiotherapy treatment (if the patient has neoadjuvant treatment)
• Booked straight for surgery with an interim of 4-8 weeks.
• Participation in another concurrent trial/ study is accepted, following discussion between the two trial /study teams

Exclusion Criteria:

• Not sarcopenic on computerised tomography (CT)
• Not eligible for surgery
• History of Deep Vein Thrombosis (DVT)/ Pulmonary Embolism (PE)/ prostate cancer/ breast cancer
• Prostate nodule identified during digital rectal examination (DRE) or magnetic resonance imaging (MRI) pelvis
• Multiple distant metastasis which are non-operable
• Prostate specific antigen (PSA) > 3 nanogram/ mililitre (ng/ml)
• Haematocrit (HCT) >52%
• Severe lower urinary tract symptoms
• Class III/ IV heart failure
• Myocardial Infarct or stroke within the last 6 months
• Dementia / No capacity to consent
• Patient on medications with anti-androgen effect eg spironolactone
• Patients with untreated severe obstructive sleep apnoea
• Morbid obesity as defined by Body Mass Index (BMI) >40
• Uncontrolled hypertension
• Patients on long term steroids during the trial period
• Patient on other anabolic agents
• Not already on treatment for primary hypogonadism
• Patients with bone metastasis

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of days required for a patient to be recruited on the study and how many patients are recruited	number of days required for patients to be recruited and number of patients recruited by the closure of the study	1 year
Number of patients who will complete the 12 week treatment	retention of the patients for a the total of 12 weeks by the time of recruitment, will be measured in days on study	12 weeks
Treatment acceptability questionnaire	questionnaire on the difficulty experience (Likert scale) for the use of the gel for 12 weeks, if they developed any side effects as described on the CTCAE version 5.0	12 weeks

Collaborators and Investigators

• Sponsor: London North West Healthcare NHS Trust
• Investigators: Principal Investigator: JT Jenkins, MD, FRCS, London North West University Hospital Healthcare NHS Trust

Publications and helpful links

General Publications

• Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyere O, Cederholm T, Cooper C, Landi F, Rolland Y, Sayer AA, Schneider SM, Sieber CC, Topinkova E, Vandewoude M, Visser M, Zamboni M; Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2), and the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing. 2019 Jan 1;48(1):16-31. doi: 10.1093/ageing/afy169. Erratum In: Age Ageing. 2019 Jul 1;48(4):601.
• Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR; Baltimore Longitudinal Study of Aging. Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab. 2001 Feb;86(2):724-31. doi: 10.1210/jcem.86.2.7219.
• Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casaburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med. 1996 Jul 4;335(1):1-7. doi: 10.1056/NEJM199607043350101.
• Mourtzakis M, Prado CM, Lieffers JR, Reiman T, McCargar LJ, Baracos VE. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab. 2008 Oct;33(5):997-1006. doi: 10.1139/H08-075.
• Mullie L, Afilalo J. CoreSlicer: a web toolkit for analytic morphomics. BMC Med Imaging. 2019 Feb 11;19(1):15. doi: 10.1186/s12880-019-0316-6.
• Bozzetti F. Forcing the vicious circle: sarcopenia increases toxicity, decreases response to chemotherapy and worsens with chemotherapy. Ann Oncol. 2017 Sep 1;28(9):2107-2118. doi: 10.1093/annonc/mdx271.
• Trejo-Avila M, Bozada-Gutierrez K, Valenzuela-Salazar C, Herrera-Esquivel J, Moreno-Portillo M. Sarcopenia predicts worse postoperative outcomes and decreased survival rates in patients with colorectal cancer: a systematic review and meta-analysis. Int J Colorectal Dis. 2021 Jun;36(6):1077-1096. doi: 10.1007/s00384-021-03839-4. Epub 2021 Jan 22.
• Lee CM, Kang J. Prognostic impact of myosteatosis in patients with colorectal cancer: a systematic review and meta-analysis. J Cachexia Sarcopenia Muscle. 2020 Oct;11(5):1270-1282. doi: 10.1002/jcsm.12575. Epub 2020 Jun 1.
• Pring ET, Malietzis G, Kennedy RH, Athanasiou T, Jenkins JT. Cancer cachexia and myopenia - Update on management strategies and the direction of future research for optimizing body composition in cancer - A narrative review. Cancer Treat Rev. 2018 Nov;70:245-254. doi: 10.1016/j.ctrv.2018.10.002. Epub 2018 Oct 6.
• Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004 May;7(3):271-7. doi: 10.1097/00075197-200405000-00006.
• Burney BO, Garcia JM. Hypogonadism in male cancer patients. J Cachexia Sarcopenia Muscle. 2012 Sep;3(3):149-55. doi: 10.1007/s13539-012-0065-7. Epub 2012 Apr 20.
• Feldman HA, Longcope C, Derby CA, Johannes CB, Araujo AB, Coviello AD, Bremner WJ, McKinlay JB. Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study. J Clin Endocrinol Metab. 2002 Feb;87(2):589-98. doi: 10.1210/jcem.87.2.8201.
• Slattery ML, Sweeney C, Murtaugh M, Ma KN, Wolff RK, Potter JD, Caan BJ, Samowitz W. Associations between ERalpha, ERbeta, and AR genotypes and colon and rectal cancer. Cancer Epidemiol Biomarkers Prev. 2005 Dec;14(12):2936-42. doi: 10.1158/1055-9965.EPI-05-0514.
• Lu Y, Ljung R, Martling A, Lindblad M. Risk of Colorectal Cancer by Subsite in a Swedish Prostate Cancer Cohort. Cancer Control. 2015 Apr;22(2):263-70. doi: 10.1177/107327481502200222.
• Gillessen S, Templeton A, Marra G, Kuo YF, Valtorta E, Shahinian VB. Risk of colorectal cancer in men on long-term androgen deprivation therapy for prostate cancer. J Natl Cancer Inst. 2010 Dec 1;102(23):1760-70. doi: 10.1093/jnci/djq419. Epub 2010 Nov 10.
• Sah BK, Chen MM, Peng YB, Feng XJ, Yan M, Liu BY, Fan QS, Zhu ZG. Does testosterone prevent early postoperative complications after gastrointestinal surgery? World J Gastroenterol. 2009 Nov 28;15(44):5604-9. doi: 10.3748/wjg.15.5604.
• Wright TJ, Dillon EL, Durham WJ, Chamberlain A, Randolph KM, Danesi C, Horstman AM, Gilkison CR, Willis M, Richardson G, Hatch SS, Jupiter DC, McCammon S, Urban RJ, Sheffield-Moore M. A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women. J Cachexia Sarcopenia Muscle. 2018 Jun;9(3):482-496. doi: 10.1002/jcsm.12295. Epub 2018 Apr 14.
• Walsh JS, Marshall H, Smith IL, Greenfield DM, Swain J, Best E, Ashton J, Brown JM, Huddart R, Coleman RE, Snowden JA, Ross RJ. Testosterone replacement in young male cancer survivors: A 6-month double-blind randomised placebo-controlled trial. PLoS Med. 2019 Nov 12;16(11):e1002960. doi: 10.1371/journal.pmed.1002960. eCollection 2019 Nov.
• Wynter-Blyth V, Moorthy K. Prehabilitation: preparing patients for surgery. BMJ. 2017 Aug 8;358:j3702. doi: 10.1136/bmj.j3702. No abstract available.
• Santa Mina D, van Rooijen SJ, Minnella EM, Alibhai SMH, Brahmbhatt P, Dalton SO, Gillis C, Grocott MPW, Howell D, Randall IM, Sabiston CM, Silver JK, Slooter G, West M, Jack S, Carli F. Multiphasic Prehabilitation Across the Cancer Continuum: A Narrative Review and Conceptual Framework. Front Oncol. 2021 Jan 11;10:598425. doi: 10.3389/fonc.2020.598425. eCollection 2020.
• Jang MK, Park C, Hong S, Li H, Rhee E, Doorenbos AZ. Skeletal Muscle Mass Change During Chemotherapy: A Systematic Review and Meta-analysis. Anticancer Res. 2020 May;40(5):2409-2418. doi: 10.21873/anticanres.14210.
• Blauwhoff-Buskermolen S, Versteeg KS, de van der Schueren MA, den Braver NR, Berkhof J, Langius JA, Verheul HM. Loss of Muscle Mass During Chemotherapy Is Predictive for Poor Survival of Patients With Metastatic Colorectal Cancer. J Clin Oncol. 2016 Apr 20;34(12):1339-44. doi: 10.1200/JCO.2015.63.6043. Epub 2016 Feb 22.
• Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, Johnston MA, Steiner MS. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013 Apr;14(4):335-45. doi: 10.1016/S1470-2045(13)70055-X. Epub 2013 Mar 14.
• Wu B, Lorezanza D, Badash I, Berger M, Lane C, Sum JC, Hatch GF 3rd, Schroeder ET. Perioperative Testosterone Supplementation Increases Lean Mass in Healthy Men Undergoing Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial. Orthop J Sports Med. 2017 Aug 9;5(8):2325967117722794. doi: 10.1177/2325967117722794. eCollection 2017 Aug.
• Shafqat A, Einhorn LH, Hanna N, Sledge GW, Hanna A, Juliar BE, Monahan P, Bhatia S. Screening studies for fatigue and laboratory correlates in cancer patients undergoing treatment. Ann Oncol. 2005 Sep;16(9):1545-50. doi: 10.1093/annonc/mdi267. Epub 2005 May 26.
• Del Fabbro E, Garcia JM, Dev R, Hui D, Williams J, Engineer D, Palmer JL, Schover L, Bruera E. Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer. 2013 Sep;21(9):2599-607. doi: 10.1007/s00520-013-1832-5. Epub 2013 May 8.
• Wischmeyer PE, Suman OE, Kozar R, Wolf SE, Molinger J, Pastva AM. Role of anabolic testosterone agents and structured exercise to promote recovery in ICU survivors. Curr Opin Crit Care. 2020 Oct;26(5):508-515. doi: 10.1097/MCC.0000000000000757.

Study record dates

Study Major Dates

• Study Start (Actual): January 15, 2022
• Primary Completion (Anticipated): March 1, 2023
• Study Completion (Anticipated): March 1, 2023

Study Registration Dates

• First Submitted: January 20, 2022
• First Submitted That Met QC Criteria: May 4, 2022
• First Posted (Actual): May 10, 2022

Study Record Updates

• Last Update Posted (Actual): May 10, 2022
• Last Update Submitted That Met QC Criteria: May 4, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Nervous System Diseases; Neoplasms; Neoplasms by Site; Neurologic Manifestations; Endocrine System Diseases; Gonadal Disorders; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Neuromuscular Manifestations; Pathological Conditions, Anatomical; Intestinal Neoplasms; Rectal Diseases; Muscular Atrophy; Atrophy; Colorectal Neoplasms; Sarcopenia; Hypogonadism; Eunuchism; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Androgens; Testosterone
• Other Study ID Numbers: RD21/025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No