Mitochondria Preservation by Exercise Training: a Targeted Therapy for Cancer and Chemotherapy-induced Cachexia

Rectal Cancer Clinical Trial

— MEx  

Official title:

Mitochondria Preservation by Exercise Training: A Targeted Therapy for Cancer and Chemotherapy-induced Cachexia.

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05028192
• Other study ID #: N. 98/2021
• Status: Enrolling by invitation
• Start date: September 27, 2021
• Est. completion date: September 1, 2024

Study information

• Verified date: September 2021
• Source: University of Turin, Italy
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study aims to define the contribution of cancer and chemotherapy to muscle and systemic alterations that drive the onset of cachexia in rectal cancer patients and validate in human cancer cachexia (CC) the alterations in mitochondrial function and neuromuscular junction (NMJ) observed in the experimental models, thus providing the rationale for potential anti-cachexia strategies based on exercise and or exercise mimetics.

Description:

This is a multicenter observational prospective cohort study in rectal cancer patients after neoadjuvant therapy (ycTNM) stage II, III, and IV (AJCC 8th edit), clinically stratified in the pre-cachectic or cachectic stage according to Fearon K et al. definition. That will be subject to curative or palliative surgery through any surgical approach. And a control subgroup of patients who will undergo any abdominal surgery type through any approach type for no neoplastic or inflammatory disease.

The study will take place in four Italian centers of colorectal surgery.

Will be run a preoperatory physical performance, and will be recorded the physical activity by wearing a SmartWatch.

The quantity of muscle will be estimated by the cross-sectional area (CSA) or the skeletal muscle area (SMA) from the magnetic resonance imaging (MRI) or computed tomography CT, respectively, and the Skeletal muscle index (SMI). The muscular quality will be studied by the mean skeletal muscle radiation attenuation (SMRA) and MRI proton density fat fraction (PDFF). All these parameters will be calculated by a radiologist from the preoperative MRI or CT imaging study.

The study includes the analysis of preoperatory inflammatory and nutritional biomarkers. And a muscular biopsy harvested by the surgeon from the rectum or oblique abdominal during rectal resection-palliative surgery. The sample will undergo morphological and structural studies using histology, immunohistochemical, immunofluorescence, biochemical, and molecular analyses.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 144
• Est. completion date: September 1, 2024
• Est. primary completion date: September 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Patients with confirmed histopathological diagnosis of rectal adenocarcinoma ycTNM stage II, III, or IV (AJCC 8th).

• Patients treated with neoadjuvant therapy.

• Patients that will be subject to curative intent or palliative surgery through any approach (open, laparoscopic, or robotic).

• Ability to sign the informed consent.

Exclusion Criteria:

• Rectal cancer stage I or any stage without neoadjuvant therapy.

• Age < 18 and >75 years

• Long steroid treatment for any cause.

• Emergency setting.

• Co-existent inflammatory bowel disease.

• Inflammatory comorbidities (liver failure, diabetes, metabolic acidosis, acute and chronic renal failure, sepsis, AIDS, acute and chronic hepatitis, autoimmune disorders, and chronic obstructive pulmonary disease).

• Healthy volunteers.

• Other (simultaneous) neoplastic disease

Related Conditions & MeSH terms

• Cachexia
• Rectal Cancer

Intervention

Other:
• no intervention
no intervention

Locations

Country	Name	City	State
Italy	Ospedale San Luigi Gonzaga	Orbassano	Turin

Sponsors (4)

Lead Sponsor	Collaborator
University of Turin, Italy	Catholic University of the Sacred Heart, University of Padova, University of Roma La Sapienza

Country where clinical trial is conducted

Italy, 

References & Publications (8)

Baracos VE. Skeletal muscle anabolism in patients with advanced cancer. Lancet Oncol. 2015 Jan;16(1):13-4. doi: 10.1016/S1470-2045(14)71185-4. Epub 2014 Dec 16. — View Citation

Codari M, Zanardo M, di Sabato ME, Nocerino E, Messina C, Sconfienza LM, Sardanelli F. MRI-Derived Biomarkers Related to Sarcopenia: A Systematic Review. J Magn Reson Imaging. 2020 Apr;51(4):1117-1127. doi: 10.1002/jmri.26931. Epub 2019 Sep 13. — View Citation

Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère 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 Jul 1;48(4):601. doi: 10.1093/ageing/afz046. — View Citation

Dev R. Measuring cachexia-diagnostic criteria. Ann Palliat Med. 2019 Jan;8(1):24-32. doi: 10.21037/apm.2018.08.07. Epub 2018 Sep 7. Review. — View Citation

Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, MacDonald N, Mantovani G, Davis M, Muscaritoli M, Ottery F, Radbruch L, Ravasco P, Walsh D, Wilcock A, Kaasa S, Baracos VE. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011 May;12(5):489-95. doi: 10.1016/S1470-2045(10)70218-7. Epub 2011 Feb 4. Review. — View Citation

Freire PP, Fernandez GJ, Cury SS, de Moraes D, Oliveira JS, de Oliveira G, Dal-Pai-Silva M, Dos Reis PP, Carvalho RF. The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis. Int J Mol Sci. 2019 Apr 22;20(8). pii: E1962. doi: 10.3390/ijms20081962. Review. — View Citation

Penet MF, Bhujwalla ZM. Cancer cachexia, recent advances, and future directions. Cancer J. 2015 Mar-Apr;21(2):117-22. doi: 10.1097/PPO.0000000000000100. Review. — View Citation

Wiegert EVM, de Oliveira LC, Calixto-Lima L, Borges NA, Rodrigues J, da Mota E Silva Lopes MS, Peres WAF. Association between low muscle mass and survival in incurable cancer patients: A systematic review. Nutrition. 2020 Apr;72:110695. doi: 10.1016/j.nut.2019.110695. Epub 2019 Dec 7. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Physical function	Determinate by the short physical performance battery (SPPB) Score, a series of tests used to evaluate lower extremity function and mobility in older people. Scores are assigned according to performance, with an overall maximum score of 12. A cut off score < 10 indicates mobility disability and cut point: = 8 points for diagnosing of severe sarcopenia	Preoperative.
Primary	Physical activity-Subjective Measurement	Determinate by the physical activity scale for the elderly (PASE) Score, the overall score ranging from 0 to 793, higher scores indicated greater physical activity	Preoperative
Primary	Physical activity-Objective Measurement (step count)	Determinate by the average daily step count (total number of steps/14 days) recorded by wearing a Smart Watch for two weeks on consecutive days.	Preoperative.
Primary	Physical activity-Objective Measurement (sleep)	Determinate by the average of daily sleep duration(total minutes of sleep/ 14 days) recorded by wearing a Smart Watch for two weeks on consecutive days.	Preoperative.
Primary	Physical activity-Objective Measurement (sedentary time)	Determinate by the average daily sedentary time (total minutes of inactivity/14 days) recorded by wearing a Smart Watch for two weeks on consecutive days.	Preoperative.
Primary	Physical activity-Objective Measurement (active time)	Determinate by the average daily active time (total duration of activity in minutes/14 days) recorded by wearing a Smart Watch for two weeks on consecutive days.	Preoperative.
Primary	Muscular quantity	Determinate by the Skeletal muscle index (SMI) = skeletal muscle area or cross-sectional area at L4-L5 (cm2)/height2(m2) from the preoperative magnetic resonance imaging.	Preoperative.
Primary	Muscular quality (muscle fat content) by magnetic resonance imaging	Determinate by the proton density fat fraction (PDFF) of paraspinal muscles at L4-L5	Preoperative.
Primary	Nutritional status - Albumin	Blood levels of albumin (g/dL).	Preoperative.
Primary	Nutritional status - Prealbumin	Blood levels of prealbumin(mg/dL).	Preoperative.
Primary	Nutritional status - transferrin	Blood levels of transferrin(mg/dL).	Preoperative.
Primary	General health marker- hemoglobin	Blood levels of Hemoglobin (g/L).	Preoperative.
Primary	Inflammatory status-White blood cells count	White blood cells count (10^/L).	Preoperative.
Primary	Inflammatory status - C-reactive protein	Blood levels of C-reactive protein (mg/dL).	Preoperative.
Primary	Muscle wasting- creatine kinase	Blood levels of creatine kinase (U/L).	Preoperative.
Primary	Morphometric analysis of skeletal muscle	Description of the dimension and type of muscular fibers from an abdominal wall muscle biopsy harvested intraoperatively.	within 30 postoperative days.
Primary	Molecular analysis of skeletal muscle	Characterization of molecular signatures associated with Neo-adjuvant Chemotherapy and rectal cancer by comparing molecular profiles of a muscular biopsies harvested intraoperatively.	within 60 postoperative days.
Primary	Muscle protein metabolism	Muscle-specific ubiquitin-ligases expression, mitophagy cargo shuttle, fusion-fission machinery, and mitochondrial biogenesis will be assayed from a muscular biopsy harvested intraoperatively.	within 60 postoperative days.
Secondary	Overall survival	to describe the percentage of participants who are alive three years after surgery	3 years after surgery.