Clinical trial NCT05028192: Mitochondria Preservation by Exercise Training: a Targeted Therapy for Cancer and Chemotherapy-induced Cachexia
Official title: Mitochondria Preservation by Exercise Training: A Targeted Therapy for Cancer and Chemotherapy-induced Cachexia.
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Cachexia
Rectal Cancer
Lead sponsor: University of Turin, Italy
Sponsor class: OTHER
Collaborators: name: University of Padova
name: Catholic University of the Sacred Heart
name: University of Roma La Sapienza
First posted: 2021-08-31
Enrollment: 144
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients from all participating centers older than 18 years, males or females, with the primary diagnosis of rectal cancer ycTNM stage II, III or IV (American Joint Committee on Cancer 8th edition), who undergone neoadjuvant therapy. Clinically stratified in the pre-cachectic or cachectic stage according to Fearon K et al. definition. That will be subject to low or ultralow anterior resection, abdominoperineal resection or palliative surgery through any approach (open, laparoscopic or robotic).

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Physical function
timeFrame: Preoperative.
measure: Physical activity-Subjective Measurement
timeFrame: Preoperative
measure: Physical activity-Objective Measurement (step count)
timeFrame: Preoperative.
measure: Physical activity-Objective Measurement (sleep)
timeFrame: Preoperative.
measure: Physical activity-Objective Measurement (sedentary time)
timeFrame: Preoperative.
measure: Physical activity-Objective Measurement (active time)
timeFrame: Preoperative.
measure: Muscular quantity
timeFrame: Preoperative.
measure: Muscular quality (muscle fat content) by magnetic resonance imaging
timeFrame: Preoperative.
measure: Nutritional status - Albumin
timeFrame: Preoperative.
measure: Nutritional status - Prealbumin
timeFrame: Preoperative.
measure: Nutritional status - transferrin
timeFrame: Preoperative.
measure: General health marker- hemoglobin
timeFrame: Preoperative.
measure: Inflammatory status-White blood cells count
timeFrame: Preoperative.
measure: Inflammatory status - C-reactive protein
timeFrame: Preoperative.
measure: Muscle wasting- creatine kinase
timeFrame: Preoperative.
measure: Morphometric analysis of skeletal muscle
timeFrame: within 30 postoperative days.
measure: Molecular analysis of skeletal muscle
timeFrame: within 60 postoperative days.
measure: Muscle protein metabolism
timeFrame: within 60 postoperative days.
Secondary outcomes:
measure: Overall survival
timeFrame: 3 years after surgery.
Other outcomes:
Locations:
city: Orbassano
country: Italy
facility: Ospedale San Luigi Gonzaga
state: Turin
Study officials:
affiliation: Università degli studi di Torino- Surgical Oncology and Digestive Surgery
name: Maurizio Degiuli, Prof.
role: STUDY_CHAIR
References:
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.
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.
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):1962. doi: 10.3390/ijms20081962.
citation: 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. No abstract available.
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.
citation: 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 Jul 1;48(4):601. doi: 10.1093/ageing/afz046. No abstract available.
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.
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.