Muscle Wasting in Cancer (MWIC) (MWIC)

September 15, 2020 updated by: University of Edinburgh

Biochemical and Functional Biomarkers of Cachexia in Cancer Patients

One way cancer affects people is through weight loss. During this weight loss (called cachexia), all types of body tissue are lost, but there is a greater rate of muscle loss than fat. Cancer patients with cachexia show decreased quality of life, decreased response to treatment (e.g. chemotherapy), increased complications from surgery, and shorter overall survival. The Investigators aim to identify molecular (and patient) factors within the tissues and bodily fluids of patients with cancer and cachexia in order to identify patients at risk of weight loss, and identify potential therapies. For this, the Investigators aim to take patient samples (muscle, fat, tumour, urine and blood) whilst patients are asleep (general anaesthesia) during their operation to remove the cancer. These samples, and similar samples taken in previous studies, will be analysed in the laboratory. Along with the sample taking, the Investigators aim to perform nutritional assessments of patients before and after surgery to get an accurate picture of their weight loss. This will include simple measurements (e.g. height/weight), and computer reanalysis of their initial diagnostic computed tomography (CT) scans (this study will not require any additional scans for patients). The Investigators also aim to assess how their muscles function, by asking them to perform walk tests and wear a physical activity meter, and assess their quality of life through questionnaires. The Investigators aim to perform nutritional and functional assessments pre-surgery and at 2-3 appointments post-surgery, up to a period of 12 months. At these timepoints, the Investigators also aim to take repeat blood and urine samples, and where possible, one additional thigh muscle biopsy. Repeated assessments allow comparison between "cancer" and "cured" states. The study will take 2 years for patient recruitment.

For comparison, the Investigators also aim to examine similar tissue and fluid samples (except tumour) from non-cancer patients who are having surgery for benign conditions (e.g. hernia).

Study Overview

Status

Unknown

Conditions

Detailed Description

Patients: Patients with upper and lower gastrointestinal cancer for planned resectional surgery will be recruited. Patients will be identified by the clinical team at the relevant multidisciplinary team meeting and then approached for study information and consent in the surgical clinic. Age-matched, healthy controls undergoing elective surgery for benign conditions (e.g. hernias) will also be recruited.

Patient Phenotyping: CT scans performed as a routine part of diagnosis and staging will be used for analysis of body composition. All patients recruited will have their CT scans analysed where present. Control patients (e.g. hernias) may not have CT scans, but where available, will be analysed. A transverse CT image from the third lumbar vertebrae will be assessed and tissue volumes estimated by a single trained observer. Cross-sectional area for muscle and adipose tissue will be normalized for stature (cm2/m2). Estimates of whole body stores will be generated from raw data (cm2) using regression equations. Cutoffs for low muscularity are based on CT-based sarcopenia plus obesity studies of cancer patients. In a previous study, the median time to muscle biopsy after CT scan was 18 days. Phenotyping will also involve measuring basic physical attributes (e. g. weight, height etc) and self-reported physical abilities (through questionnaires).

Muscle function/Physical activity assessment: An objective assessment of physical ability will be undertaken in the clinic for all patients. This will involve a "timed up and go" test and a "6 minute walk" test. These tests have been well-validated in the literature and have good inter-rater reliability. Whilst they do add a slight burden of inconvenience to the patient clinic visit this is minimal. Additionally, a physical activity meter will be applied to the patients' thigh under a waterproof dressing. The Investigators have validated these meters in cancer patients, and they are small (35x53x7mm) and light (20g). When used in previous studies as above the patients have found them unobtrusive and they have been well-tolerated. Where possible, the Investigators will ask the patients to repeat the "timed up and go" and "6 minute walk test" in postoperative clinic up to 12 months after surgery.

Patient self-reported assessment: At routine clinic, all patients will be asked to complete validated questionnaires regarding their physical health, and their perceptions of this. These will be used to assess severity of co-morbidity, and also to assess frailty. Example questionnaires include the Scottish Co-Morbidity Severity Score, the Charlson Co-morbidity Index, and the Edmonton Frail Scale. Other questionnaires relating to self-reported appetite and function will be considered but the overall aim will be to ask select questions to reduce the burden of questioning and prevent questionnaire fatigue. The Investigators will ask participants to repeat these questionnaires in routine clinic up to 12 months post surgery.

Blood and urine sampling: At routine National Health Service (NHS) clinic, all patients will be asked to provide a blood and a urine sample. Where this is not possible, the research team will ask for permission to take these samples under general anaesthetic at planned surgery via urinary and vascular catheters inserted as part of routine care. In the postoperative phase the Investigators will ask participants to provide blood and urine samples, where possible, in routine clinic up to 12 months following surgery.

Muscle Biopsy: A biopsy of rectus abdominis muscle will be taken at surgery by the operating surgeon for all patients. This will be taken from the incision performed for the planned surgery and requires no further incisions. Where possible, an additional needle biopsy of quadriceps (thigh muscle) will also be sampled for comparison. Samples will be cleaned of fats, blood/fibrous tissue, snap frozen in liquid nitrogen and stored at -80°C, For immunohistochemistry (IHC), muscle specimens will be stitched onto a cork, treated with optimum cutting temperature (OCT) and then lowered into cooled isopentane solvent (-190°C) prior to storage at -80°C.

Fat biopsy: A biopsy of subcutaneous fat, and where possible, visceral fat will be collected at the time of surgery for all patients by the operating surgeon. This procedure does not require any additional incisions. These samples will be snap frozen in liquid nitrogen and stored at -80°C.

Tumour biopsy: For the cancer patients, once the resection specimen has been removed at surgery, this will be taken fresh to the pathology lab where the duty pathologist will retrieve sections of tumour. This will be done without compromising clinical staging and in accordance with current procedures. The tumour samples will be divided into aliquots and snap frozen in liquid nitrogen at -80°C. This will not apply to the control group.

Repeat sampling: At follow-up NHS clinic, all patients will be asked to provide repeat blood and urine samples which will be divided into aliquots and snap frozen in liquid nitrogen at -80°C. Where the patient is amenable, they will also be asked to provide a single repeat needle biopsy of the quadriceps muscle. This will be performed in clinic under local anaesthetic using standard aseptic technique. There is some discomfort associated with the injection of local anaesthetic but this is transitory. There is also some discomfort associated with the muscle biopsy but this is short-lived and in the past has been well-tolerated. Quadriceps biopsy will be requested at routine follow-up (at around 6-8 months after surgery) only. Where possible, repeat blood and urine samples will be requested at subsequent routine follow-up appointments for the duration of the study. The Investigators would anticipate this to take place for up to 12 months postoperatively.

Immunohistochemistry (IHC) and Western Blots: These will be performed as per previous publications. For IHC, frozen muscle sections will be co-stained for laminin and myosin heavy chain or lla to distinguish fibre type. Paraffin sections may also be used and stained. The distribution of fibre types, cross-sectional area of individual fibres, and the distribution of nuclei (central versus peripheral location to assess level of regeneration) will be assessed by a proprietary image analysis platform. Potential markers for measurement will include pathways members of autophagy (beclin, lamp, anti-thymocyte globulin (ATG)); apoptosis (poly adenosine di-phosphate ribose polymerase (PARP), caspase-3); oxidative stress (nitrosylated 4-Hydroxynonenal (HNE) and ubiquitinated [K48, K63] proteins); cell stress (Nuclear factor (erythroid derived 2)-like 2 Kelch-like erythroid cell-derived protein with Cap 'N' Collar homology-associated protein 1 (NRF2KEAP1), Heat Shock Protein (HSP), endoplasmic reticulum (ER)-stress); inflammation (IkB kinase (IKK), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB)-9p65, p.38, extracellular signal-related kinase (erk)1/2, c-Jun N-terminal kinase (jnk)); satellite cell maturation (Paired Box (Pax)3, Pax7, Myogenic factor (MYF)5, M-cadherin); myogenesis (myogenin, desmin); sma/mothers against decapentaplegic(SMAD) (SMAD3, phosphoSMAD3); and P-selectin.

C - reactive protein (CRP) Analysis: Systemic inflammation (SI) will be assessed using plasma CRP concentration, which will be measured with an automated immunoturbidimetric assay by the Department of Clinical Chemistry, Royal Infirmary of Edinburgh (RIE).

These analyses will be carried out both in the University of Edinburgh and at the premises of international collaborators. Any tissue transferred out of the care of the University will be fully anonymised using unique study identifiers.

This current study is a continuation of a previous study funded and supported by Cancer Research United Kingdom (UK). As part of that study tissue samples were collected, some of which remain in the University. The Investigators intend to use these remaining samples to add power to the new samples the Investigators collect by increasing the cohort size and thus the likelihood of any potential biomarker identified being significant rather than erroneous. In addition, including these samples in the analysis will add to their value, over and above that already gained by inclusion in the previous project.

Study Type

Observational

Enrollment (Anticipated)

120

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Patients referred to the NHS Lothian oesophagogastric, hepatobiliary, and colorectal MDT will be screened for eligibility. In addition, patients attending NHS Lothian outpatient clinics will be screened for eligibility.

Description

Inclusion Criteria:

  • Patients identified at multidisciplinary team meetings (MDT) as having oesophagogastric, hepatobiliary, and colorectal cancer suitable for resection
  • Patients over 18 years of age
  • Patients identified at surgical clinic as being planned for an abdominal operation for a non-cancer, non-inflammatory condition

Exclusion Criteria:

  • Patients with inflammatory conditions or other condition other than cancer that might cause muscle wasting
  • Patients without the capacity to consent
  • Members of vulnerable groups
  • Patients not undergoing abdominal surgery
  • Patients undergoing totally minimally invasive (laparoscopic) surgery, with no open or hand-assisted component affording easy access to rectus muscle biopsy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Cancer
Patients with oesophagogastric, hepatobiliary, and colorectal cancer for resectional surgery
Non-cancer
Patients undergoing abdominal operation for non-inflammatory, non-cancer conditions

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Skeletal muscle index of cancer and control patients
Time Frame: Analysis of CT scans performed between diagnosis and operation, up to 16 weeks from diagnosis
CT measured muscularity performed on preoperative CT scans using validated software
Analysis of CT scans performed between diagnosis and operation, up to 16 weeks from diagnosis

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biochemical analysis of rectus muscle biopsies
Time Frame: Performed in batches on rectus biopsies taken at time of operation, within 6 months of operation
The soluble protein content of Rectus muscle, as measured by the bicinchoninic acid assay (BCA) method.
Performed in batches on rectus biopsies taken at time of operation, within 6 months of operation
Cancer patient 5-year postoperative survival
Time Frame: Up to 5 years postoperatively
Time between operative intervention and patient death as recorded in clinical record
Up to 5 years postoperatively
Measurement of patients BMI
Time Frame: Performed at clinic between diagnosis and operation, up to 16 weeks from date of diagnosis
Height and weight will be measured and combined to report BMI in kg/m^2
Performed at clinic between diagnosis and operation, up to 16 weeks from date of diagnosis
Detailed phenotyping of patients gait speed
Time Frame: Performed at preoperative clinic, up to 16 weeks from date of diagnosis
Gait speed will be measured over a defined distance to produce a gait speed in metres per second
Performed at preoperative clinic, up to 16 weeks from date of diagnosis
Detailed description of patients quality of life
Time Frame: Performed at clinic before operation, up to 16 weeks from date of diagnosis
Quality of life will be measured using the "QLQ-C30" questionnaire
Performed at clinic before operation, up to 16 weeks from date of diagnosis

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Edinburgh

Collaborators

Novartis
NHS Lothian

Investigators

  • Principal Investigator: Michael I Ramage, MBChB, University of Edinburgh

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

November 1, 2015

Primary Completion (ANTICIPATED)

August 1, 2022

Study Completion (ANTICIPATED)

August 1, 2022

Study Registration Dates

First Submitted

May 30, 2017

First Submitted That Met QC Criteria

June 14, 2017

First Posted (ACTUAL)

June 19, 2017

Study Record Updates

Last Update Posted (ACTUAL)

September 17, 2020

Last Update Submitted That Met QC Criteria

September 15, 2020

Last Verified

August 1, 2020

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Surg2015MWIC

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymised individual participant data (IPD), including phenotypic data but not including patient identifiable data will be shared with other researchers in collaboration with our research group. Interested parties may contact the lead researcher with data requests.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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