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Trial registered on ANZCTR


Registration number
ACTRN12618000289213
Ethics application status
Approved
Date submitted
12/02/2018
Date registered
26/02/2018
Date last updated
26/02/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Can mitochondrial function predict response to radiation therapy for rectal cancer?
Scientific title
Can mitochondrial function predict response to radiotherapy for rectal cancer?
Secondary ID [1] 294022 0
Nil known
Universal Trial Number (UTN)
U1111-1209-2421
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rectal adenocarcinoma 306548 0
Condition category
Condition code
Cancer 305646 305646 0 0
Bowel - Back passage (rectum) or large bowel (colon)

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
The exposure of interest is neoadjuvant radiotherapy +/- chemotherapy for locally advanced (T3 or T4 tumour, or any lymph node involvement) rectal cancer. The duration of observation is from diagnosis with rectal cancer prior to radiotherapy to surgical resection and is approximately 2 months. We are looking to identify a correlation between markers of mitochondrial function and response to radiotherapy for rectal cancer.
Intervention code [1] 300295 0
Diagnosis / Prognosis
Comparator / control treatment
We aim to recruit 5 patients with rectal cancer who are not having radiotherapy to act as a control group. Patients in the control group will receive standard care for rectal cancer that does not include radiotherapy - usually tissue diagnosis based on colonoscopy and biopsy, followed by surgical resection as the sole treatment (+/- adjuvant chemotherapy, although that will be outside the window of this study). There will not be an indication for radiotherapy in this group i.e. T2 or less tumour and no lymph node involvement, or there may be a contraindication to radiotherapy e.g. patient co-morbidity.
Control group
Active

Outcomes
Primary outcome [1] 304758 0
Correlation between markers of mitochondrial function and Tumour Regression Grade (TRG). Protein markers of mitochondrial function are to be assessed using the Western Blot technique and this testing is performed on the rectal tumour tissue biopsies taken before radiotherapy treatment. TRG is performed on the surgical resection specimen. The TRG routinely used in our institution is the Dworak system and will be determined by the reporting pathologist.
Timepoint [1] 304758 0
Mitochondrial function of tumour cells at time of diagnosis or shortly after (<2 weeks) will be correlated with TRG at time of surgical resection. Resection is generally 2-3 months after diagnosis if patient undergoes radiotherapy, for the control group surgical resection is likely to occur 2-4 weeks after diagnosis.
Secondary outcome [1] 343018 0
Measure changes in both tumour cell and normal rectal epithelial mitochondrial activity using protein markers as surrogates of mitochondrial function and the Western Blot technique before and after radiotherapy. Pre-radiation tissue biopsies will be compared with tissue samples from the resection specimen.
Timepoint [1] 343018 0
At time of tissue diagnosis with rectal cancer and then at time of surgical resection.
Secondary outcome [2] 343019 0
Perform analysis of clinical, pathological and radiological factors that are associated with pCR, significant pathological response and no significant pathological response. This is a composite secondary outcome.

Specific factors that will be assessed are below. This information will be obtained from the clinical records.

Clinical
• Demographics
o Date of birth
o Gender
o Ethnicity
• Co-morbidity
o Diabetes
o Chronic respiratory disease
o Chronic cardiac disease
o ECOG status
Radiological (MRI and CT)
• TNM staging
o Pre-treatment
o Post-treatment (if performed)
• Threatened CRM Yes or No
• Distance from anus (MRI)
Pathological
• Complete pathological response (pCR) Yes or No
• Tumour characteristics
o T stage T1-T4
o Differentiation Poor or Not Poor
o LVI Yes or No
o Margin (mm) - radial and closests distal or proximal
o Histological sub-type e.g. mucinous
o Tumour budding Yes or No
o TME grade
• Nodal status
o Number of nodes involved/number of nodes excised
o Extra-nodal extension Yes or No
Treatment
• Radiotherapy
o Short course or long course
o Chemotherapy given with radiotherapy Yes or No
• Surgery performed Yes or No
o If yes which operation - transanal/TAMIS, anterior resection or abdomino-perineal resection
Timepoint [2] 343019 0
Time of surgical resection
Secondary outcome [3] 343020 0
Compare mitochondrial activity levels between early and late T stage tumours using the same measure of mitochondrial activity as described previously i.e. protein markers of mitochondrial function assessed using the Western Blot technique. This will be performed on the pre-radiation biopsy specimens i.e. at time of diagnosis.
Timepoint [3] 343020 0
Time of surgical resection
Secondary outcome [4] 343021 0
Compare participant’s global mitochondrial activity, as indicated by blood cells, with rectal tumour cell mitochondrial activity. The mitochondrial activity of blood cells will be assessed using the Seahorse XF24 Analyser which provides an advanced quantitative analysis of cellular respiration. This analysis can only be performed on blood and not tissue currently. Rectal tumour mitochondrial function will be assessed using protein markers and Western Blotting as previously described. A correlation between the two will be looked for..
Timepoint [4] 343021 0
At time of diagnosis with rectal cancer (pre-radiation)

Eligibility
Key inclusion criteria
Confirmed rectal cancer on histology and patient fit for active treatment
o All patients treated with neoadjuvant radiotherapy +/- chemotherapy
o Five patients not treated with neoadjuvant radiotherapy, opportunistically sampled
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Unable to obtain valid consent
Repeat sigmoidoscopy procedure poses more than minimal clinical risk e.g. frail patient, anticoagulants or other medications requiring cessation with significant attendant risk

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Univariate analysis will be performed using the t-test for normally distributed data to look for correlation between tumour regression grade and markers of mitochondrial activity levels. Multiple logistic regression analysis will be attempted if statistically feasible based on total numbers recruited, but it is likely this won’t be possible.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 9579 0
New Zealand
State/province [1] 9579 0
Canterbury

Funding & Sponsors
Funding source category [1] 298643 0
Charities/Societies/Foundations
Name [1] 298643 0
Colorectal Surgical Society of Australia and New Zealand
Address [1] 298643 0
Colorectal Surgical Society of Australia and New Zealand
Suite 6, 9 Church St, Hawthorn VIC 3122
Country [1] 298643 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Colorectal Surgical Society of Australia and New Zealand
Address
Colorectal Surgical Society of Australia and New Zealand
Suite 6, 9 Church St, Hawthorn VIC 3122
Country
Australia
Secondary sponsor category [1] 297816 0
None
Name [1] 297816 0
Address [1] 297816 0
Country [1] 297816 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299603 0
Southern Health and Disability Ethics Committee (HDEC)
Ethics committee address [1] 299603 0
Ministry of Health
Health and Disability Ethics Committees
PO Box 5013
Wellington 6140
Ethics committee country [1] 299603 0
New Zealand
Date submitted for ethics approval [1] 299603 0
26/01/2018
Approval date [1] 299603 0
21/02/2018
Ethics approval number [1] 299603 0
18/STH/40

Summary
Brief summary
Project Summary and Overview
Rationale and Background Information
Mitochondria are known to perform important cellular functions including energy production and regulation of cell death, and are also affected by ionising radiation. There is evidence to suggest that the level of mitochondrial activity has a role in the response to radiotherapy for malignancy. Rectal cancer has a highly variable response to neoadjuvant radiotherapy, and while there are some known factors associated with the degree of response, there no robust markers that can predict it. The development of such a marker could potentially allow more targeted use of neoadjuvant radiotherapy for rectal cancer, thereby avoiding associated morbidity in patients unlikely to benefit.
Objectives
This study aims to determine whether the level of mitochondrial function within the tumour cells is associated with tumour regression after radiotherapy for rectal cancer.
Methods
This is an observational pilot study. Patients with rectal cancer will undergo colonoscopy and have biopsies of both tumour tissue and normal appearing rectal mucosa. Surrogates of mitochondrial function will be measured using the Western Blot technique, with a panel of ten proteins representative of mitochondrial activity being assessed. Routine loco-regional staging with MRI of the pelvis will be performed before treatment. After radiotherapy and surgical resection, repeat testing of the tumour tissue and adjacent rectal mucosa will be performed to assess for changes in mitochondrial function after treatment with radiotherapy. A tumour regression grade (TRG) will be recorded for each patient based on the final pathology of the resection specimen. Correlation between markers of mitochondrial activity and tumour regression will be assessed.
Population and timeframe
All patients diagnosed with rectal cancer and treated with neoadjuvant radiotherapy at Christchurch Hospital for a 12 month period from February 1 2018. Five patients not treated with radiotherapy will also be included to act as a control group.
Expected outcomes
The markers of mitochondrial activity will be examined in an attempt to identify those which correlate with the TRG. The results may be used to guide further investigation of a specific biomarker(s).

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80994 0
Prof Frank Frizelle
Address 80994 0
Department of Surgery
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 80994 0
New Zealand
Phone 80994 0
+64 3 364 0014
Fax 80994 0
Email 80994 0
frank.frizelle@cdhb.health.nz
Contact person for public queries
Name 80995 0
Dr Jesse Fischer
Address 80995 0
Department of Surgery
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 80995 0
New Zealand
Phone 80995 0
+64 3 364 0014
Fax 80995 0
Email 80995 0
jesse.fischer@postgrad.otago.ac.nz
Contact person for scientific queries
Name 80996 0
Dr Jesse Fischer
Address 80996 0
Department of Surgery
University of Otago, Christchurch
PO Box 4345
Christchurch 8140
Country 80996 0
New Zealand
Phone 80996 0
+64 3 364 0014
Fax 80996 0
Email 80996 0
jesse.fischer@postgrad.otago.ac.nz

No information has been provided regarding IPD availability
Summary results
No Results