Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03641118 |
| Other study ID # |
16/SS/0188 |
| Secondary ID |
215694 |
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 1, 2017 |
| Est. completion date |
March 2024 |
Study information
| Verified date |
October 2022 |
| Source |
University Hospital Southampton NHS Foundation Trust |
| Contact |
Malcolm West, PhD |
| Email |
m.west[@]soton.ac.uk |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Primary Aim:
To establish a reliable relationship between oxygen uptake (VO2) at estimated lactate
threshold (AT) and CT-derived body composition measurments (e.g. muscle radiation
attenuation), and to relate these to post-operative outcomes (i.e. post-operative
complications or 1-year survival) in cohort of upper (UGI) and lower (LGI) gastrointestinal
and hepatobiliary (HPB) cancer patients undergoing surgery +/- cancer therapies.
Rationale:Objectively measured reduction of muscle radiation attenuation (i.e. Computed
Tomography (CT) measured indices of muscle wasting) coupled with reduced physical fitness
(measured objectively using Cardiopulmonary Exercise Testing (CPET)) will result in worse
post-operative surgical outcome and reduced survival.
Trial Design: Observational Sample size: See statistical analyses section for individual
cohort power calculations Inclusion Criteria: Male or female patients, aged over 18 years old
with UGI, LGI or HPB cancer undergoing surgery +/- cancer therapies; WHO performance status
0-2.
Exclusion Criteria: Patients will be excluded if they have surgery for benign disease, a
diagnosis of inflammatory bowel disease, patients physically unable to perform a CPET on a
cycle ergometer, patients having no surgery performed or interim emergency surgery, patients
lacking complete in-hospital morbidity and survival data.
Primary Trial Endpoints: UGI patients - 2 year overall survival, LGI and HPB patients -
post-operative complications (Calvien-Dindo and Composite Endpoint in
pancreaticoduodenectomy)
Description:
Study overview and background
We hypothesise that an objectively measured reduction in muscle radiation attenuation (i.e.
Computed Tomography (CT) measured indices of muscle wasting and/or sarcopenia) coupled with
reduced physical fitness (measured objectively using Cardiopulmonary Exercise Testing (CPET))
will result in worse post-operative surgical outcome and reduced survival in patients going
straight to surgery or having cancer therapies.
An analyses of prospectively collected clinical data from routine clinical practice in a
cohort of upper and lower gastrointestinal and hepatobiliary (liver, pancreas and biliary
tree) cancer patients will be undertaken. These patients may undergo neoadjuvant (before
surgery) cancer therapies before undergoing surgery.
We aim to interrogate prospectively collected objectively measures of radiological markers of
muscle wasting and body composition, as well as objectively measured markers of physical
fitness in 3 cohorts: upper and lower gastrointestinal and hepatobiliary (liver, pancreas and
biliary tree) cancer patients and to explore if body composition is related with physical
fitness. In addition, body composition and physical fitness will be related to post-operative
outcomes and survival. These data will be readily available as they are collected as part of
routine clinical care at University Hospital Southampton NHS Foundation Trust. Our hospital
performs a large number of major cancer operations in these 3 cancer patient groups. These
patients already undergo accurate radiological cancer staging and sometimes re-staging (after
cancer therapies) and also a CPET as part of their pre-operative pathway. As part of their
enhanced recovery pathway, which is now well embedded into routine clinical care,
post-operative surgical outcomes, cancer outcomes and survival are routinely collected.
METHODOLOGY
Patients will be identified from prospectively maintained enhanced recovery databases. All
patients will be having surgery at University Hospital Southampton where all upper and lower
gastrointestinal and hepatobiliary (liver, pancreas and biliary tree) cancer teams maintain
well validated enhanced recovery databases with patient and cancer specific demographics,
operative records, histopathological, cancer specific and post-operative outcomes. These
databases are maintained to a high level due to their usage in national cancer audits. All
patients will undergo a staging CT (as part of routine care), this will be used to measure
radiological markers of sarcopenia and body composition in the research setting. No
additional radiological scanning sequences, contrast or scanner time is required here. In
addition all patients will also undergo a CPET (also as part of routine care), this will be
used to objectively measure markers of pre-operative physical fitness. The CPET protocol is
defined in Appendix 1 of the trial protocol. All variables measured by CT and CPET that will
be collected are outlined in Appendix 2 of the trial protocol.
Following staging investigations patients may undergo neoadjuvant cancer treatments.
Re-staging radiological investigations will be performed as part of standard care in all 3
cohorts. All patients will undergo major cancer specific surgical procedures. Following
surgery routinely collected clinically relevant observational data will be used to define
post-operative outcomes. These data will relate to hospital length of stay, the level
intensive or high dependency care required following surgery, post-operative morbidity
(Postoperative Morbidity Survey - POMS and Clavine-Dindo Score) and survival. Most of this
information can be accessed from prospectively maintained enhanced recovery databases;
however patient notes and electronic patient records are acceptable alternatives. All of
these data are already collected as part of routine care and not additional resources for
data collection will be required. Appendix 2 shows the minimum dataset that will be
collected. Survival at 2 years will be collected for all patients.
All patients will be given a patient information sheet and formally consented to ask for
their permission for these data to be used for research purposes.
Contraindications to CPET based on ACCP/ATS Guidelines are summarised in the American Journal
of Respiratory and Critical Care Medicine 2003; 167: 211-77.
Please see also for further information:
http://www.thoracic.org/statements/resources/pfet/cardioexercise.pdf
http://www.pcpet.co.uk/Links
HYPOTHESIS
We hypothesise that an objectively measured reduction of muscle radiation attenuation (i.e.
Computed Tomography (CT) measured indices of myosteatosis) is related to reduced physical
fitness (measured objectively using Cardiopulmonary Exercise Testing (CPET)) and both will
result in worse operative or cancer progression related outcome and reduced survival.
Specifically we aim to interrogate the relationship between oxygen uptake (Vo2) at estimated
lactate threshold (LT) and muscle radiation attenuation and post-operative outcomes (i.e.
post-operative complications - LGI and HPB cohorts and 2-year survival - UGI cohort) in
patients undergoing surgery +/- neoadjuvant cancer therapies.
DATA ANALYSES - CT-scan analysis and data transfer
Abdominal CT-scans will be analysed in anonymized format by one blinded independent
researcher trained in radiologic anatomy and body composition analysis. These analyses will
be done at the University of Maastricht by Prof Steven Olde Damnik. A single fully anonymised
CT image (as described hereunder) will be sent to Prof Olde Damnik using encrypted software
using encrypted and password protected hardware (NHS purchased Safe Stick). No other data
will be sent to Maastricht. This image will be processed and data relating to variables below
will be sent back to the PI. All other data analyses will be done by the PI at University
Hospitals Southampton. All data will be stored, processed and analysed on secure NHS
computers on NHS encrypted and password-protected servers used by the Critical Care Research
Team.
A single slice of each patient's CT-scan will be selected at the level of the third lumbar
vertebra (L3). CT-scans with large radiation artefacts or with missing parts of muscle tissue
on the ventral, dorsal, or both lateral edges of the scan will be excluded. Muscles included
into the analysis are the internal and external obliques, transversus abdominus, rectus
abdominus, psoas, quadratus lumborum, and erector spinae muscles. CT-scans will be analysed
using sliceOmatic 5.0 (TomoVision, Magog, Canada) software for Microsoft Windows®. Using
predefined Hounsfield unit (HU) ranges, the total cross-sectional area (cm2) of skeletal
muscle tissue ( 29 to 150 HU), visceral adipose tissue (VAT; -150 to 50 HU), subcutaneous
adipose tissue (SAT; 190 to 30 HU), and intermuscular adipose tissue (IMAT; 190 to 30 HU)
will be determined. In addition, the radiation attenuation for skeletal muscle will be
assessed by calculating the average HU value of the total muscle area within the specified
range of -29 to 150 HU (i.e. this is calculated from the muscle tissue only excluding the
IMAT). The total areas of skeletal muscle, VAT and SAT will be corrected for stature to
calculate the L3-muscle index, L3-VAT index, and L3-SAT index in cm2/m2, providing good
estimates of total body skeletal muscle, VAT, and SAT mass.
Cardiopulmonary Exercise Tests (CPET)
The CPET test involves cycling on an exercise bike for 8-12 minutes. Starting with a very low
resistance on the pedals the patient will pedal at 60 revolutions per minute. After 3 minutes
of cycling, the resistance will gradually increase until the patient can no longer turn the
pedals at the required speed. The test will be thoroughly explained to the patient beforehand
and trained staff will make the experience as comfortable as possible. CPETs will be stopped
early by the study researcher/doctor in the presence of any adverse events. Each CPET
appointment will last approximately one hour.
CPETs carry a small risk (1:10,000) of exercise induced myocardial infarction or dysrhythmia.
Patients are continuously monitored using a 12 lead electrocardiograph (ECG) during all tests
and recovery. The CPET test will entail the patient becoming slightly hot or maybe sweaty,
and appropriate clothing should be worn. The patient's heart will be monitored by an
electrocardiogram. The patient will wear a soft rubber mask in order to continuously sample
expired air with an online breath by breath gas analyzer. This may cause some mild
claustrophobia. Full detail of the CPET procedure is given in appendix 1. Physiologists with
experience in analysis of exercise tests will analyse all of the exercise data. Patients will
be anonymised and the physiologist performing the data analysis will be blinded to the
sarcopenia measurements and the outcome data. All data will be stored, processed and analysed
on secure NHS computers on NHS encrypted and password-protected servers used by the Critical
Care Research Team.
STATISTICAL METHODOLOGY
For all CT body composition measurements, sex-specific cut-offs will be determined at the
median. The main parameter will be muscle radiation attenuation, as this parameter was found
to have the most effect on post-operative complications in our previous study. Data will be
analysed using IBM SPSS 23 for Microsoft Windows®. Differences in patient characteristics
will be analysed using the independent T-test or Pearson chi-square test. The Pearson
chi-square test will be used to assess the difference in post-operative complications or
survival; for patients with low vs. high muscle radiation attenuation and other body
composition measurements. For correlations, Pearson's correlation coefficient (rp) will be
used. A p-value of <0.05 was considered significant.
Power analysis
HPB cohort
The sample sizes calculation for this study were determined using our previous results in a
Dutch pancreatic cancer patient cohort. In this study, the occurrence of the CEP was compared
between patients with HPB cancer and a low muscle radiation versus high muscle radiation
attenuation. We found a significantly higher CEP occurrence in the low muscle radiation group
(p=0.027). Using this population (n=184) we calculated an effect size (w) of 0.331. Using
this effect size we conducted a power analysis for the HPB cohort with a power of 0.80 and an
α of 0.05 considered as significant which resulted in a total sample size of 72 patients.
Upper gastrointestinal cancer cohort
The sample size calculation for this study was based on a study by Yip et al. We are planning
a study with one control per experimental subject, an accrual interval of 9 months, and
additional overall survival follow-up after the accrual interval of 24 months. Prior data
indicate that the median survival time on the control treatment is 25.6 months. If the true
median survival times on the control and experimental treatments are 25.6 and 55 months,
respectively, we will need to study 138 patients to be able to reject the null hypothesis
that the experimental and control survival curves are equal with probability (power) 0.800.
The Type I error probability associated with this test of this null hypothesis is 0.05.
Lower gastrointestinal cancer cohort
The sample size calculation for this study was based on a study by Lieffers et al. Prior data
indicate a 24% post-operative complication rate in the sarcopenia group as opposed to a 13%
complication rate in the non-sarcopenia group (OR 0.460). We will need to study 404 patients
with probability (power) 0.800. The Type I error probability associated with this test of
this null hypothesis is 0.05.
