Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03637647 |
| Other study ID # |
17/SC/0331 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2012 |
| Est. completion date |
March 1, 2022 |
Study information
| Verified date |
March 2022 |
| Source |
University Hospital Southampton NHS Foundation Trust |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational [Patient Registry]
|
Clinical Trial Summary
Primary Aim: The present study is a retrospective analysis of prospectively collected
clinical data. Anonymized data from patients collected during routine clinical care from 9
units in the United Kingdom who undertake upper gastrointestinal (UGI) cancer surgery and
perform pre-operative cardiopulmonary exercise testing will be interrogated. Data will be
pooled at a central location (University Hospitals Southampton) and used to investigate the
relationship between selected cardiopulmonary exercise testing (CPET) variables, in-hospital
post-operative and survival outcomes after major UGI cancer surgery.
Rationale: Our primary aim is to establish a reliable relationship between post-operative
survival (1 and 3 -year) and oxygen uptake (VO2) at peak exercise (VO2 Peak); a secondary aim
is to explore the multivariable relationship between selected CPET variables especially VO2
at the estimated lactate threshold/anaerobic threshold (AT), together with other selected
CPET derived variables, and other important prognostic variables with post-operative
complications (morbidity and mortality) in an attempt to risk stratify patients before major
UGI surgery.
Trial Design: Multicentre observational
Inclusion Criteria: We aim to include all patients aged >18 years considered eligible by the
MDT for major curative UGI cancer surgery and undergoing an enhanced recovery programme after
surgery. Patients undergoing neoadjuvant chemotherapy or chemoradiotherapies will also be
included. Patients having a CPET and initially scheduled for curative surgery, but end up not
having surgery due to disease progression or other clinical reasons will be included and
analysed separately.
Exclusion Criteria: Patients will be excluded if they are physically unable to perform a CPET
on a cycle ergometer, patients having emergency surgery, patients lacking complete
in-hospital morbidity or mortality data and patients undergoing preoperative exercise
interventions.
Primary Trial Endpoints: 3 year overall survival
Description:
Study overview and background
We hypothesise that reduced physical fitness (measured objectively using Cardiopulmonary
Exercise Testing (CPET)) will result in worse post-operative surgical outcome (reduced
overall survival, and increased in-hospital morbidity measured by Clavien-Dindo-Demartines
Score). We propose multicentre patient recruitment and analyses of routinely collected
clinical data, in an attempt interrogate this hypothesis in patients prior to upper
gastrointestinal cancer surgery. Patients undergoing cancer therapies pre-operatively
(neoadjuvant chemotherapy or chemoradiotherapy) will be included in the analyses. Patients
that become ineligible for an operation, mainly due to metastasis or progression of their
cancer on neoadjuvant cancer treatments will also be included but will be analysed
separately.
Despite advances in anti-cancer therapies, surgery remains the most important treatment for
oesophageal and gastric cancer. Major UGI cancer surgery carries substantial morbidity and
mortality, particularly in elderly patients and those with co-morbidities. Recent UK cancer
audits show 30-day mortality of up to 3% for elective surgery and a 90-day mortality rate of
5.2%. Outcomes after major cancer surgery depend on modifiable factors such as peri-operative
medical care and intra-operative technique and what were previously thought to be
unmodifiable components, such as the ability of the patient to tolerate surgical trauma.
Centralisation of services and optimisation of perioperative pathways have led to improved
outcomes, but substantial gains may yet be achieved with accurate and objective preoperative
risk prediction.
Current approaches to risk prediction include a plethora of prediction scores and tests, but
none have proven efficacy above experienced clinical acumen. More recently reduced physical
fitness (objectively measured using CardioPulmonary Exercise Testing - CPET) has been
associated with increased postoperative morbidity in a variety of major surgical cohorts.
CPET provides an objective method of evaluating physical fitness under stress, partly
mimicking the stress of a major surgical event. Accurate risk prediction methods prior to
surgery or indeed other forms of 'trauma' like pre-operative cancer therapies might allow
better patient selection, permit modification of the patients preoperative status, as well as
improve the optimisation of intra- and postoperative management, and enhances shared
decision-making. Furthermore CPET allows interrogation of the causes of exercise intolerance,
when exercise capacity is reduced, with the exciting opportunity of intolerance modulation
for therapeutic gain (Fit for Surgery).
To date, 37 cohort studies (including over 7,800 patients) have reported the relationship
between preoperative CPET-derived variables and postoperative outcome. These data have been
brought together in several systematic reviews that, in summary, show a remarkably consistent
positive correlation between physical fitness and postoperative outcome. The Southampton
based Fit-4-Surgery group have clearly demonstrated this in patients undergoing major
colorectal surgery, however the relationship between fitness and post-operative outcomes in
UGI cancer surgery is not yet well defined.
METHODOLOGY
Patients in all the recruiting centres will undergo a maximal CPET prior to major UGI cancer
surgery (defined as a procedure involving oesophageal, junctional or gastric cancer
resection) according to the CPET protocol defined in Appendix 1 of protocol. If the CPET
deviates from this protocol, the centre would need to clear their local CPET protocol with
the Chief Investigator (CI). All variables measured by CPET that will be collected are
outlined in Appendix 2 of protocol. If the patient is scheduled to have neoadjuvant cancer
therapies, the recruiting site might elect to test patients pre- and post the neoadjuvant
therapy to estimate the change in fitness. This is based on changes observed in fitness with
neoadjuvant chemotherapy in UGI and chemoradiotherapy in rectal cancer patients.
Following surgery only routine clinically relevant observational data will be collected.
These data will relate to hospital length of stay, the level of care required following
surgery, post-operative morbidity (Postoperative Morbidity Survey - POMS and/or
Clavien-Dindo-Demartins Score) and the recovery process. Most of this information can be
accessed from prospectively maintained enhanced recovery databases, however electronic
patient records that are maintained and recorded prospectively are also acceptable
alternatives.
Each site would also contribute existing data held on the hospital patient database in
addition to recruiting patients as they present at the hospital as per methodology above. All
data from each individual hospital will be anonymized at source by the PI prior to transfer
to the CI and any analyses. CPET variables, post-operative outcome data, and basic patient
demographics (outlined in Appendix 2 of the protocol) cannot be linked back to the original
patient.
All patients undergoing CPET at each NHS site are given a patient information sheet related
to risks and benefits related to CPET and routinely undergo written consent prior to testing,
also asking for their permission for these data to be used for research purposes.
Contraindications to CPET based on ACCP/ATS Guidelines. (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
This study tests the hypothesis that selected CPET variables are related to overall survival
(1 and 3-year) and to in-hospital morbidity in patients undergoing major UGI cancer surgery.
Our primary aim is to establish a reliable relationship between 1-year overall survival
(present or absent) and oxygen uptake (Vo2) at peak exercise (Vo2 Peak); a secondary aim is
to explore the multivariable relationship between Vo2 at the estimated lactate threshold
(AT), other selected CPET variables (weight, BMI and Body Surface Area (BSA) adjusted) and
other important prognostic variables with post-operative complications in an attempt to risk
stratify patients before major surgery.
3. DATA ANALYSES
Cardiopulmonary Exercise Tests (CPET)
The CPET 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. Accredited doctors
or allied health professionals with experience in analysis of exercise tests will analyse all
of the exercise data. Patients will be anonymised and the person performing the data analysis
will be blinded to the outcome data. All data will be stored, processed and analysed on
secure NHS computers on NHS encrypted and password-protected servers.
4. STATISTICAL METHODOLOGY
Non-parametric receiver operator characteristic (ROC) curves will be constructed for Vo2 at
AT, Vo2 at Peak, O2 Pulse at AT and ventilatory equivalents for carbon dioxide (VE/Vco2 at
AT) in order to assess their independent ability to discriminate between patients with and
without post-operative morbidity. All selected CPET variables will be adjusted for weight,
BMI and BSA. Optimal cut-points will be obtained by minimising the distance between points on
the ROC curve and the upper left corner. Variables (to satisfy the 10 events per variable
rule) will be identified as candidates for a multivariable logistic regression model
including but not limited to: Vo2 at AT and at Peak, gender, operation type
(laparoscopic/open), and O2 Pulse at AT and VE/VCo2 at AT. A final multivariable model will
be obtained using forward stepwise selection (minimising Akaike Information Criteria (AIC)).
Its sensitivity to variable exclusion and re-inclusion will also be assessed using AIC. Model
fit will be assessed using the Hosmer-Lemeshow goodness-of-fit test. In order to explore the
univariate relationship between CPET variables and length of stay, continuous CPET variables
will be dichotomised at the optimal cut-point for the ROC curve and Kaplan-Meier curves will
be constructed. The log rank test will be used to compare survival curves; patients who died
before discharge will be treated as right-censored. All analyses will be conducted using
Stata (StataCorp. 2011 Stata Statistical Software: Release 12. College Station, TX: StataCorp
LP.). Continuous variables will be reported as mean and standard deviation (SD) or median and
inter-quartile range (IQR) depending on the distribution. Categorical variables will be
presented as frequency (percentage). P-values will be obtained using univariate logistic
regression (continuous) and Chi-squared or Fisher's Exact tests (categorical). Statistical
significance will be taken at 5%.
We anticipate an overall death rate of 33.5% in 12 months post-surgery. We assumed that the
death event rate would increase in the unfit (control) patient group up to 50% while the fit
group would show the same average of 33.5% rate thus showing a difference of at least 16.5%.
We consider that this size of the effect (50% reduced to 33.5%) is clinically relevant.
Assuming 5% (2-sided) significance and 90% power, 150 events are needed to detect this size
of difference in a log-rank survival comparison of the two trial groups. This requires 376
patients in total in the analysis. We will inflate this total by approximately 20% to allow
for attrition, giving a target recruitment of 470 patients (with complete data on CPET
variables and outcome).
