Download TRISST protocol - MRC Clinical Trials Unit

MRC TE24 (TRISST)
TRISST
TRIAL OF IMAGING AND SCHEDULE IN SEMINOMA
TESTIS
Developed with
the NCRI Testis
Clinical Studies
Group
MRC TE24
ISRCTN65987321
MREC: 07/H1306/127
NCT00589537
Part of the
National Cancer
Research
Network Portfolio
Protocol version 4.0
19 May 2015
Funded by Cancer
Research UK
Authorised by:
Name
Prof Johnathan Joffe
Signature
Role
Chief Investigator
Date
Name
Dr Fay Cafferty
Signature
Role
Project Lead
Date
TRISST protocol v4.0 19-May-2015.docx
19 May 2015
19 May 2015
1
MRC TE24 (TRISST)
GENERAL INFORMATION
Acronym:
TRISST
Title: Trial of imaging and schedule in seminoma testis
This document describes a Medical Research Council Clinical Trials Unit at UCL (referred to
throughout this protocol as MRC CTU) / NCRI Testis Clinical Studies Group trial and provides
information about the trial procedures. The protocol should not be used as an aide-memoire
or guide for the treatment of other patients. Amendments may be necessary; these will be
circulated to known investigators in the trial.
Any general queries relating to the trial and this protocol should be directed to the Trial
Management Team at MRC CTU (see section Trial Administration below for contact details).
Clinical problems relating to this study should be referred to Professor Johnathan Joffe.
This trial will adhere to the principles outlined in the International Conference on
Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. It will be conducted in
compliance with the protocol, Data Protection Act (DPA no. Z6364106) and any other
appropriate regulatory requirements.
Please note: this version of the protocol was released at a time when randomisation to
TRISST had ended. There remain various sections relating to randomisation and related
procedures; to avoid having to make many small protocol changes (e.g. in tense), the text in
these sections may have remained unchanged since previous protocol versions.
2
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
TRIAL ADMINISTRATION
Chief
Investigator
Dr Johnathan Joffe
Greenlea Oncology Unit
Huddersfield Royal Infirmary
Lindley
Huddersfield
West Yorkshire, HD3 3EA
T: 01484 342150
F: 01484 342187
E: [email protected]
Co-Investigator
Dr Robert Huddart
Oncology & Radiotherapy
Royal Marsden Hospital
Downs Road
Sutton
Surrey, SM2 5PT
T: 020 8661 3529
F: 020 8643 8809
E: [email protected]
Co-Investigator
Dr Michael Williams
Imaging Directorate
Derriford Hospital
X-ray East, Level 6
Plymouth
Devon, PL6 8DH
T: 01752 763163
E: [email protected]
Medical Physics
Expert
Dr Nick Rowles
Derriford Hospital, Plymouth
T: 01752 439669
E: [email protected]
Project Lead and
senior trial
statistician
Dr Fay Cafferty
MRC CTU
T: 0207 670 4707
E: [email protected]
Clinical Project
Manager
Anna Bara
MRC CTU
T: 0207 670 4643
E: [email protected]
Trial Manager
William Cragg
MRC CTU
T: 0207 670 4845
E: [email protected]
Statistician
Liz Wedd
MRC CTU
T: 0207 670 4682
E: [email protected]
Data Manager
Brendan Murphy
MRC CTU
T: 0207 670 4784
E: [email protected]
Trial
Coordination:
MRC CTU
Institute of Clinical Trials and
Methodology,
Aviation House
125 Kingsway
London, WC2B 6NH
Email: [email protected]
Fax: 0207 670 4818
Website: www.ctu.mrc.ac.uk
TRISST protocol v4.0 19-May-2015.docx
3
MRC TE24 (TRISST)
CONTENTS
1.
Summary ................................................................................. 8
2.
Background ........................................................................... 10
3.
Selection of Centres/Clinicians ............................................. 14
4.
Selection of Patients .............................................................. 15
5.
Randomisation & Enrolment procedure ................................ 16
6.
Patient Management ............................................................. 17
7.
Cessation of Follow-up .......................................................... 27
8.
Statistical Considerations ...................................................... 29
9.
Trial Monitoring ..................................................................... 33
10.
Ethical Considerations and Approval ..................................... 34
11.
Regulatory Issues .................................................................. 35
12.
Insurance .............................................................................. 35
13.
Ancillary Studies .................................................................... 35
1.1
1.2
1.3
2.1
2.2
2.3
2.4
4.1
4.2
4.3
6.1
6.2
6.3
6.4
6.5
6.6
7.1
7.2
7.3
8.1
8.2
8.3
8.4
8.5
9.1
9.2
9.3
10.1
10.2
4
Abstract and summary of the trial design ........................................................ 8
Flow diagram ................................................................................................ 9
Translational Study ........................................................................................ 9
General overview ........................................................................................ 10
Surveillance in stage I seminoma .................................................................. 10
Rationale for TRISST ................................................................................... 11
Management of surveillance relapses ............................................................ 12
Patient inclusion criteria ............................................................................... 15
Patient exclusion criteria .............................................................................. 15
Screening procedures and pre-randomisation investigations ............................ 15
Surveillance schedule................................................................................... 17
Procedures for assessing safety .................................................................... 18
Cross-sectional imaging schedules ................................................................ 19
Recommended management of relapsed patients .......................................... 24
Stopping trial intervention ............................................................................ 26
Follow-up of patients who have relapsed ....................................................... 26
Loss to follow-up ......................................................................................... 27
Trial closure ................................................................................................ 27
Complete withdrawal from the trial ............................................................... 27
Method of randomisation ............................................................................. 29
Outcome measures...................................................................................... 29
Sample size ................................................................................................ 30
Interim monitoring and analyses................................................................... 31
Analysis plan (brief) ..................................................................................... 31
Risk assessment .......................................................................................... 33
Monitoring at MRC CTU ................................................................................ 33
Clinical site monitoring ................................................................................. 33
Ethical considerations .................................................................................. 34
Ethical approval .......................................................................................... 34
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
13.1
13.2
13.3
Health economics study ................................................................................35
Economic analysis ........................................................................................35
Translational research ..................................................................................36
14.
Finance .................................................................................. 37
15.
Trial Committees ................................................................... 37
16.
Publication ............................................................................ 40
17.
Protocol Amendments ........................................................... 41
18.
References ............................................................................ 47
15.1
15.2
15.3
17.1
17.2
17.3
Trial Management Group (TMG) ....................................................................37
Trial Steering Committee (TSC) .....................................................................37
Independent Data Monitoring Committee (IDMC) ...........................................37
Version 4.0 (May 2015) ................................................................................41
Version 3.0 (March 2010) .............................................................................43
Version 2.0 (December 2008) .......................................................................44
Appendices ...................................................................................... 49
APPENDICES
APPENDIX 1: HEALTH ECONOMICS: EQ-5D .................................................................. 50
APPENDIX 2: CRITERIA FOR CLASSIFICATION OF STAGE I DISEASE [24, 25] ................. 51
APPENDIX 3: ROYAL MARSDEN HOSPITAL STAGING SYSTEM - TESTICULAR TUMOURS .. 53
TRISST protocol v4.0 19-May-2015.docx
5
MRC TE24 (TRISST)
ABBREVIATIONS AND GLOSSARY
-HCG
5-HT3
Abdo
AE
AFP
AR
AUC
BEP
CF
CI
CRF
CT
CTA
CTAAC
CXR
DCF
DFS
DPA
DMC
EDTA
EP
EQ-5D
ERC
EU
EUDRACT
FBC
GCP
GCT
GP
HE
HRQOL
IB
IDMC
IGCCCG
ISRCTN
IVU
LDH
MHRA
MLC
MRC
MRC CTU
MRI
NHS
NSGCT
ONS
PA
PI
PIS
PTV
QL
REC
RMH
RFS
SAE
SD
SOP
6
Beta human chorionic gonadatrophin
5-hydroxytryptamine3
Abdominal
Adverse event
Alpha-fetoprotein
Adverse reaction
Area under the curve
Bleomycin, etoposide, platinum
Consent form
Chief Investigator
Case report form
Computed tomography
Clinical Trials Authorisation
Clinical Trials Award & Advisory Committee
Chest X-ray
Data clarification form
Disease free survival
Data Protection Act
Data Monitoring Committee
Ethylenediaminetetraacetic acid
Etoposide and platinum [cisplatin]
A standardised instrument to measure health outcome (www.eurqol.org)
Endpoint Review Committee
European Union
European Union Drug Regulatory Agency Clinical Trial
Full blood count
Good clinical practice
Germ cell tumour
General Practitioner
Health economics
Health related quality of life
Investigator’s brochure
Independent Data Monitoring Committee
International Germ Cell Cancer Collaborative Group
International standard randomised controlled trial number
Intravenous urogram
Lactate dehydrogenase
Medicines and Healthcare Regulatory Authority
Mixed lymphocyte culture
Medical Research Council
MRC Clinical Trials Unit
Magnetic resonance imaging
National Health Service
Non seminoma germ cell tumour
Office of National Statistics
Para-aortic
Principal Investigator
Patient information sheet
Planning target volume
Quality of life
Research Ethics Committee
Royal Marsden Hospital
Relapse Free Survival
Serious adverse event
Standard Deviation
Standard operating procedures
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
SPC
SSA
TGCT
TMG
TRISST
TSC
U&E
Summary of product characteristics
Site specific assessment
Testicular germ cell tumours
Trial Management Group
Trial of imaging and schedule in seminoma testis
Trial Steering Committee
Urea and electrolytes
TRISST protocol v4.0 19-May-2015.docx
7
MRC TE24 (TRISST)
1. SUMMARY
1.1 Abstract and summary of the trial design
The purpose of TRISST is to assess whether a reduced computed tomography (CT)
schedule or Magnetic Resonance Imaging (MRI) could be used as a safe and effective
alternative to standard CT-based surveillance in the management of stage I seminoma
testis patients in a randomised phase III trial. A reduced CT schedule or MRI-based
surveillance would reduce exposure to radiation in this group of patients. Patients with any
non-seminomatous elements within their testicular tumour are excluded from participating
in this trial.
TRISST is an open, randomised, non-inferiority trial with 4 surveillance arms in a factorial
design. Patients are randomised to one of the following 4 imaging surveillance groups: 7
CTs, 3 CTs, 7 MRIs, or 3 MRIs of the retroperitoneum. The 7 scan schedules (7 CTs, 7
MRIs) involve imaging at 6, 12, 18, 24, 36, 48, 60 months, and the 3 scan schedules (3
CTs, 3 MRIs) involve imaging at 6, 18, 36 months after randomisation.
Planned visits for all patients include clinical assessment, chest X-ray (CXR) and tumour
markers. These visits are 3-monthly in the first 2 years, 4-monthly in the third year and 6monthly to the end of year 6.
Patients undergo cross-sectional imaging of the
retroperitoneum with either MRI or CT, depending on their randomisation. Patients in
whom relapse is identified by MRI will have a CT within 2 weeks, to confirm relapse and
allow comparative tumour measurements between MRI and CT. All patients with evidence
of relapse by clinical symptoms, examination, CXR or serum markers will have imaging of
the retroperitoneum and chest by CT within two weeks. Patients randomised to MRI will
also have an additional MRI of the retroperitoneum when relapse is identified by other
means.
The trial aimed to recruit 660 patients and closed to accrual on 31st July 2014 with 669
patients randomised. The primary outcome measure is the proportion relapsing with Royal
Marsden Hospital (RMH) stage IIC or greater disease. Secondary outcome measures
include difference in mean size of the abdominal relapse between CT and MRI, time to
relapse, mode of identification of relapse, disease-free survival, overall survival and
evaluation of prognostic factors for relapse. A treatment recommendation is made for
patients who relapse with low volume disease (RMH IIA and IIB, Appendix 3). A health
economics study is being carried out and we have asked permission from patients for
collection of formalin fixed paraffin embedded tumour samples.
8
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
1.2 Flow diagram
During the analysis, the main comparisons will be:
1. (CT any) vs (MRI any)
2. (7 MRI or 7 CT) vs (3 MRI or 3 CT)
All patients in the study will be managed by surveillance for a minimum of 6 years
according to the schedule below:
At each visit chest x–ray, tumour markers (AFP, ß-HCG and LDH) and clinical
assessment will be performed as below (detailed schedule in section 6.1.):
Year
1
2
3
4
5
6
Frequency
3 monthly
3 monthly
4 monthly
6 monthly
6 monthly
6 monthly
1.3 Translational Study
Patients were asked to consent to tissue samples from their orchidectomy specimens to be
used in the future for genomic analysis. This will facilitate future translational studies.
TRISST protocol v4.0 19-May-2015.docx
9
MRC TE24 (TRISST)
2. BACKGROUND
2.1 General overview
Although the overall incidence of testicular germ cell tumours (TGCT) is low (2% of all male
cancers), they are the most common male cancer in the UK in the age group 15-35, with
approximately 1380 new cases in 1995 [1]. The incidence is increasing by 10 - 20% every
5 years in most European countries and, hence, there were 1990 cases in 1999 in the UK
[2]. TGCT can be divided into 2 broad groups according to histology: seminoma and nonseminoma (NSGCT). Non-seminomas comprise 50-60% of the total and seminomas the
remainder.
Following radical orchidectomy, routine evaluation of patients presenting with TGCTs
includes physical examination, CXR, blood tumour markers (AFP, β-HCG, LDH) and CT
scanning of the chest, abdomen and pelvis. Additionally, in patients with advanced
disease, lactate dehydrogenase (LDH) is of prognostic significance. In up to 70% of
patients with NSGCT and 85% of patients with seminoma, no evidence of disseminated
disease is found and patients are classified as stage I. Tumour markers can indicate
residual or active disease and become elevated in 70 – 80% of NSGCT patients but
significantly less than 50% of patients with seminoma (10% in stage I pre-orchidectomy
and 30-40% in advanced disease).
In NSGCT there is good evidence that patients can be divided into a majority of about 5060% in whom the risk of relapse is low (15%-20%), and a smaller group in whom the risk
of relapse is around 35-50% for whom it is accepted that adjuvant combination
chemotherapy is an appropriate standard of care. For the larger group, the standard of
care in the UK and many other parts of the world is to adopt a follow-up program called
surveillance. Patients on surveillance who relapse, usually do so in the first year and most
commonly in the para-aortic region or lungs. Most of these relapses can be successfully
treated by chemotherapy so the overall cure rate is in the order of 99%. These studies
have led to the widespread adoption of surveillance for NSGCT, especially in the UK.
The process of surveillance involves regular review, tumour marker estimation and imaging
including CT scanning. There is no agreed standard imaging schedule for surveillance of
stage I TGCTs, and schedules vary considerably between centres both within the UK and
internationally [3]. Recently a 2 CT schedule at 3 and 12 months in the first year has been
shown to be safe in a prospective randomised comparison with a 5 CT schedule over two
years in stage I non-seminoma patients [4].
2.2 Surveillance in stage I seminoma
The role of surveillance in seminoma has been more controversial. A number of single
centre surveillance studies have shown that 15-20% of patients will relapse, with a longer
median time to relapse of approximately 18 months. The majority of relapses are in the
retroperitoneum with very few chest-only relapses. The lower expression of serum tumour
markers, when compared to non-seminoma, raises concerns about reducing the intensity
10
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
and duration of radiological surveillance of the retroperitoneum. The relatively late nature
of relapse, the lack of tumour markers and the efficacy at preventing relapse of adjuvant
radiotherapy, have made uptake of this strategy less widespread in the UK. The advent of
carboplatin as an adjuvant therapy has also encouraged many practitioners to offer this
treatment to all stage I patients, however, because most of these patients are cured by
surgery alone, between 68% and 88% of patients are put at risk by this treatment without
any benefit. Additionally, nearly all relapses in stage I seminoma fall into a good prognostic
group and can be salvaged by local or systemic therapy, resulting in eventual cure rates
that are no worse than in NSGCT. An early analysis of treatment using carboplatin AUC7
and Para-aortic radiotherapy to 30Gy has revealed no relapses in 23 patients treated by
this approach over the last 5 years at the Royal Marsden Hospital (R A Huddart, personnel
communication).
The accumulating data on late effects of adjuvant radiation therapy, and the unknown long
term risks of carboplatin, along with the publication of a potentially predictive prognostic
classification [5] for relapse has led to a resurgence of interest in this approach in the UK
and abroad. In particular, two studies have investigated a risk-adapted approach to the
management of stage I seminoma. In the first [6], using different risk criteria, low risk
patients underwent surveillance while high risk patients received 2 cycles of adjuvant
carboplatin. 143 patients underwent surveillance and with a median follow-up time of 52
months, 23 (16.1%) had relapsed while 3.3% relapsed after carboplatin. 100% causespecific survival was achieved. In the second [7], the Warde criteria were applied and
patients with no risk factors (n=100) were followed by surveillance. With a median followup of 34 months, 6 patients (6%) had relapsed and no disease-related deaths were
reported. These data led to a European Consensus meeting (Amsterdam 2006) to
recommend surveillance for all low/intermediate risk patients and as an option for patients
classified as high risk according to the Warde criteria.
2.3 Rationale for TRISST
A typical programme for seminoma in Canada consists of over 20 CT scans over 8 years (P
Warde, personal communication) whilst the Royal Marsden Hospital involves 7 CT scans
over 5 years; Aparicio et al used a similar scheme of 8 scans over 6 years in the first study
and 9 over 6 years in the second. This scanning is not necessarily a benign procedure.
Standard radiological data suggests that the risk of second malignancy from a single chest,
abdominal and pelvic scan is in the order of 1 in 2000. This would suggest that a standard
7 CT surveillance protocol carries a risk of 1 in 300 of second malignancy related to imaging
alone [8].
In Denmark where a significant number of stage I seminoma patients are managed by
surveillance, a slightly less intense 5 CT program is undertaken (Dr Gedske Daugaard,
personal communication) over 5 years, but this still carries a significant risk of developing a
new primary cancer within the radiation field (1 in 400).
In these young patients, who are unlikely to die from seminoma, avoiding radiation
exposure is an important goal. Some progress has been achieved. Most studies suggest
routine screening of the pelvis in the absence of disease elsewhere is unnecessary [9].
TRISST protocol v4.0 19-May-2015.docx
11
MRC TE24 (TRISST)
Chest X-rays have proven utility in the surveillance of germ cell tumours and reliably detect
most pulmonary relapses and many mediastinal relapses (which are almost always
associated with retroperitoneal disease in untreated patients). Data from the TE08 study
[4] in stage I non-seminomatous germ cell tumours suggests that CXR is the only modality
of imaging required for the thorax in follow-up of early stage GCTs.
These data support the hypothesis that the only cross-sectional imaging required in
seminoma, as in NSGCT, may be of the retroperitoneum. As MRI is of relatively less utility
in assessment of the thorax, this raises the possibility of replacing the current CT based
protocols with MRI, which produces no x-ray radiation at all. Data from the Royal Marsden
has shown that MRI can demonstrate more retroperitoneal lymph nodes than CT [10]. We
have conducted pilot studies to confirm whether MRI scanning can identify abdominal
disease with a similar sensitivity to CT scanning. In these pilot studies at the Royal Marsden
Hospital and Leeds a total of over 100 patients were staged by both CT and MRI of the
retroperitoneum without any loss of sensitivity in the detection of retroperitoneal disease by
MRI [11] (Dr Sarah Swift, Dr A Sohaib, personal communication).
It has been suggested that a transfer to MRI is inevitable, however, there are no
comparative randomised studies on which to base such a change in management, and
access to MRI is less easily available than CT, with significant pressure on most MRI
facilities. It is therefore very unlikely, currently or in the foreseeable future, that any centre
would be prepared to switch from a 3 or 7 CT schedule to a 3 or 7 MRI schedule without
strong supporting clinical evidence within the business case. This is irrespective of whatever
developments occur in MRI or CT technology over the next few years.
Since the issue regarding radiation exposure in surveillance can be addressed both by a
switch from CT to MRI, or a potential reduction in the intensity of CT imaging, and both
issues are relevant in terms of service planning and risk, it is proposed to address both
issues in a single protocol. A 7 CT schedule will be used as the standard intensity arm, in
keeping with current UK seminoma surveillance practice.
2.4 Management of surveillance relapses
The management of patients at relapse with extensive disease (stage IIC - stage IV) is with
systemic chemotherapy (usually BEP), but different approaches to the management of
patients with stage IIA and IIB are currently employed. Traditional management has been
with radiotherapy to a “dog-leg” field which results in a relapse-free survival of between
85-90%, with 90% of patients who relapse being successfully salvaged with combination
chemotherapy. Other centres use systemic chemotherapy as for less bulky disease. A
Spanish study of this approach achieved a RFS of 91% (CI 80-99%) in patients with stage
IIA/B seminoma and this treatment had significant toxicity associated with it [12]. An
alternative strategy, which has been piloted at the Royal Marsden Hospital, is to combine
radiotherapy with a single dose of carboplatin chemotherapy. Studies of carboplatin in
stage I disease have suggested it can reduce the risk of recurrence due to microscopic
disease. This was explored in a report from the Royal Marsden [13]. In this study, patients
received carboplatin at a dose of 400mg/m2 followed by dog-leg radiotherapy to a dose of
12
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
35Gy in 17-18f commencing 4 weeks later. 33 patients were treated in this fashion (30 by 1
cycle carboplatin) between 1989 and 1996. A 5 year disease-free survival (DFS) of 96.9%
compared to a DFS of 80.7% in historically and concurrently treated patients (1979-1998).
This work has been developed to reduce both the dose and extent of radiotherapy. An
analysis of this approach is underway.
TRISST provides an opportunity to document, in a multicentre setting, the outcome of
patients who relapse with localised disease (defined in Section 6.3) and are offered salvage
therapy with this regimen of combined modality therapy for possible comparison with
historical data for dog-leg radiotherapy alone.
TRISST protocol v4.0 19-May-2015.docx
13
MRC TE24 (TRISST)
3. SELECTION OF CENTRES/CLINICIANS
TRISST is a UK-only trial. At the time of the release of this protocol version, recruitment
had been completed. Patients were randomised to the trial at 35 centres, based in a variety
of different locations across the UK.
Centres who wish to participate in the trial should be registered with the MRC CTU. Before
a centre can randomise patients or administer trial procedures, the MRC CTU must receive
the following:







Copy of approval from the centre’s Trust R&D department
Signed agreement for non-commercial research in the NHS
Signed Investigator statement
Trial contact list
Signature list and delegation log
Copies of the patient information sheet, GP letter and consent form on hospital
headed paper
Normal ranges for tumour markers (AFP, ß-HCG and LDH)
Please note that any sites that joined the trial prior to 1 April 2009 were also required to
submit a completed site-specific assessment (SSA) and associated SSA approval
documents.
In addition to at least one named local clinical investigator, each participating centre will
have at least one named local investigator who is a consultant radiologist with experience
in the assessment of patients with germ cell tumours.
Before a patient is entered into the trial, written informed consent must be obtained. The
approved patient information sheet and informed consent form are supplied by the MRC
CTU and should be presented on locally headed paper.
14
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
4. SELECTION OF PATIENTS
4.1 Patient inclusion criteria
1. Histologically proven seminoma of the testis without evidence of NSGCT
elements.a
2. Clinical stage I on the basis of clinical examination and CT scan of the chest,
abdomen and pelvis. This CT scan should have been performed no more
than 8 weeks before randomisation.
3. No planned adjuvant therapy.
4. Normal serum AFP post-orchidectomy and not known to be raised preorchidectomy
5. Normal serum β-HCG at randomisation (may have been raised preorchidectomy).
6. Patient written, informed consent.
7. Patients must be able to attend for regular surveillance.
8. The interval between orchidectomy and randomisation should not normally
exceed 8 weeks (although up to 10 weeks is acceptable in exceptional
circumstances following discussion with the trial team)
9. Patients must be at least 16 years old.
a
Patients with synchronous bilateral, histologically proven seminoma after bilateral
orchidectomy are eligible.
4.2 Patient exclusion criteria
1. Co-existent or previously treated malignancy within 10 years, with the only
exceptions being (i) successfully treated non-melanoma skin cancer or, (ii)
RMH stage I germ cell tumour of the contralateral testis diagnosed more
than 5 years earlier and managed by surveillance.
2. Inability for any reason to comply with the trial investigations or follow-up
schedules.
3. Any contra-indication to MRI, for example, ferrous metal implants of any
type, cardiac pacemaker or defibrillators, or history of injury by metal
fragments.
4. Spermatocytic seminomas
4.3 Screening procedures and pre-randomisation investigations

Assay of serum AFP, β-HCG and LDH within the 4 weeks before
randomisation.

Chest X-ray.

Patient completed questionnaire of health outcome (EQ-5D)
TRISST protocol v4.0 19-May-2015.docx
15
MRC TE24 (TRISST)
5. RANDOMISATION & ENROLMENT PROCEDURE
The TRISST trial closed to randomisation on 31 July 2014. Randomisation was performed
via the MRC CTU Randomisation line. Patients were allocated a surveillance mode (CT or
MRI), schedule (7 or 3 scans) and a unique identification number during the call. Written
confirmation of the details provided at randomisation, the allocated surveillance and a scan
schedule were also sent within one day of entry.
16
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
6. PATIENT MANAGEMENT
6.1 Surveillance schedule
All patients in this study will be followed up for a minimum of 6 years irrespective of which
arm they have been randomised to. Instructions on follow-up for patients relapsing before
the end of this 6 year period are given in section 6.6. Clinical follow-up beyond 6 years is
not mandated by this protocol and is at the supervising clinicians’ discretion, according to
local policies. Patients will undergo the cross-sectional imaging by CT or MRI of the
retroperitoneum only, at a frequency determined by their randomised trial arm (details in
section 6.3). In addition, the following tests will be undertaken at visits corresponding to
the time points from randomisation given below:
Year
Month
Pre-randomisation
0
0
3
6
9
1
12
15
18
21
2
24
28
32
3
36
42
4
48
54
5
60
66
6
72
Chest
X-ray
Tumour markers
(AFP, ß-HCG, LDH)


RANDOMISATION


































Clinical
assessment


















Patient-completed questionnaire
EQ-5D (Appendix 1), resource use
and scan acceptability questions








The pre-randomisation CT scan must be performed no earlier than 8 weeks prior to
randomisation. The patient-completed questionnaire must be completed after the patient
has consented to participate in TRISST, and before the patient is made aware of their arm
allocation. Pre-randomisation assessments will allow comparison with results at later time
points during follow-up. For example, patients will be asked about their experience of the
routine (pre-randomisation) CT scan. This will allow comparisons regarding acceptability of
the future allocated scanning schedule (whether it be CT or MRI based).
TRISST protocol v4.0 19-May-2015.docx
17
MRC TE24 (TRISST)
6.2 Procedures for assessing safety
6.2.1 Reporting of Serious Adverse Events (SAEs) to MRC CTU
An untoward event involving a TRISST patient may be considered an SAE if it falls into any
of the following categories:
a. results in death;
b. is life-threatening;
c. requires hospitalisation or prolongation of existing hospitalisation;
d. results in persistent or significant disability or incapacity;
e. consists of a congenital anomaly or birth defect;
f.
other important medical condition.
All such events occurring between randomisation and the date of each patient’s final
protocol-scheduled scan (e.g. 36 months post-randomisation for a patient on a 3-scan
schedule, or 60 months for a 7-scan schedule) must be reported to CTU, regardless of
whether or not they are thought to be related to trial procedures.
Reporting of events that are thought to be at least potentially related to trial procedures
continues indefinitely, even beyond the point when the patient has ended scheduled
surveillance.
It is the responsibility of the centre to notify the MRC CTU of any SAEs within 24 hours of
the investigator becoming aware of the Serious Adverse Event. Accredited sites will be
supplied with the TRISST Serious Adverse Event CRF along with the other trial CRFs. This
CRF is also included in CRF folders sent to centres for each patient randomised.
Centres should complete the SAE CRF and send to MRC CTU using the instructions given on
the CRF. The CRF will be forwarded by the MRC CTU to the Chief Investigator for
assessment. Reports of related and unexpected SAEs (i.e. Suspected Unexpected Serious
Adverse Reactions, or SUSARs) will be submitted, within 15 days of the CTU being notified
of the event, to Leeds (East) REC.
Any queries about SAE reporting should be directed to the TRISST Trial Manager (see Trial
Administration section above for details).
6.2.2 Onward reporting of serious adverse events
Since there is no medicinal intervention in this study, there will be no formal toxicity
assessments except on the Relapse Treatment Form. The only potential safety issue is that
regarding radiation exposure. In fact, the aim of this study is to reduce radiation exposure
either through a reduced number of CT scans or MRI. The impact of this on incidence of
second cancers would be measured as a long-term secondary outcome. If we find either
MRI or a reduced CT scanning schedule to be the optimal surveillance intervention, then
18
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
the patients allocated to these experimental arms (i.e. 3 CT, 7 MRIs, or 3 MRIs) will have
received a safer intervention with respect to radiation exposure.
Whilst there is no obligation to report a serious adverse event (SAE) to the MHRA (as there
is no medicinal intervention in the study) the MRC CTU is required to report any SAE that
meets reporting requirements to Leeds (East) REC, which gave a favourable ethical opinion
to this study.
The MRC CTU will report to Leeds (East) REC if the SAE is an untoward and unexpected
occurrence that falls into one of the event categories listed above, and in the opinion of
the Chief Investigator was:

‘related’ – that is, it resulted from administration of any of the research procedures;
and

‘unexpected’ – that is, the type of event is not listed in the protocol as an expected
occurrence.
We expect adverse events to be rare in the context of this trial, with the interventions
being CT or MRI scanning and therefore, there is no expected list of event occurrences in
this protocol. Events such as disease relapse or death as a result of disease relapse are not
considered to be SAEs and should be reported on the appropriate CRF.
6.3 Cross-sectional imaging schedules
6.3.1 General information

After randomisation, scanning will be of the RETROPERITONEUM ONLY unless there
is a past history of ipsilateral inguino-scrotal surgery, in which case the pelvis should
also be imaged.

Imaging will be either by CT or MRI according to randomised allocation

A standard protocol for prolonged cross-sectional imaging will be undertaken in all
patients, with frequency determined by their randomised allocation:
Schedule 1: months 6, 12, 18, 24, 36, 48, 60
Schedule 2: months 6, 18, 36
Compliance with scanning schedule:
If a patient cannot attend a scheduled scan appointment, the replacement appointment
should be made as close to the original appointment as possible. The next scan after this,
should keep its original time. For example, if someone had scheduled scans on 1 May and
then 6 months later on 1 November, but has to rearrange their first scan to be 1 month
later on 1 June, the next scheduled scan after this should remain on 1 November and not
be pushed forward in time.
When a patient is randomised, the front cover sheet of the CRF booklet that is sent to the
centre will contain an individualised patient schedule. This will list suggested dates for
TRISST protocol v4.0 19-May-2015.docx
19
MRC TE24 (TRISST)
follow-up visits and scanning that correspond to the patient’s allocated schedule from date
of randomisation. This table can be completed by sites and is intended to help sites keep
patients to their allocated scanning schedule. An example is given below for a 7 scan
schedule:
Once the randomly allocated schedule is known, centres should book all or as many of the
scans as is possible in advance for the patient. At the time of receiving this individualised
patient schedule, centres should complete the scheduled date column for the booked
scans. The actual date of the scans should be completed when the scan has taken place..
This will allow the MRC CTU to monitor compliance within the study as it is ongoing. It is
very important for this trial that the actual scanning schedules for patients comply as
closely as possible with the allocated schedules. Centres experiencing particular difficulty in
booking future scans for patients in TRISST should contact the TRISST Trial Manager.
Unscheduled Scans
Centres should provide data on all scans regardless of whether they comply with the
schedule or not. Data on unscheduled scans, such as an ultrasound of the testes or a CT
scan of the chest, should be recorded using the Unscheduled Investigations Section of the
Follow-Up CRF.
20
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
6.3.2 CT protocol for surveillance
Unless indicated otherwise, protocol scans should be of the retroperitoneum only. The
study specifies a spiral or multi-detector CT scanner, with a maximum reconstructed slice
thickness of 5mm. Scans should be obtained from the top of the diaphragm on the scout
view to the S1 vertebra. Patients should be prepared with oral contrast medium over one
hour prior to the procedure and imaged in the portal venous phase, post-injection of 100ml
intravenous contrast medium.
Patients who are allergic to iv contrast media should have the retroperitoneal CT scan with
just oral contrast medium. This change of procedure should be at the first instance notified
to the TRISST trial team and recorded on a note to file in the patient’s records.
6.3.3 MRI protocol for surveillance
Unless indicated otherwise, protocol scans should be of the retroperitoneum only. Minimum
field strength 1 Tesla with phased array coils. Scan from dome of diaphragm to S1 vertebra
from coronal scout view. Then a minimum of:


Axial T1 weighted scans, breath hold or end expiratory triggered, which may be
gradient echo, and axial T2 weighted images.
The axial images must be contiguous 5mm sections. They may be supplemented
by coronal images at the discretion of the Radiologist, but measurements of nodes
should be taken from the axial images.
Please note that although use of any other scan sequences, e.g. diffusion MRI scans, is at
site discretion, the above scans must be performed at all scheduled timepoints, and only
the above scans can be used to diagnose disease relapse in TRISST.
6.3.4 Definition of relapse on cross-sectional imaging and plain CXR
In the absence of raised tumour markers, relapse will be determined by clinical examination
and imaging. The criteria for relapse on lesion size is the same for MRI and CT. Appendix 2
gives the criteria for nodal and extra-nodal lesions considered significant by size criteria.
Equivocal lesions
Patients who develop borderline or equivocal lesions on MRI or CT at any stage of followup will have repeat imaging with the same modality 6 weeks later to confirm/exclude
relapse. After repeat imaging, enlargement will be deemed to indicate relapse (at the date
of the first MRI/CT scan) and patients with stable or smaller lesions will continue with the
original imaging schedule.
Equivocal lesions on CXR in any trial arm will be followed by a CT thorax within 6 weeks.
Enlargement on CT (beyond the levels set out in Appendix 2) will be deemed to indicate
relapse (at the date of the CXR) and patients with stable or smaller lesions will continue
with the original imaging schedule.
TRISST protocol v4.0 19-May-2015.docx
21
MRC TE24 (TRISST)
At any time lesions larger than those identified in Appendix 2 will be regarded as evidence
of relapse and patients will come off surveillance and receive appropriate standard therapy.
The identification of relapse by clinical examination, CXR, CT or MRI will be deemed to be
the date of relapse.
6.3.5 Definition of relapse on tumour markers alone
In the event of a rise in tumour markers, a second sample should be obtained at –1-2
weeks. If still elevated at two weeks, a CT of the thorax and imaging of the
retroperitoneum by CT/MRI according to randomisation, should be requested. If relapse is
confirmed then the date of relapse will be the date of first elevation of the tumour marker.
In the event of no measurable disease being identified in a patient with two elevated
tumour markers, then the following protocol should be followed:





A third sample should be assayed at 2-4 weeks from the 2nd and then repeated 4
weekly until confirmation of relapse or identification of an alternative explanation
for the rise in serum levels.
If markers remain elevated then an ultrasound of the remaining testis should be
requested
If no new primary tumour is identified in the testis and tumour markers remain
elevated at > 2x upper limit of normal then CT or MRI imaging of the
retroperitoneum depending on trial arm should be repeated after 6 weeks to
include the pelvis, with consideration given to CT or MRI of the brain.
If relapse is identified on imaging through this process, the date of relapse will be
deemed to be the date of the first measurement of raised tumour markers.
If no relapse is identified then the management should be discussed with the Chief
Investigator.
A raised AFP with or without raised -HCG is not compatible with activity of pure
seminoma. Any patient with raised AFP on two occasions should have an ultrasound of the
remaining testis whether or not metastatic disease is identified. Relapse with measurable
extra-testicular disease associated with a raised AFP without a new testicular primary
should be discussed with the Chief Investigator.
6.3.6 Further imaging after confirmed relapse
At relapse the following will be undertaken:
Patients on CT-based surveillance
 All patients should undergo chest CT.
 Patients whose relapse is identified by means other than retroperitoneal CT (i.e.
CXR, markers, symptoms or clinical examination) will also have cross-sectional
imaging of the retroperitoneum by CT.
22
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
Patients on MRI-based surveillance
 All patients should undergo chest CT.
 Patients whose relapse is identified by CXR, markers, symptoms or clinical
examination will also have cross-sectional imaging of the retroperitoneum by MRI.
 Patients whose relapse is identified by retroperitoneal MRI must have CT of the
retroperitoneum within 2 weeks to confirm relapse by standard criteria and allow
comparative tumour measurements between MRI and CT. – Note in the event
that CT does not confirm relapse, patients will return to surveillance with
MRI. This will be recorded on the “Equivocal scan investigation form” in
the CRF folder to enable reporting of the false-positive rate.
All patients
 Other staging investigations, as indicated by symptoms and prognostic group
according to the IGCCCG Classification. Patients with poor or intermediate
prognosis will have CT of brain and bone scan if indicated.
Treatment of relapse is at the clinician’s discretion, but it is recommended that patients are
considered for ongoing trials appropriate to their IGCCCG stage at relapse. In the event of
relapse, the MRC CTU should be notified and details of relapse and response to relapse
treatment will be recorded.
At relapse, the following information will be recorded on the relapse investigation form in
the CRF folder and sent to the MRC CTU:





First indication of relapse (clinical findings, symptoms, serological, MRI, CT, CXR,
other)
Date of relapse
Site(s) of relapse
Maximum size of lesion(s) at each anatomical site
Tumour marker and LDH levels at relapse
Details of the treatment and response to treatment should be recorded on the relapse
treatment form in the CRF folder.
6.3.7 Scan review
All scanned images will be collected from baseline until and just after diagnosis for each
patient who relapses (regardless how their relapse was detected). This is crucial to
investigations regarding important secondary outcomes.
The MRC CTU is notified of relapses via the relapse form in the CRF folder. The Trial
Manager will contact the centre regarding collection of the scans for central review.
Only scans for RELAPSING PATIENTS are required, but for these patients, we would like
ALL CT AND/OR MRI SCANS WHILE PARTICIPATING IN TRISST. This includes:





All baseline CTs for relapsing patients
All scans before diagnosis of relapse, since the time the patient was enrolled in
TRISST
Scans at which a relapse may have been detected
Scheduled AND unscheduled CT or MRI scans
All confirmatory CTs if a patient was allocated MRI
TRISST protocol v4.0 19-May-2015.docx
23
MRC TE24 (TRISST)
When the Trial Manager contacts the centre for the scans, the nominated first point of
contact at the centre should send CDs containing digitised, anonymised images of these
scans to the TRISST Trial Manager at the MRC CTU.
Non-digitised images e.g. anonymised plain film X-ray images should also be copied and
sent to the TRISST Trial Manager.
6.4 Recommended management of relapsed patients
The following are recommendations, but centres may use their own standard treatment
management strategies. Please note, we will continue to collect data beyond relapse (see
section 6.6) for a minimum of 6 years post-randomisation.
6.4.1 Limited stage disease
Management options for this group of patients are discussed in the section 2.4. For patients
with para-aortic relapse only (masses <5cm, RMH stage IIA or IIB disease) we recommend
considering management with the combined regimen of para-aortic radiotherapy and one
cycle of carboplatin AUC7 as below:
Carboplatin treatment
Patients will be treated by a single cycle of Carboplatin AUC 7 prescribed according to the
Calvert formula
Dose of carboplatin in mg = 7 x (GFR +25)
GFR should be determined by best local practice but an accurate 3 point EDTA clearance is
advised.
Patient Care
Patients should be reviewed at commencement of chemotherapy and have FBC, U+E , LFT
and tumour markers taken. Fertility issues should be discussed with all patients and sperm
banking undertaken if appropriate. Patients should be reviewed at 2 weeks following
chemotherapy with repeat nadir blood count.
Radiotherapy treatment
Radiotherapy should start 4 weeks and not later than 6 weeks following carboplatin
treatment.
Planning Target Volume (PTV)
The PTV is: Para-aortic mass plus 1cm, non-involved para-aortic lymph nodes, ipsilateral
renal hilar nodes, retrocrural nodes.
In most instances the PTV will be covered by field extending
Superior: Bottom of D10 vertebra
Inferior: Bottom of L5
Laterally: In most instances a 8-10 cm wide field will be used to cover to the tips of the L4
spinal laminae. The lateral border should extend to include the ipsilateral renal hilar in the
case of ipsilateral para-aortic masses and to provide a 1cm margin on the para-aortic mass.
24
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
Planning technique
The PTV should be covered by parallel fields with a minimum energy of 6mV.
Planning the field using CT virtual simulation is advised. Using CT simulation allows
confirmation of coverage of the para-aortic mass, avoids need for IVU and maximises
avoidance of renal parenchyma.
If unavailable, conventional simulation with IVU (using 50mls of Iodine contrast agent
given over 5-10 minutes) is acceptable. In these circumstances, reconstruction of mass size
and position onto planning films is encouraged to ensure adequate coverage by radiation
fields.
Lead block or MLC shielding of renal parenchyma is permitted.
Radiation Dose
30Gy in 15 fractions (2 gray per fraction) prescribed to mid plane dose
Dose constraints
Maximum ipsilateral renal dose: 50% of renal parenchyma to 15Gy
Maximum contralateral renal dose: 10% of renal parenchyma to 15Gy
In cases of bilateral para-aortic masses the ipsilateral dose should not be exceeded in
either kidney.
Patient Care
Patients should be managed according to standard local practice. The following care is
advised:
 Tumour markers (β-HCG, AFP, LDH) at commencement of treatment
 Routine use of an antiemetic (preferably a 5HT3 antagonist [14] administered 1
hour pre-radiotherapy)
 Full blood count weekly
 Weekly out-patient review
Clinical follow-up
Please refer to section 6.6 below for details of follow-up required post-relapse.
6.4.2 Advanced disease
It is recommended that patients who relapse with RMH stage IIC disease or greater stage
should be managed with systemic chemotherapy according to their IGCCCG prognostic
stage [15].
Those with good prognosis disease should be considered for appropriate National or
International studies or managed with 3 cycles of standard BEP (500mg/m 2 etoposide per
cycle) or 4 cycles of EP chemotherapy.
Patients with intermediate prognosis disease should be considered for appropriate National
or International studies, or should be treated with 4 cycles of BEP chemotherapy.
TRISST protocol v4.0 19-May-2015.docx
25
MRC TE24 (TRISST)
6.5 Stopping trial intervention
A patient may stop, or be stopped, from protocol surveillance (i.e. the randomly allocated
CT or MRI scans) for the following reasons:



Relapse
Withdrawal of consent for protocol management by patient
Any alterations in the patient’s condition which justifies the discontinuation of protocol
management in the clinician’s opinion.
The reason for stopping should be recorded. Please refer to section 7.3, Complete
withdrawal from the trial, for details.
6.6 Follow-up of patients who have relapsed
After relapse, we would still like to follow up patients for outcomes on the treatment they
received, dates of discharge, new malignancies and in-patient care for the same total
duration as relapse-free patients, i.e. for a minimum of 6 years post-randomisation.
Therefore, we would like centres to fill out the post-relapse follow-up form for patients who
have relapsed and continue to collect the patient-completed EQ-5Ds. Both of these should
be completed and returned to MRC CTU at least annually from the date of relapse.
26
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
7. CESSATION OF FOLLOW-UP
7.1 Loss to follow-up
Every effort should be made to follow-up patients who have been randomised. Patients
should, if possible, remain under the care of an oncologist or urologist familiar with this
protocol for the duration of the trial. If care of a patient is returned to the GP, it is the
responsibility of the consultant (who obtained the patient’s consent to participate in the
trial) to ensure that the data collection forms are completed and returned to the MRC CTU.
If the clinician moves, appropriate arrangements should be made to arrange for trial followup to continue at the centre and the CTU should be contacted with information pertaining
to these new arrangements.
It is expected that during the average 6 years of protocol follow-up of TRISST, some
patients will move away from the area where they are being seen for the trial. If a patient
moves to a place where there is another participating TRISST centre, then the randomising
clinician should arrange for the patient to be transferred to that site, details of which can
be obtained from the CTU. A copy of the patient’s TRISST CRFs and medical records will
need to be provided to the new site. If no appropriate TRISST site is available,
arrangements should be made for data to be collected from their new clinician via phone
contact or letter. All information obtained should be noted in the patient’s records and on
the appropriate CRF.
The CTU should be notified of all changes to the patient’s monitoring. If any
patient is considering moving centre, please contact MRC CTU to discuss
possible centre transfers.
7.2 Trial closure
The trial will be considered closed after the last patient has had 6 years post-randomisation
follow-up, to allow the final protocol-specified scans and follow-up visits to take place.
7.3 Complete withdrawal from the trial
In all cases where a patient is considering withdrawing from part or all of TRISST
participation, or a patient is potentially lost to follow-up, sites should contact MRC CTU to
discuss available options.
In consenting to the trial, patients are consenting to trial surveillance, trial follow-up and
data collection. If a patient wishes to stop trial surveillance, centres should explain the
importance of remaining on trial follow-up, or failing this, of allowing routine follow-up data
to be used for trial purposes.
A clear distinction must be made as to whether the patient is stopping trial surveillance
whilst allowing further follow-up or whether the patient refuses any further trial surveillance
and refuses any follow-up participation (i.e. a complete withdrawal). In all cases,
withdrawal should be documented on the Withdrawal File Note and returned to the MRC
CTU as soon as possible.
TRISST protocol v4.0 19-May-2015.docx
27
MRC TE24 (TRISST)
Complete withdrawal is expected to be a very rare occurrence, however, all communication
surrounding the withdrawal should be noted in the patient’s records and no further TRISST
(MRC TE24) CRFs should be completed for that patient. Data up to the time of withdrawal
can be included in the trial if anonymised. Further follow-up is possible only through the
usual NHS mechanisms (e.g. ONS), providing the patient consented to this when joining
the trial.
Patients can change their minds about withdrawal at any time and re-consent to participate
in the trial. Follow-up data should be collected only from the point of re-consent.
28
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
8. STATISTICAL CONSIDERATIONS
TRISST is a non-inferiority, factorial, randomised trial. In general terms, in a factorial trial, 2
or more groups are combined to test multiple hypotheses in the same patients, and the aim of
a non-inferiority trial is to show that both the new and standard interventions have similar
levels of effectiveness or adverse events.
In TRISST, we will be comparing how the experimental interventions (reduced scanning
schedule, use of MRI) compare to what we consider to be standard practice (more frequent
scans, use of CT). During the analysis, the main comparisons will be (i) CT versus MRI (7 CT
+ 3 CT versus 7 MRI + 3 MRI), and (ii) 7 scans versus 3 scans (7 MRI + 7 CT versus 3 MRI +
3 CT). This is known as a factorial comparison, since we are combining groups to allow us to
address 2 research questions (i) whether CT can be replaced by MRI and (ii) the optimum
number of scans.
Our primary outcome is the proportion relapsing with advanced stage disease as described in
section 8.2 below. For MRI to be deemed a better schedule than CT, the proportion relapsing
with advanced stage disease in the MRI groups must be similar to and no worse than a prespecified margin around that detected in the CT groups. Similarly, for 3 scans to be deemed a
better schedule than 7 scans, the proportion relapsing with advanced stage disease in the 3
scan groups must be similar to and no worse than a pre-specified margin around that
detected in the 7 scan groups. TRISST is therefore termed a non-inferiority trial.
8.1 Method of randomisation
Treatment arm will be allocated using minimisation incorporating a random element.
Minimisation factors will include centre and other factors not listed here to decrease
predictability.
8.2 Outcome measures
8.2.1 Primary outcome
Proportion of all randomised patients relapsing with RMH stage IIC or greater
disease:
The comparison of imaging frequency will be based on evidence of migration of RMH stage at
relapse from ≤ IIB (sub-diaphragmatic disease, masses  5cm in diameter) to ≥ IIC (subdiaphragmatic disease, masses > 5cm in diameter or supradiaphragmatic disease). The
proportion of patients relapsing with ≥ IIC disease will therefore be compared. This is of
practical significance, since the modality of curative therapy is changed from an option for
local therapy with radiation in stage IIA or IIB disease to an expectation of treatment with
systemic chemotherapy in the majority of patients with stage IIC disease or greater. Patients
are deemed to relapse if they meet criteria set out in section 6.3.4 and 6.3.5.
Patients in whom relapse is identified by MRI will have a confirmatory abdominal CT within
two weeks, to confirm relapse and allow comparative tumour measurements between MRI
and CT.
All patients with evidence of relapse by clinical symptoms, examination, CXR or serum markers
will have imaging of the retroperitoneum and chest by CT within two weeks. Patients
TRISST protocol v4.0 19-May-2015.docx
29
MRC TE24 (TRISST)
randomised to MRI will also have an additional MRI of the retroperitoneum when relapse is
identified by other means.
All imaging of relapsed patients will be reviewed centrally for tumour measurements.
8.2.2 Secondary outcomes









Mean abdominal mass size at relapse between CT and MRI
Time on surveillance before detection of relapse
Prospective identification of first modality to detect relapse (Patient symptom, clinical
examination, tumour marker, CXR, cross-sectional image)
Extent of relapse according to IGCCCG classification [15]
Disease free and overall survival according to schedule randomisation and prognostic
grouping
Prospective evaluation of prognostic factors for relapse of stage I seminoma patients.
Number of false positive MRIs
Second primary malignancies
Resource use and costs
8.3 Sample size
The estimated 5-year relapse rate for these patients is 15%, based on the assumption that
the population will comprise mainly those with one or no risk factors, as identified by Warde et
al [3].
Sample size calculations are based on the characteristics of patients relapsing on carboplatin
in the MRC TE19 trial [16] and from the surveillance studies [17]. In both settings, 89% of
patients who relapsed had para-aortic node involvement. In TE19, the mean size of
retroperitoneal nodal relapse after carboplatin was 4cm (SD 2cm), and 38% of relapses were
of RMH stage IIC or greater.
All patients contribute to both comparisons (CT vs MRI and more vs less frequent imaging). To
exclude an increase in the proportion of relapses with RMH Stage IIC from 38% to 76%
through either a move from CT to MRI, or from more frequent to less frequent scanning,
would equate to excluding a change in the proportion of all randomised patients relapsing with
higher stage disease from 5.7% to 11.4%. For this latter comparison, 630 patients provide
≥80% power to exclude a difference at least this great (5% significance level, 1-sided). We
anticipate that some patients (<5%) will find MRI unacceptable and thus have inflated the
sample size to a target recruitment of 660 patients.
This primary analysis will compare the proportion of relapses at ≥ stage IIC using all
randomised patients as the denominator; if stage at relapse is compared only in those who
relapse - assuming 15% of patients relapse, 95 relapses would be observed - the power to
exclude an increase from 38% to 76% in the proportion of relapses at stage IIC or greater
would be over 95% (5% significance level, 1-sided).
For the scan modality comparison in particular (CT versus MRI), the size of abdominal mass at
detection of relapse is an important additional outcome measure. The confirmatory CT scan
that is carried out on patients whose relapse is detected by other means, will ensure
comparability of mass size. Although small changes in mass size are not of major clinical
significance in testis cancer patients, the results of this comparison may have relevance to
30
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
other cancers. 530 patients (70 PA node relapses, 79 relapses in total) would be required to
exclude a 1cm increase in the mean size of abdominal masses (standardised difference 0.5,
power 90%, 5% significance level, 1-sided). Some caution is needed with this analysis
because, although it would include all relapsed and followed patients regardless of first mode
of detection of relapse, it cannot include all randomised patients, introducing the potential for
bias. However as the trial interventions affect only the timing of relapse, and not whether or
not it occurs, any bias would be minimised by ensuring adequate follow-up in both groups
beyond the time of the final scan.
Patients will be asked to consent to be randomised to any of the four surveillance methods. If
this impacts adversely on recruitment for example if centres or patients have a strong
preference for CT-based surveillance, or inadequate access to MRI, then consideration in the
future may be given to allowing randomisation either between the two scanning schedules
(using CT in all patients), or between CT and MRI (with the same scan frequency in all
patients). This would however substantially increase the overall sample size.
8.4 Interim monitoring and analyses
Formal interim analyses of the accumulating data will be performed at regular intervals (at
least annually) for review by an Independent Data Monitoring Committee (IDMC) (see also
section 15.3). These analyses will be performed at the MRC CTU. The IDMC will be asked to
give advice on whether the accumulated data from the trial, together with results from other
relevant trials, justifies continuing recruitment of further patients or further follow-up. A
decision to discontinue recruitment, in all patients or in selected subgroups will be made only
if the result is likely to convince a broad range of clinicians including participants in the trial
and the general clinical community. No formal statistical stopping rules will be used in TRISST.
If a decision is made to continue, the IDMC will advise on the frequency of future reviews of
the data on the basis of accrual and event rates. The IDMC will make recommendations to the
Trial Steering Committee (TSC, see section 15.2) as to the continuation of the trial.
8.5 Analysis plan (brief)
The primary outcome measure will be assessed by comparing (2 test) the proportion of all
randomised patients relapsing with RMH stage IIC disease or greater. The comparison of scan
modality will be stratified by the scan frequency allocation, and vice versa. The difference in
the proportions with an adverse outcome in each randomised comparison will be presented
with a 90% confidence interval. All patients will be included in the primary analysis according
to their allocated trial arm, regardless of whether they adhered to the scan schedule. This is
known as an intention to treat analysis. The impact of non-adherence will be explored in
sensitivity analyses.
The secondary outcome measure of abdominal mass size at relapse will be assessed by
comparing the mean abdominal mass size from CT measurements at relapse, using a twosample t-test or a corresponding non-parametric test if appropriate.
Time to detection of relapse will be presented using Kaplan-Meier event-free survival curves
and compared across randomised arms using the logrank test.
In patients who relapse with small volume disease, the characteristics at initial diagnosis and
at relapse of patients undergoing treatment with combined radiotherapy and carboplatin will
be presented, together with a Kaplan-Meier progression-free survival curve.
The
TRISST protocol v4.0 19-May-2015.docx
31
MRC TE24 (TRISST)
characteristics of patients who relapse with small volume disease and undergo alternative
treatment will also be described.
In general, imputation techniques will not be used for missing data in the analyses.
A detailed statistical analysis plan will be developed and maintained by the trial Statisticians.
This will be finalised prior to the final analysis.
32
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
9. TRIAL MONITORING
9.1 Risk assessment
TRISST is an NRCI and NCRN endorsed trial. TRISST has been reviewed by independent
experts on the Cancer Research UK CTAAC committee and the Cancer Group at the MRC
CTU.
It is the view of the Chief Investigator and Trial Management group that TRISST is
considered to be a low risk study with respect to governance, safety and finance.
9.2 Monitoring at MRC CTU
Data stored at the MRC CTU will be checked for missing or unusual values and checked for
consistency within participants over time. If any such problems are identified, a data
clarification form will be sent to the centre by post or email for checking and confirmation
or correction, as appropriate and returned to the CTU – any data which are changed should
be crossed through with a single line and initialled on the site copy of the CRF. MRC CTU
will send reminders for any overdue and missing data. It is also our intention to monitor
centres for data compliance in terms of data quality and measuring CRF return. CRF return
is likely to be measured by dividing the number of CRFs received by the CTU by the
number of CRFs expected for all patients randomised at that centre to provide a single
percentage figure for the centre’s CRF compliance. Furthermore, it is likely that this figure
will be broken down into different CRF percentages e.g. CRF compliance for return of
randomisation forms, return of follow-up forms. It is anticipated that 75% will be
considered satisfactory for a centre’s overall CRF compliance.
9.3 Clinical site monitoring
Participating investigators should agree to allow trial-related monitoring, including audits,
ethics committee review and regulatory inspections by providing direct access to source
data/documents as required. Patients’ consent for this is obtained as part of the consent
process.
TRISST protocol v4.0 19-May-2015.docx
33
MRC TE24 (TRISST)
10. ETHICAL CONSIDERATIONS AND APPROVAL
10.1 Ethical considerations
As with all randomised trials, patients cannot chose the treatment they receive and must be
willing to accept any of the management options being compared. It is possible that less
frequent CTs will lead to relapse being detected at a slightly more advanced stage, or that
MRI will prove less sensitive than CT. However, treatment of relapse is highly successful in
these patients and no impact on long-term outcome is anticipated.
The study will abide by the principles of the Declaration of Helsinki.
10.2 Ethical approval
The protocol will have Main Research Ethics Committee (MREC) approval but each centre
must obtain site-specific approval from the Local Research Ethics Committee (LREC) before
patients are entered. Copies of the documents listed in Section 3 must be sent to the MRC
CTU before randomising patients.
The patient’s consent to participate in the trial should be obtained after a full explanation
has been given of the surveillance options, including the conventional and generally
accepted methods of surveillance. Patients should be given sufficient time after being
given the trial patient information sheet to consider and discuss participation in the trial
with friends and family. A contact number should be given to the patient should they wish
to discuss any aspect of the trial. Following this, the randomising clinician should
determine that the patient is fully informed of the trial and their participation, in accordance
with ICH GCP guidelines. Patients should always be asked to sign a consent form. One
copy should be given to the patient, one copy should be kept with patient’s hospital notes
and one copy should be kept in the local investigator’s file.
The right of the patient to refuse to participate in the trial without giving reasons must be
respected. After the patient has entered the trial, the clinician must remain free to give
alternative surveillance to that specified in the protocol, at any stage, if he/she feels it to be
in the best interest of the patient. However, the reason for doing so should be recorded
and the patient will remain within the trial for the purpose of follow-up. Data analysis will
be performed according to the surveillance option to which the participant was originally
allocated. Similarly, the patient must remain free to withdraw at any time without giving
reasons and without prejudicing any further surveillance, treatment or the standard of care
received.
A statement of MRC policy on ethical considerations in clinical trials on cancer therapy,
including the question of informed consent, is available from the MRC Head Office web site
(http://www.mrc.ac.uk). This may be used to give guidance to participating investigators
and to accompany LREC applications
34
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
11. REGULATORY ISSUES
The MRC is the UK research governance sponsor of TRISST. This trial does not involve a
medicinal product, and as such does not fall under the EU regulatory guidelines. The trial
will be conducted in accordance with the 1996 version of the Declaration of Helsinki, the
principles of ICH GCP, DPA and the NHS Research Governance Framework for Health and
Social Care. The treatment recommendations for relapsed patients represent standard
management strategies.
In addition, TRISST has been, and will continued to be, set up and managed in accordance
with the Standard Operating Procedures of the MRC CTU.
12. INSURANCE
University College London (UCL) holds insurance against claims from participants for injury
caused by their participation in this clinical trial. Participants may be able to claim
compensation if they can prove that UCL has been negligent. However, as this clinical trial
is being carried out in a hospital, the hospital continues to have a duty of care to the
participant of the clinical trial. University College London does not accept liability for any
breach in the hospital’s duty of care, or any negligence on the part of hospital employees.
This applies whether the hospital is an NHS Trust or otherwise.
Hospitals selected to participate in this clinical trial must provide clinical negligence
insurance cover for harm caused by their employees and a copy of the relevant insurance
policy or summary shall be provided to University College London, upon request.
13. ANCILLARY STUDIES
13.1 Health economics study
Resource use and costs are important secondary outcomes for TRISST. The trial will
measure all the major costs (from an NHS perspective) of participants in the trial regardless
of why costs were incurred, starting prior to randomisation and continuing for the duration
of follow-up. Utilization data covering levels of service receipt will be collected via the follow
up form in the CRF folder and via a questionnaire developed specifically for the study from
the patient. The feasibility of accessing information from medical records will also be
explored. Questions will be retrospective, covering the previous 3 months. The EQ-5D will
be administered at each patient visit when a scheduled scan may be due, as well as
annually following relapse, to permit cost-utility analysis [18].
13.2 Economic analysis
The trial will afford the opportunity to undertake a detailed cost-effectiveness analysis of
(a) CT vs. MRI as the basis of surveillance and (b) alternative surveillance intensities. An
economic evaluation will be conducted from the health services perspective. Resource use
data will be collected on each patient in the trial. These will include in-patient days in
hospital, out-patient and day-case visits, and therapeutic and diagnostic interventions. This
TRISST protocol v4.0 19-May-2015.docx
35
MRC TE24 (TRISST)
will include the cost of surveillance (differentiating between different modalities) and of the
management of any recurrence. Unit costs will be attached to resource use, using the best
available estimates of long run marginal opportunity cost, to obtain a cost per patient over
the period of follow-up. Routinely available national unit costs will be used where possible
(for example, NHS Reference Costs – DOH 2005), with local estimations where necessary.
Patients’ health-related quality of life (QoL) will also be collected at regular intervals using
the EQ-5D instrument [19].
For the within-trial analysis, the differential cost of the treatment interventions will be
related to their differential outcomes in terms of the primary outcome. The relative costeffectiveness of the alternative forms of surveillance will then be assessed using standard
decision rules and a full stochastic analysis will be undertaken. A cost-utility analysis will
also be conducted based on EQ-5D health states. For each state, a utility is assigned as an
adjustment factor for quality of life. Utility weights range from 0 to 1 where 0 represents
death and 1 signifies perfect health. The total utility of a particular state is made up of the
length of time spent in a state multiplied by the utility of that state. This will offer a simpler
decision rule and allow explorations of cost per quality-adjusted life-year gained (QALY)
[20]. A cost consequence analysis will estimate, by randomised group, mean cost per
patient and changes in EQ5D ‘utility’. Regression modelling will be used to explore
variation in costs and utilities according to patient characteristics and by location of
treatment [21, 22].
The within-trial analysis will be augmented by extrapolation beyond the trial follow-up using
decision-analytic modelling [23]. The aim of this analysis will be to predict the implications
of any difference in clinical endpoints in the trial for subsequent quality-adjusted survival
duration and long-term resource costs. This will inform the question of whether any shortterm savings in follow-up cost within the trial period are offset by additional costs or health
decrements in the long-term. The model will estimate the rate of lower and higher stage
recurrence with the alternative surveillance strategies being evaluated in the trial. Using
data from the trial and other published sources as necessary, the implications of a high
stage recurrence for costs and QoL will be estimated. Long-term prognosis following a
recurrence will be taken from the literature. Together with information on the competing
risk of mortality from other causes and the cost of health service use for other causes (in
both cases by age), the model will be able to generate estimates of mean long-term costs
and quality-adjusted survival duration for the strategies being compared. Potential
heterogeneity in baseline risks and treatment-by-baseline risk interactions will be modelled
in terms of sub-group cost-effectiveness. The ultimate outputs of the economic evaluation
will be estimates, by each of the four treatment groups, of long-term quality-adjusted
survival duration and costs including the presentation of incremental cost per quality
adjusted life year as necessary. In addition, probabilistic methods will be used to present
the probability that each form of surveillance is cost-effective in the long-term. Scenario
analysis will be used to explore the range of structural assumptions used in the analysis.
The analysis will be undertaken to inform decisions in the UK health service. However, the
model will be available for possible adaptation to other health systems.
13.3 Translational research
We have asked all patients for permission to collect formalin fixed paraffin embedded
tumour samples. This will facilitate future translational studies.
36
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
14. FINANCE
No additional funding is available to cover the costs of MRI scans, but as service support
costs, these should in principle be met locally via the concordat/partnership agreement
between the DH and the MRC/Cancer Research UK. In addition, calculations on the cost of
treating patients within the study indicate no significant overall excess costs.
It will be possible to claim £15 per relapsed patient to cover costs of administration,
postage and packaging for the scan review. If you should wish to do this on behalf of your
centre, please prepare an invoice detailing the items and patient trial numbers for whom
scans have been sent, and send this to the TRISST Trial Manager.
15. TRIAL COMMITTEES
15.1 Trial Management Group (TMG)
A Trial Management Group (TMG) is responsible for the day-to-day running and
management of the trial. Clinical advice and support is provided by the TMG which meets 6
monthly. The TMG, collaborating clinicians and CTU staff promote the trial through
national and international meetings, newsletters, patient-advocacy groups, and (where
suitable) the media. They encourage compliance and sustain interest by the same means
and through visits to collaborating centres. The TMG includes the chief investigator(s), the
trial statistician and the trial manager.
Full details of the membership and responsibilities of the TRISST TMG are described in the
TRISST TMG Charter, held in the TRISST trial master file.
15.2 Trial Steering Committee (TSC)
The independent Trial Steering Committee (TSC) meets annually and its role is to provide
overall supervision of the trial and ensure that it is conducted to rigorous standards. The
TSC considers each report of the IDMC, as well as other trials, and recommend appropriate
action. The TSC can prematurely close the trial if it is considered necessary. MRC trials
require an independent Chairman for a TSC, and further independent members will be
appointed. The MRC CTU has its own Urological Cancer Trial Steering Committee.
Full details of the membership and responsibilities of the Urological Cancer TSC are
described in the Urological Cancer TSC Charter, a copy of which is held in the TRISST trial
master file.
15.3 Independent Data Monitoring Committee (IDMC)
The Independent Data Monitoring Committee is an advisory body that meets annually to
review confidential interim trial data. The IDMC can recommend premature closure or
modification of the trial to the TSC. The MRC CTU Testis Cancer Trials IDMC has agreed to
take on this trial.
TRISST protocol v4.0 19-May-2015.docx
37
MRC TE24 (TRISST)
Full details of the membership and responsibilities of the TRISST IDMC are described in the
TRISST IDMC Charter, held in the TRISST trial master file.
38
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
Figure 1:
Diagram of relationships between trial committees
Sponsor/Funder
DMC: Data
Monitoring
Committee
DMC feedback to TSC & TSC
response to DMC
via Trials Unit
TSC: Trial
Steering
Committee
Report from
Trials Unit
Report from
Trials Unit
Trials
Unit
Question &
Feedback
Question &
Feedback
TMG: Trial
Management
Group
Participating centres
Trial expert panels
TRISST protocol v4.0 19-May-2015.docx
39
MRC TE24 (TRISST)
16. PUBLICATION
The results from different centres will be analysed together and published as soon as
possible. Individual Clinicians must not publish data concerning their patients that are
directly relevant to questions posed by the study until the Trial Management Group has
published its report. The Trial Management Group will form the basis of the Writing
Committee and advise on the nature of publications.
All publications shall include a list of participants, and if there are named authors, these
should include the trial’s Chief Investigator(s), Statistician(s) and Trial Manager(s) involved
at least. If there are no named authors (i.e. group authorship) then a writing committee
will be identified that would usually include these people, at least. The ISRCTN (65987321)
that has been allocated to this trial should be attached to any publications resulting from
this trial.
The members of the TSC and IDMC should be listed with their affiliations in the
Acknowledgements/Appendix of the main publication.
40
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
17. PROTOCOL AMENDMENTS
Please note that changes underlined are considered to be key changes in each respective
protocol version.
17.1 Version 4.0 (May 2015)
Page 1 – Change from version 3.0, March 2010 to version 4.0, May 2015.
Page 1 – Change in CI title and Change from Dr Rhian Gabe to Dr Fay Cafferty to reflect
staff changes.
Page 2 – General Information: change to name of clinical trials unit; removal of references
to randomisation and related procedures; clarification of compliance to Data Protection Act
but not to ‘MRC GCP’, referenced in the previous protocol version.
Page 3 – various contact details changed following staff and email address changes.
Page 6 – additions to Abbreviations and Glossary to explain abbreviations used in the
protocol.
Page 8 – some tenses changed from future tense to present tense; confirmation of
recruitment completion; change from ‘…it is our intention to seek permission from patients
for collection of…samples’ to ‘we have asked permission…’ to reflect that this request for
tissue sample use has now been made.
Page 9 – section 1.3, change from ‘Patients will be asked to consent to tissue samples…to
be used’ to ‘Patients were asked…’ to reflect that the request has now been made.
Page 14:
- Addition of introductory sentence about number and type of participating centres
- Abbreviation to ‘MRC CTU’ as elsewhere in the document
- Addition of ‘…or trial administer trial procedures’ to clarify that sites may still open
for TRISST in order to manage patients transferred from other sites
- Removal of ‘model’ from ‘Signed agreement’
- Removal of site-specific approval requirement from list, but acknowledgement
added to confirm that these were previously required.
Page 15: removal of reference to randomisation.
Page 16: removal of references to randomisation and amendment of text to reflect that
recruitment is now completed for TRISST.
Page 17: addition for clarification of ‘…and before the patient is made aware of their arm
allocation.’
Page 18 – Section 6.2 Procedures for assessing safety
Text largely unchanged from previous protocol version, however re-ordered and some
changes made to ensure responsibilities of participating centres and of MRC CTU are
distinct and clear, and to confirm that:
TRISST protocol v4.0 19-May-2015.docx
41
MRC TE24 (TRISST)
-
all events falling into one of listed categories a-f should be reported to MRC CTU if
they occur between randomisation and each patient’s final protocol-scheduled scan,
regardless of relatedness to trial procedures
all events falling into one of listed categories a-f should be reported to MRC CTU
regardless of when they occur (post-randomisation) if they are thought to be at
least potentially related to trial procedures
Page 18: capitalisation of initials in Relapse Treatment Form; change made for clarity from
‘…does occur…’ to ‘meets reporting requirements’.
Page 20: ‘…for follow-up visits and’ added; sentence added: ‘This table can be completed
by sites and is intended to help sites keep patients to their allocated scanning schedule.’
Page 20: example table replaced by example of currently-used report.
Page 20: sentence removed as no longer reflective of procedures: ‘From time to time the
Trial Manager may request copies of these individualised patient schedules.’
Page 20: text added to give example of unscheduled scans, ‘…such as an ultrasound of the
testes or a CT scan of the chest…’; text removed for clarity: ‘…in the same way’.
Page 21: added ‘the’ into ‘…change of procedure should be at the first instance…’
Page 21: 6.3.3 MRI protocol for surveillance
Text added to confirm status of diffusion MRI scans within the trial: ‘Please note that
although use of any other scan sequences, e.g. diffusion MRI scans, is at site discretion,
the above scans must be performed at all scheduled timepoints, and only the above scans
can be used to diagnose disease relapse in TRISST’.
Page 22: ‘one-two’ changed to ‘1-2’ for consistency.
Page 24: title changed from ‘Management of relapsed patients’ to ‘Recommended
management of relapsed patients’, to make clear these procedures not mandated; text
added ‘…for a minimum of 6 years post-randomisation’ for clarification; in section
‘Radiotherapy treatment’ text added for clarification ‘…carboplatin treatment’.
Page 25: due to conflict with section 6.6, existing text replaced with reference to that
section for details of post-relapse follow-up.
Page 26:
- ‘…entry into the TE3 study…’ replaced by ‘…appropriate National or International
studies…’
- in final sentence of 6.5, ‘…on the follow up forms’ removed, replaced by ‘Please
refer to section 7.3, Complete withdrawal from trial, for details’.
- Title of 6.6 changed from ‘Trial follow-up…’ to just ‘Follow-up…’ as all protocol
procedures are trial procedures.
- Text added for clarification: ‘…for the same total duration as relapse-free patients,
i.e. for a minimum of 6 years post-randomisation.’
- Text added for clarification: ‘Both of these should be completed and returned to
MRC CTU at least annually from the date of relapse.’
Page 27:
42
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
- Section 7.1, text added ‘If any patient is considering moving centre, please contact
MRC CTU to discuss possible centre transfers.’
- Section 7.2, ‘protocol-mandated follow up’ replaced with ‘post-randomisation followup’ for clarity; also ‘…and follow-up visits…’ added.
- Section 7.3, text added ‘In all cases…sites should contact MRC CTU to discuss
available options.’
- Section 7.3, text added ‘…withdrawal should be documented on the Withdrawal File
Note and returned to…’, to replace existing instruction to contact CTU ‘in writing’.
Page 30: secondary outcome added, ‘Second primary malignancies’; symbol added to
confirm that ‘…for this latter comparison, 630 patients provide ≥ 80% power…’
Page 31: sentence added for clarity in line with MRC CTU standard operating procedures,
‘No formal statistical stopping rules will be used in TRISST.’
Page 31: text added in section 8.5 to confirm plan to conduct an intention-to-treat analysis,
and to explore the impact of non-adherence to scheduled scans using sensitivity analyses.
Page 32: text added to confirm that imputation techniques will not be used for missing data
in the analyses.
Page 32: text added to describe the development and maintenance of the statistical
analysis plan.
Page 35: section 11 text updated to confirm compliance to Declaration of Helsinki, DPA and
NHS Research Governance Framework; reference to ‘MRC GCP’ removed. Sentence added
to confirm compliance with MRC CTU Standard Operating Procedures.
Page 35: Section 12 ‘Insurance’, formerly ‘Indemnity’ – various changes made to confirm
insurance arrangements following MRC CTU becoming an ‘MRC university unit’ within
University College London.
Page 35: ‘Euroqol’ removed as unnecessary; text added to clarify regarding timepoints,
‘…when a scheduled scan may be due, as well as annually following relapse…’
Page 36: in final sentence of final paragraph in section 13.2, text removed as no longer
relevant, ‘…particularly other countries recruiting patients into the trial’; in section 13.3 first
sentence changed to, ‘We have asked all patients for permission to collect…’ to reflect that
the permission has already been sought.
Page 37: text changed from ‘It is possible to claim £15…’ to ‘It will be…’; text added for
clarity: ‘…for whom scans have been sent…’.
Page 37: changes of tense in sections 15.1, 15.2 and 15.3 to reflect that these committees
are in place already; text added for each section to confirm that full details of membership
and responsibilities can be found in each committee’s respective charter.
17.2 Version 3.0 (March 2010)
Page 1 - Change from version 2.0, December 2008, to version 3.0, 9th March 2010.
TRISST protocol v4.0 19-May-2015.docx
43
MRC TE24 (TRISST)
Page 3 – Added ‘Dr’ to Fay Cafferty’s name
- Updated new data manager details
Page 13 -Section 4.1 Patient inclusion criteria
Change to allow patients without pre-orchidectomy AFP data to be randomised, provided
that post-orchidectomy markers are normal (bullet 4).
Change to indicate that, in exceptional circumstances, a patient with an interval of 8-10
weeks between orchidectomy and randomisation may be allowed to enter the study
following discussion with the trial team (bullet 8).
Page 13 -Section 4.2 Patient exclusion criteria
Addition of spermatocytic seminoma (bullet 4).
Page 15/16 -Section 6.2 Procedures for assessing safety
Clarification that there will be no formal toxicity assessments, however if there are any
toxicities these are to be recorded only on the Relapse Treatment Form
Clarification that SAEs should be reported to the MRC CTU within 24 hours of the
investigator becoming aware of the event.
Page 18 – Section 6.3.2. CT protocol for surveillance
Treatment procedures for patients who are allergic to iv contrast media
Page 22 – Section on 6.4.1. Limited stage disease
Addition of a sentence to state that toxicity data to be collected on the Relapse Treatment
Form.
17.3 Version 2.0 (December 2008)
Page 1 - Change from version 1.0, October 2007 to version 2.0 December 2008
Page 3 - Trial Administration
Updated contact details - new trial statistician, trial manager, data manager, and medical
physics expert
Page 8 - 1.2 Flow diagram
Updated flow diagram to include ‘retroperitoneum’ in each of the 4 trial arm imaging
schedules
Page 9 – Section 2.1 General Background
The incidence of testicular germ cell tumours was added
Page 12 – Section 3.0 Selection of Centres/Clinicians
The following sentence was removed: ‘Other radiologists who report cross-sectional
imaging for this study should be listed as investigators’
Page 13 -Section 4.1 Patient inclusion criteria
Specified the inclusion of synchronous bilateral seminomas
44
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
Changed the inclusion criteria concerning the interval between orchidectomy and
randomisation, such that “should not exceed 8 weeks” has been changed to “should
normally be within 8 weeks of each other”
Page 13 – Section 4.2
Clarified the criteria for exclusion of stage 1 contralateral testis cancer, such that the first
exclusion criteria now reads “Co-existent or previously treated malignancy within 10 years
other than successfully treated non-melanoma skin cancer, or RMH stage I germ cell
tumour of the contralateral testis diagnosed more than 5 years earlier.”
Page 13 – Section 4.3 Screening procedures and pre-randomisation investigations
Specified that the assay of serum AFP, β-HCG and LDH should normally be within 4 weeks
of randomisation
Changed the instruction on the CT scan of the chest and retroperitoneum and pelvis to say
this should “normally” be performed no more than 4 weeks before randomisation.
Added an instruction to contact the trial manager before randomising if test results
described in the selection criteria section fall outside the specified normal limits and
acceptable ranges.
Page 15 - Section 6.0 Patient Management
Added instructions on follow-up for patients relapsing before the end of the 6 year period.
Section 16 – 6.3.1 General Information
The following bullet points were added:
 After randomisation, scanning will be of the RETROPERITONEUM ONLY unless there
is a past history of ipsilateral inguino-scrotal surgery, in which case the pelvis should
also be imaged.

Imaging will be either by CT or MRI according to randomised allocation
Page 17 –Section 6.3.1 General Information
Added advice on filling out the individualised scanning schedule for compliance monitoring.
A paragraph added on how to deal with ‘Unscheduled Scans’
Page 17- Section 6.3.2 CT protocol for surveillance
A sentence on protocol scans should be of the retroperitonuem only (unless otherwise
indicated) was added.
Page 18 - Section 6.3.3 MRI protocol for surveillance
A sentence on protocol scans should be of the retroperitonuem only (unless otherwise
indicated) was added.
Page 18 - Section 6.3.5 Definition of relapse on tumour markers alone
Added the following text (in bold) in Bullet point 3: If no new primary tumour is identified
in the testis and tumour markers remain elevated at > 2x upper limit of normal then CT or
MRI imaging of the retroperitoneum depending on trial arm should be repeated after
6 weeks to include the pelvis, with consideration given to CT or MRI of the brain.
Page 20 – 6.3.6 Further imaging after confirmed relapse
Deleted ‘abdominal’ and replaced with ‘retroperitoneal’ from bullet point 2
TRISST protocol v4.0 19-May-2015.docx
45
MRC TE24 (TRISST)
Page 20 - 6.3.6 Further imaging after confirmed relapse
Patients on MRI-based surveillance
The following was deleted from bullet point 3: “An event notification will be sent to the
CTU” and replaced with “This will be recorded on the ‘Equivocal scan investigation form’ in
the CRF folder”
Page 20- 6.3.7 Scan review
A new section has been added to describe what scans are required when a patient
relapses.
Page 22 – Follow-up of patients who have relapsed
New instructions added regarding follow-up after relapse
Page 29 – Section 13.1 Health economics study
The following sentence was changed from:
Utilization data covering levels of service receipt will be collected via a self report
questionnaire developed specifically for the study.
To:
Utilization data covering levels of service receipt will be collected via the follow up form in
the CRF folder and via a questionnaire developed specifically for the study from the patient
Page 31- Section 14.0 Finance
The following has been added:
It is possible to claim £15 per relapsed patient to cover costs of administration, postage
and packaging for the scan review. If you should wish to do this on behalf of your centre,
please prepare an invoice detailing the items and patient trial numbers and send this to the
TRISST Trial Manager.
Page 31- Section 15.0:
MRC Testis IDMC confirmed as TRISST IDMC
Page 40 – Appendix 2: Criteria for classification of Stage I Disease
Table 1: Deleted retroperitoneum with abdomen
Patient Information Sheet
Change from version 1.0, 24th October 2007 to version 2.0 5th December 2008
46
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
18. REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
CRC, Testicular Cancer Factsheet 16.1.98. 1998.
Cancer Research UK, Cancer Stats - Testicular Cancer. 2002.
Joffe, J.K., Risks and benefits of follow-up of early germ cell tumours - a survey of
current practice, in Germ cell tumours V, W.G. Jones, P. Harnden, and J.K. Joffe,
Editors. 2002, John Libbey: London.
Rustin, G.J., et al., Randomized trial of two or five computed tomography scans in
the surveillance of patients with stage I nonseminomatous germ cell tumors of the
testis: Medical Research Council Trial TE08, ISRCTN56475197--the National Cancer
Research Institute Testis Cancer Clinical Studies Group. J Clin Oncol, 2007. 25(11):
p. 1310-5.
Warde, P., et al., Prognostic factors for relapse in stage I seminoma managed by
surveillance: a pooled analysis. J Clin Oncol, 2002. 20(22): p. 4448-52.
Aparicio, J., et al., Multicenter study evaluating a dual policy of postorchiectomy
surveillance and selective adjuvant single-agent carboplatin for patients with clinical
stage I seminoma. Ann Oncol, 2003. 14(6): p. 867-72.
Aparicio, J., et al., Risk-adapted management for patients with clinical stage I
seminoma: the Second Spanish Germ Cell Cancer Cooperative Group study. J Clin
Oncol, 2005. 23(34): p. 8717-23.
Berrington de Gonzalez, A. and S. Darby, Risk of cancer from diagnostic X-rays:
estimates for the UK and 14 other countries. Lancet, 2004. 363(9406): p. 345-51.
White, P.M., et al., The role of computed tomographic examination of the pelvis in
the management of testicular germ cell tumours. Clin Radiol, 1997. 52(2): p. 124-9.
Grubnic, S., et al., MR evaluation of normal retroperitoneal and pelvic lymph nodes.
Clin Radiol, 2002. 57(3): p. 193-200; discussion 201-4.
Huddart, R.A. and J.K. Joffe, Preferred treatment for stage I seminoma: a survey of
Canadian radiation oncologists. Clin Oncol (R Coll Radiol), 2006. 18(9): p. 693-5.
Arranz Arija, J.A., et al., E400P in advanced seminoma of good prognosis according
to the international germ cell cancer collaborative group (IGCCCG) classification: the
Spanish Germ Cell Cancer Group experience. Ann Oncol, 2001. 12(4): p. 487-91.
Patterson, H., et al., Combination carboplatin and radiotherapy in the management
of stage II testicular seminoma: comparison with radiotherapy treatment alone.
Radiother Oncol, 2001. 59(1): p. 5-11.
Mitchell, G. and R. Huddart, 5HT3 antagonists and radiotherapy. Ann Oncol, 1997.
8(3): p. 302.
International Germ Cell Consensus Classification: a prognostic factor-based staging
system for metastatic germ cell cancers. International Germ Cell Cancer
Collaborative Group. J Clin Oncol, 1997. 15(2): p. 594-603.
Oliver, R.T., et al., Radiotherapy versus single-dose carboplatin in adjuvant
treatment of stage I seminoma: a randomised trial. Lancet, 2005. 366(9482): p.
293-300.
Horwich, A., Testicular cancer : investigation and management. 1996, London:
Chapman & Hall Medical.
Brooks, R., EuroQol: the current state of play. Health Policy, 1995. 37: p. 53-72.
Kind, P., The EuroQoL instrument: an index of health-related quality of life, in
Quality of life and pharmacoeconomics in clinical trials , B. Spilker, Editor. 1996,
Lippincott-Raven: Philadelphia. p. 191-201.
Klarman, H., J. Francis, and G. Rosenthal, Cost-effectiveness analysis applied to the
treatment of chronic renal disease. Medical Care, 1968. 6: p. 49-54.
TRISST protocol v4.0 19-May-2015.docx
47
MRC TE24 (TRISST)
21.
22.
23.
24.
25.
48
Hoch, J.S., A.H. Briggs, and A.R. Willan, Something old, something new, something
borrowed, something blue: a framework for the marriage of health econometrics
and cost-effectiveness analysis. Health Econ, 2002. 11(5): p. 415-30.
Manca, A., et al., Assessing generalisability by location in trial-based costeffectiveness analysis: the use of multilevel models. Journal of Health Economics,
2004.
Briggs, A.H., K. Claxton, and M.J. Sculpher, Decision modelling for health economic
evaluation. Handbooks in health economic evaluation series. 2006, Oxford: Oxford
University Press.
Carrington, B.M., Lymph node metastases, in Imaging in Oncology, J.E. Husband
and R.H. Reznek, Editors. 2004, Taylor & Francis: London.
Huddart, R.A., et al., 18fluorodeoxyglucose positron emission tomography in the
prediction of relapse in patients with high-risk, clinical stage I nonseminomatous
germ cell tumors: preliminary report of MRC Trial TE22--the NCRI Testis Tumour
Clinical Study Group. J Clin Oncol, 2007. 25(21): p. 3090-5.
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
APPENDICES
APPENDIX 1: HEALTH ECONOMICS: EQ-5D .................................................................. 50
APPENDIX 2: CRITERIA FOR CLASSIFICATION OF STAGE I DISEASE [24, 25] ................. 51
APPENDIX 3: ROYAL MARSDEN HOSPITAL STAGING SYSTEM - TESTICULAR TUMOURS .. 53
TRISST protocol v4.0 19-May-2015.docx
49
MRC TE24 (TRISST)
APPENDIX 1: HEALTH ECONOMICS: EQ-5D
By placing a tick in one box in each group below, please indicate which
statements best describe your own health state today.
Mobility
I have no problems in walking about
I have some problems in walking about
I am confined to bed



Self-Care
I have no problems with self-care
I have some problems washing or dressing myself
I am unable to wash or dress myself



Usual Activities (e.g. work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities
I have some problems with performing my usual activities
I am unable to perform my usual activities



Pain/Discomfort
I have no pain or discomfort
I have moderate pain or discomfort
I have extreme pain or discomfort



Anxiety/Depression
I am not anxious or depressed
I am moderately anxious or depressed
I am extremely anxious or depressed
50
TRISST protocol v4.0 19-May-2015.docx



MRC TE24 (TRISST)
APPENDIX 2: CRITERIA FOR CLASSIFICATION OF
STAGE I DISEASE [24, 25]
Patients will be judged as having clinical stage I disease in the absence of definitive evidence
of disease using standard CT criteria as defined below. In areas of uncertainty patients can be
scored as having equivocal lesions as defined below but are eligible for entry into this
protocol.
Patients will be considered to have metastatic disease if:
1) There are pelvic, abdominal or mediastinal lymph nodes above the upper limit of the
normal range as given below. Nodes above the normal limit in axilla and neck, in the
absence of abnormal lymph nodes elsewhere will be considered equivocal unless specific
evidence of malignant involvement.
Table 1, Lymph node size at various anatomic sites: short axis diameter, upper
limits of normal
Site
Group
Head & Neck
Facial
Cervical
Axilla
Mediastinum
Any
Subcarinal
Paracardiac
Retrocural
All other sites
Gastrohepatic ligament
Porta hepatis
Portacaval
Coeliac axis to renal artery
Renal artery to aortic
bifurcation
Common iliac
External iliac
Internal iliac
Obturator
abdomen
Pelvis
Short axis size
(mm)
Not visible
10 (<10mm with
central necrosis)
10
12
8
6
10
8
8
10
10
12
9
10
7
8
2) The following categories of pulmonary nodules (defined as soft tissue or ground glass
opacity of rounded shape.) will be defined as malignant:
a) Solitary lesion ≥ 10mm, unless (i) there are features suggestive of a benign cause
(lesions showing central, rim, uniform or other benign distribution of calcification; fat
attenuation within the nodule, clear linear or linear branching densities). If these
features are present they should be classified as equivocal, or (ii) known to be stable
size for at least 12 months (for CT, defined as within measurement error of up to
~20%).
b) Single nodules of 4-10 mm diameter with documented increase in size
c) Multiple (3 or more lesions) > 4mm
TRISST protocol v4.0 19-May-2015.docx
51
MRC TE24 (TRISST)
d) The following pulmonary nodules will be considered equivocal:

Nodules of 4-10 mm diameter (unless multiple) whose growth rate is, as yet,
undetermined which do not have benign features as described above will be
classified as equivocal.

Larger nodules with benign features
Micronodules ie:  4 mm diameter, will be classified as benign but
should be documented for purposes of future comparison.
3) Liver lesions:
In the absence of metastases elsewhere liver metastases are considered to be
rare. All such lesions should be considered equivocal and should undergo further
evaluation by ultrasound and/or MRI/ and/or biopsy. If after further evaluation
the appearances are considered to be due to haemangioma or cysts or other
benign pathology patients will be considered benign and may enter the trial.
Patients with multiple or single solid liver lesions >1 cm diameter in whom metastasis cannot
be excluded should be considered malignant and not included in this study.
Solid lesions <1cm are considered equivocal (unless specific evidence of metastasis is
present) and may enter into the trial.
4) Lesions at other sites are considered rare and should be evaluated by standard radiological
criteria.
52
TRISST protocol v4.0 19-May-2015.docx
MRC TE24 (TRISST)
APPENDIX 3: ROYAL MARSDEN HOSPITAL
STAGING SYSTEM - TESTICULAR TUMOURS
I
No evidence of metastases
II
Para-aortic node metastases
III
Supradiaphragmatic and infradiaphragmatic lymph node involvement
A - metastases < 2 cm in diameter
B - metastases 2 - 5 cm in diameter
C - metastases > 5 cm in diameter
Abdominal status A, B, C as above.
IV
Extra-lymphatic metastases
Abdominal status A, B, C as above
Lung status
L1
L2
L3
 3 metastases
multiple, none > 2cm diameter
multiple at least one > 2cm diameter
Liver status
H+
liver involvement
TRISST protocol v4.0 19-May-2015.docx
53