TRISST. Protocol version 4.0 TRIAL OF IMAGING AND SCHEDULE IN SEMINOMA TESTIS MRC TE24 ISRCTN MREC: 07/H1306/127 NCT

Transcription

1 TRISST TRIAL OF IMAGING AND SCHEDULE IN SEMINOMA TESTIS Developed with the NCRI Testis Clinical Studies Group Part of the National Cancer Research Network Portfolio MRC TE24 ISRCTN MREC: 07/H1306/127 NCT Protocol version May 2015 Funded by Cancer Research UK Authorised by: Name Prof Johnathan Joffe Signature Role Chief Investigator Date 19 May 2015 Name Dr Fay Cafferty Signature Role Project Lead Date 19 May 2015 TRISST protocol v May-2015.docx 1

2 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. Z ) 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 v May-2015.docx

3 TRIAL ADMINISTRATION Chief Investigator Dr Johnathan Joffe Greenlea Oncology Unit Huddersfield Royal Infirmary Lindley Huddersfield West Yorkshire, HD3 3EA T: F: E: Co-Investigator Dr Robert Huddart Oncology & Radiotherapy Royal Marsden Hospital Downs Road Sutton Surrey, SM2 5PT T: F: E: Co-Investigator Dr Michael Williams Imaging Directorate Derriford Hospital X-ray East, Level 6 Plymouth Devon, PL6 8DH T: E: mike.williams5@nhs.net Medical Physics Expert Dr Nick Rowles Derriford Hospital, Plymouth T: E: Nick.Rowles@phnt.swest.nhs.uk Project Lead and senior trial statistician Clinical Project Manager Dr Fay Cafferty MRC CTU T: E: f.cafferty@ucl.ac.uk Anna Bara MRC CTU T: E: a.bara@ucl.ac.uk Trial Manager William Cragg MRC CTU T: E: w.cragg@ucl.ac.uk Statistician Liz Wedd MRC CTU T: E: e.wedd@ucl.ac.uk Data Manager Brendan Murphy MRC CTU T: E: b.murphy@ucl.ac.uk Trial Coordination: MRC CTU Institute of Clinical Trials and Methodology, Aviation House 125 Kingsway London, WC2B 6NH mrcctu.trisst@ucl.ac.uk Fax: Website: TRISST protocol v May-2015.docx 3

4 CONTENTS 1. Summary Abstract and summary of the trial design Flow diagram Translational Study Background General overview Surveillance in stage I seminoma Rationale for TRISST Management of surveillance relapses Selection of Centres/Clinicians Selection of Patients Patient inclusion criteria Patient exclusion criteria Screening procedures and pre-randomisation investigations Randomisation & Enrolment procedure Patient Management Surveillance schedule Procedures for assessing safety Cross-sectional imaging schedules Recommended management of relapsed patients Stopping trial intervention Follow-up of patients who have relapsed Cessation of Follow-up Loss to follow-up Trial closure Complete withdrawal from the trial Statistical Considerations Method of randomisation Outcome measures Sample size Interim monitoring and analyses Analysis plan (brief) Trial Monitoring Risk assessment Monitoring at MRC CTU Clinical site monitoring Ethical Considerations and Approval Ethical considerations Ethical approval Regulatory Issues Insurance Ancillary Studies TRISST protocol v May-2015.docx

5 13.1 Health economics study Economic analysis Translational research Finance Trial Committees Trial Management Group (TMG) Trial Steering Committee (TSC) Independent Data Monitoring Committee (IDMC) Publication Protocol Amendments Version 4.0 (May 2015) Version 3.0 (March 2010) Version 2.0 (December 2008) References Appendices APPENDICES APPENDIX 1: HEALTH ECONOMICS: EQ-5D APPENDIX 2: CRITERIA FOR CLASSIFICATION OF STAGE I DISEASE [24, 25] APPENDIX 3: ROYAL MARSDEN HOSPITAL STAGING SYSTEM - TESTICULAR TUMOURS.. 53 TRISST protocol v May-2015.docx 5

6 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 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 ( 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 6 TRISST protocol v May-2015.docx

7 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 v May-2015.docx 7

8 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 6- monthly 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 31 st 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 v May-2015.docx

9 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.): 1.3 Translational Study Year Frequency 1 3 monthly 2 3 monthly 3 4 monthly 4 6 monthly 5 6 monthly 6 6 monthly 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 v May-2015.docx 9

10 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 50-60% 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 v May-2015.docx

11 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 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 v May-2015.docx 11

12 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/m 2 followed by dog-leg radiotherapy to a dose of 12 TRISST protocol v May-2015.docx

13 35Gy in 17-18f commencing 4 weeks later. 33 patients were treated in this fashion (30 by 1 cycle carboplatin) between 1989 and A 5 year disease-free survival (DFS) of 96.9% compared to a DFS of 80.7% in historically and concurrently treated patients ( ). 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 v May-2015.docx 13

14 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 v May-2015.docx

15 4. SELECTION OF PATIENTS 4.1 Patient inclusion criteria a 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. 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 v May-2015.docx 15

16 5. RANDOMISATION & ENROLMENT PROCEDURE The TRISST trial closed to randomisation on 31 July 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 v May-2015.docx

17 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 Chest X-ray Tumour markers (AFP, ß-HCG, LDH) Clinical assessment Pre-randomisation 0 0 R A N D O M I S A T I O N 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 v May-2015.docx 17

18 6.2 Procedures for assessing safety 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) 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 v May-2015.docx

19 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 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 v May-2015.docx 19

20 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 v May-2015.docx

21 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 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 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 v May-2015.docx 21

22 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 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 2 nd 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 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 v May-2015.docx

23 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 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 v May-2015.docx 23

24 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 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 v May-2015.docx

25 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 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 v May-2015.docx 25

26 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 v May-2015.docx

27 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 v May-2015.docx 27

28 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 v May-2015.docx

29 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 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 and 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 v May-2015.docx 29