BMJ Open · For peer review only 21459857_File000009_484491841.doc Page 2 of 11 Abstract...

For peer review only

Protocol for PIT: A Phase III Trial of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural

Mesothelioma Following Invasive Chest Wall Intervention.

Journal: BMJ Open

Manuscript ID bmjopen-2015-010589

Article Type: Protocol

Date Submitted by the Author: 17-Nov-2015

Complete List of Authors: Bayman, Neil; The Christie NHS Foundation Trust, Clinical Oncology Ardron, David; The National Cancer Research Institute (NCRI), Consumer Liaison Group

Ashcroft, Linda; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU) Baldwin, David; Nottingham University Hospitals NHS Trust, Respiratory Medicine Unit Booton, Richard; The University of Manchester, Respiratory and Allergy Research Group Darlison, Liz; University Hospitals of Leicester NHS Trust , Department of Respiratory Medicine; Mesothelioma UK Charitable Trust, c/o Glenfield Hospital Edwards, John; Sheffield Teaching Hospitals NHS Foundation Trust UK, Department of Cardiothoracic Surgery Lang-Lazdunski, Loic; The Lister Hospital, Department of Thoracic Surgery

Lester, Jason; Velindre NHS Trust UK, Department of Clinical Oncology Peake, Michael; Glenfield Hospital, Department of Respiratory Medicine Rintoul, Robert; Papworth Hospital NHS Foundation Trust, Department of Thoracic Oncology Snee, Michael; Leeds Teaching Hospitals NHS Trust, Department of Clinical Oncology Taylor, Paul; The Christie NHS Foundation Trust, Department of Medical Oncology Lunt, Colin; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU) Faivre-Finn, Corinne; The Christie NHS Foundation Trust, Radiotherapy

Related Research; University of Manchester, Manchester Academic Health Science Centre, Institute of Cancer Sciences

<b>Primary Subject Heading</b>:

Oncology

Secondary Subject Heading: Radiology and imaging, Respiratory medicine, Evidence based practice

Keywords: Respiratory tract tumours < ONCOLOGY, Radiation oncology < RADIOLOGY & IMAGING, Clinical trials < THERAPEUTICS

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Protocol for PIT: A Phase III Trial of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural Mesothelioma Following Invasive Chest Wall Intervention. N. Bayman

1, D. Ardron

2, L. Ashcroft

3, D.R. Baldwin

4, R. Booton

5, L. Darlison

6,10, J.G.

Edwards7, L. Lang-Lazdunski

8, J.F. Lester

9, M. Peake

10,11, R.C. Rintoul

12, M. Snee

13, P.

Taylor14,15

, C. Lunt3 C. Faivre-Finn

16,17.

Correspondence to: Dr Neil Bayman; [email protected] 0161 446 3337 1Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX UK,

2The National Cancer Research Institute (NCRI) Consumer Liaison Group, London UK,

3Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU), The Christie NHS

Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK 4Respiratory Medicine Unit, David Evans Research Centre, , Nottingham University Hospitals NHS Trust, Nottingham

City Hospital Campus, , Nottingham, NG5 1PB, UK, 5 Respiratory and Allergy Research Group, Institute of Inflammation & Repair, The University of Manchester North

West Lung Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK 6Mesothelioma UK Charitable Trust, c/o Glenfield Hospital, Leicester, LE3 9QP, UK

7Department of Cardiothoracic Surgery, Chesterman Unit, Northern General Hospital, Sheffield Teaching Hospitals

NHS Foundation Trust UK, Herries Rd, Sheffield, S5 7AU, UK 8Department of Thoracic Surgery, The Lister Hospital, Chelsea Bridge Road, London SW1W 8RH

9Department of Clinical Oncology, Velindre NHS Trust UK, Velindre Rd, Cardiff, South Glamorgan CF14 2TL, UK

10Department of Respiratory Medicine, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, LE3

9QP, UK 11

National Cancer Intelligence Network, (NCIN), Public Health England, 2nd

Floor, Skipton House, 80 London Road, London, SE1 6LH 12

Department of Thoracic Oncology, Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK, 13

Department of Clinical Oncology, Leeds Teaching Hospital NHS Trust, St James Hospital, Leeds, LS9 7TF UK, 14

Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK 15

Department Pulmonary Oncology, Wythenshawe Hospital Manchester M23 9LT 16

The University of Manchester, Manchester Academic Health Science Centre, Institute of Cancer Sciences, Manchester Cancer Research Centre (MCRC), Wilmslow Road, Manchester, M20 4BX 17

Radiotherapy Related Research, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK

Author’s contributions CFF and NB conceived of the study. CFF, NB, DA, LA, DRB, RB, LD, JGE, LLL, JFL, MP, RCR, MS, PT, initiated the study design and helped with implementation. CFF is the grant holder. LA provided statistical expertise in clinical trial. All authors contributed to refinement of the study protocol and approved the final manuscript. Keywords: mesothelioma, prophylactic radiotherapy, chemotherapy, phase III, tracts Word Count: 3,405 (excluding title page, abstract, references, figures and tables)

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Abstract

Introduction

Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT

guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or

thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention

site and patients can develop tumour nodules within the chest wall. In an effort to prevent

nodules developing, it has been widespread practice across Europe to irradiate intervention

sites post-procedure – a practice known as prophylactic irradiation of tracts (PIT). To date

there has not been a suitably powered randomised trial to determine whether PIT is effective

at reducing the risk of chest wall nodule development.

Methods and Analysis

In this multicentre phase III randomised controlled superiority trial, 374 patients who can

receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive

PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will

be 21 Gy in 3 fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A

reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6

months after randomisation would be clinically significant. All patients will be followed up for

up to 2 years with monthly telephone contact and at least 4 outpatient visits in the first year.

Ethics and dissemination

PIT was approved by NRES Committee North West - Greater Manchester West (REC

reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to

be randomised by the end of 2015. The analysis of the primary endpoint, incidence of chest

wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer

reviewed journal and results will also be presented at scientific meetings and summary results

published online. A follow-up analysis is expected to be published in 2018.

Trial identifiers: ISRCTN: 04240319; Clinical Trials.gov: NCT01604005

Summary of strengths and limitations of study

Strengths:

• Largest, adequately powered randomised controlled study of prophylactic

radiotherapy in this population

• Radiotherapy fields reflect current practice for thoracoscopy and drain insertion

• Monthly telephone follow-up to supplement out-patient follow-upClinical significance

of chest wall metastases measured with VAS pain score

Limitations:

• Will not determine role of prophylactic radiotherapy at the site of an indwelling pleural catheter

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Introduction Malignant pleural mesothelioma (MPM) is almost exclusively linked to asbestos exposure with a latency period that is usually more than 30 years and prognosis is poor.

1-4 The median

survival in the UK is 8.8 months and the 1 year survival 38.5%.5

Diagnosis of mesothelioma is usually made by pleural biopsy either via computerised tomography (CT) guided needle biopsy, thoracoscopy, video assisted thoracic surgery (VATs), or thoracotomy. Patients often have associated pleural effusions and require chest drains to relieve symptoms such as chest pain and difficulty breathing. These invasive procedures encourage tumour cell seeding at the site of the intervention, which can result in formation of a subcutaneous tumour. The rate of chest wall metastases ranges from 2-50%, and depends on the procedure performed.

4, 6-14 In an effort to minimise tumour seeding and prevent nodule development, it has been widespread practice for more than 20 years in the UK to irradiate intervention sites post-procedure – a practice known as prophylactic irradiation of tracts (PIT). Only three randomised controlled trials, the largest with 61 patients, have assessed the role of PIT with conflicting results reported.

14-19 One study reported a statistically significant reduction

in the frequency of malignant seeding of tracts in the PIT arm compared to the control arm14

; the other two studies did not

15, 16. Systematic reviews of the literature have concluded that the

randomised trials conducted to date were considered the best available evidence for PIT, but that there was insufficient evidence to definitively recommend PIT.

17-20 Inconsistencies are

also evident in current national recommendations on the use of PIT. The British Thoracic Society

21 recommends the use of PIT to prevent chest wall nodule formation following an

interventional procedure. In contrast, the Cancer Care Ontario Program22

stated that a recommendation for PIT in MPM could not be made due to inconsistent evidence, reflecting a lack of high quality data. Similarly, in 2010 the European Respiratory Society stated “The value of prophylactic radiotherapy is questionable”

23 and the European Society of Medical

Oncology (ESMO) clinical recommendations for diagnosis, treatment and follow-up of MPM state that “it remains impossible to draw definitive conclusions regarding its efficacy”

24.

Currently in the UK the routine use of PIT in patients with MPM depends on locality. A 2008 UK survey showed that 75% of radiotherapy centres are routinely using PIT.

17 In addition, the

small number of patients recruited to each arm, the high death rates, and overestimation of the rate of chest wall metastasis in the control arms, question whether the three previous randomised controlled trials were adequately powered. Furthermore, recent evidence shows that portal tracts are not always perpendicular to the skin

25 and thus the small radiation fields

centred on the chest wall scar employed by the previous negative studies may have been suboptimal. There is now strong evidence to support the role of palliative chemotherapy in patients with MPM

26 which is approved in the UK by the National Institute of Clinical Excellence (NICE)

27.

Importantly, the previous studies were conducted before palliative chemotherapy was widely used in MPM. Therefore, the role of PIT in the era of effective palliative chemotherapy remains undefined. In addition, no previous studies have used validated pain scoring tools to assess pain from tract metastases. We believe a trial is essential for the following reasons: firstly an adequately powered RCT employing radiotherapy techniques ensuring adequate coverage of the entire portal tract will establish whether PIT should be offered routinely to MPM patients after chest wall intervention in the era of palliative chemotherapy; secondly to establish whether chest wall metastases are symptomatic and thus, whether PIT, if effective, is clinically significant

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Methods and Analysis Trial Design This is a 2-arm, phase III multi-centre randomised superiority trial comparing radiotherapy vs. no radiotherapy in patients with a histological diagnosis of Malignant Pleural Mesothelioma following chest wall intervention (see Figure 1). 374 patients will be randomised on a 1:1 basis to receive PIT or no PIT. Patients can receive chemotherapy post radiotherapy/randomisation at the discretion of the treating physician. The follow-up period for the study is up to 2 years post randomisation which includes regular telephone follow-up and a minimum of 4 outpatient visits in the first year. Figure 1 – Trial Schema / Flowchart Patient Selection Potential participants will be identified by the principal investigator and his/her team at each centre, via the discussion of cases in a multidisciplinary team meeting (MDT). If a patient is identified as a potential participant in the PIT trial they will be approached at their next clinic visit, as part of discussions with the patient about their options for treatment. Patients who are interested in receiving further information about the trial will be given a copy of the patient information sheet and consent form, and will have the opportunity to discuss the trial in detail before deciding whether to participate.

Inclusion criteria

• Either sex, age ≥ 18 years. • Diagnosis of mesothelioma by multi-disciplinary team (MDT) • All histological subtypes. Where the histological diagnosis is unclear, a specialist thoracic

pathologist should be consulted. • ECOG performance status 0-2. • Inoperable disease or operable disease in patients unsuitable for surgery as decided by a

MDT. • Chest wall intervention with video-assisted thoracoscopy (VATS), open surgical biopsy,

local anaesthetic thoracoscopy or chest drain. • Able to start radiotherapy within 42 days (6 weeks) from most recent chest wall

intervention. • Chest wall intervention scar visible at time of randomisation. • No indwelling pleural catheters in-situ at the intervention site • Radiotherapy target volume acceptable by the local radiotherapist. • No previous open thoracotomy. • No previous radiotherapy to the region of the chest wall intervention site. • Not currently receiving chemotherapy and not received chemotherapy for mesothelioma

before randomisation • No other previous or concomitant illness or treatment which in the opinion of the clinician

will interfere with the trial treatments or comparisons. • Patients enrolled on other clinical trials could be considered after discussion with the chief

investigators. • Female patients must satisfy the investigator that they are not pregnant, or are not of

childbearing potential, or are using adequate contraception. • Patients must not be breastfeeding • Absence of any psychological, familial, sociological or geographical condition potentially

hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before randomisation in the trial

• Patients can only be randomised in this trial once.

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Exclusion criteria • Patients who underwent a thoracotomy (as large thoracotomy scars may not be

adequately covered by this radiotherapy technique) • Previous radiotherapy to the region of the chest wall intervention site • Indwelling pleural catheter in-situ at the intervention site • Patients currently receiving chemotherapy Consent All patients will be informed of the aims of the trial, the procedures and possible adverse effects, and the mechanism of treatment allocation. Patients will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorised individuals other than their treating physician. It will be emphasized that the participation is voluntary and that the patient is allowed to decline further participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. Documented informed consent will be obtained for all patients included in the trial before they are registered or randomised in the trial in accordance with the national and local regulatory requirements. Randomisation Procedure Patients will be randomised by phone or fax on a 1:1 basis to one of two treatment arms. A variant of an adaptive biased coin randomisation method will be used to favour balance between treatment arms in the four strata formed from the following two factors:

• histology (epithelIoid or not)

• Intention to give chemotherapy Randomisation will be undertaken centrally by Manchester Academic Health Science Centre Clinical Trials Unit (MAHSC-CTU). Radiotherapy Patients are treated on a linear accelerator using a single electron field. Treatment fields can be shaped using individualised lead cut-outs of the appropriate thickness. The total dose of radiotherapy in the PIT arm is 21 Gy in 3 fractions, once daily over 3 consecutive days. The patient can be treated supine, prone, or in the lateral position depending on the position of the chest wall intervention site. To ensure > 90 percent of the prescribed dose is delivered to the skin surface, 0.5 cm tissue-equivalent bolus can be applied to the whole treatment field. The field position for radiotherapy is recorded so that if the patient develops chest wall nodules it can be determined if the nodules are inside or outside the treatment field. The Clinical Target Volume (CTV) comprises the visible and palpable scar with a 1 cm margin of clinically normal tissue in the lateral, medial and inferior directions at the skin surface. The Planning Target Volume (PTV) comprises the CTV with a 1 cm margin in all directions at the skin surface. The CTV to PTV expansion allows for set up errors, changes in the electron beam profile at depth and patient motion. The treatment field is defined by adding a further 1 cm margin in all directions to account for the beam penumbra. The superior margin will vary and should be the determined by counting 3 ribs superiorly. The upper border of the 3rd rib superior to the scar will be the superior border of the treatment field. This will take into account microscopic spread but also ensure that chest wall intervention tracts (which will commonly run over the rib superior to the scar) are covered at depth (see Figure 2). No organs at risk need to be identified and if a patient has two intervention sites, and therefore two scars (e.g. a VATS scar and adjacent chest drain scar) these can be treated within a single treatment field or two separate fields. A gap of > 1cm must separate two treatment fields. Figure 2 - PIT radiotherapy field margins

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Chemotherapy Patients can be treated with palliative chemotherapy at the physician’s discretion after completion of radiotherapy. The efficacy and/or safety of chemotherapy is not being investigated as part of the study. The chemotherapy regimen used should be cisplatin or carboplatin plus pemetrexed, although alternative chemotherapy regimens (including clinical trial agents) may be considered after discussion with the chief investigators. The number of cycles given is left to the physician’s discretion. A gap of at least 1-week must separate the completion of radiotherapy and the start of palliative chemotherapy. The chemotherapy regimen, start and stop dates and total number of cycles administered should be recorded. No further data needs to be collected concerning the patients chemotherapy treatment. Outpatient visits The patient is reviewed in clinic 6, 12, 26 and 52 weeks following randomisation to assess for any signs of chest wall metastasis and to record any treatment related toxicities. In addition, telephone follow-up at 4-weekly intervals following randomisation will determine if the patient has noted any chest wall nodules. If a patient is suspicious that a nodule has appeared, they will be invited to clinic for assessment. If a chest wall metastases is confirmed, the position of the metastases is recorded in relation to the reconstructed radiotherapy treatment field. Patients are asked to complete a Visual Analogue Score (VAS) for pain at baseline, and at each telephone and clinic follow-up. Patients are specifically asked to only consider pain at the original site of chest wall intervention. If the patient develops chest wall nodules they will be asked to complete a VAS for pain at the site of the chest wall intervention at for the 3 nodules closest to the original intervention. Outcome measures The primary end point is the incidence of chest wall tract metastasis 6 months from randomisation. If a patient raises suspicion that a chest wall nodule had developed at telephone follow-up, they will be invited to attend an out-patient appointment with the investigator. If there is clinical evidence of a chest wall metastases, a chest wall metastasis CRF is completed using the clinic date as date of chest wall metastasis. The secondary endpoints are: • Time from randomisation to chest wall tract metastasis (recorded on chest wall

metastasis CRF) • Position of chest wall tract metastasis recurrence in relation to radiotherapy field in

patients randomised to experimental arm (in field/out-of-field, recorded on chest wall metastasis CRF)

• Acute and late skin radiotherapy toxicity (recorded by CTCAE v4.0 at baseline and at each out-patient visit on CRF)

• Pain from chest wall tract metastasis (recorded by Visual Analogue Scale (VAS) pain scores recorded on chest wall metastasis CRF)

Sample size calculation The crude rate of tract metastases following chest wall intervention until death, based on historical data, is expected to be 15%. It is estimated that the majority of events will occur within 6 months of the intervention. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy would be clinically significant. Based on a 2-arm trial with a 5% significance level, 2-sided test, and 80% power this would require 280 patients. Furthermore it is anticipated that 25% of patients will not survive for 6 months therefore an additional 94 patients will be required, making the total number of patients to be enrolled 374.. Analysis Incidence of Chest Wall Tract Metastasis All patients randomised will be analysed on an intention to treat basis. A two-sided chi-squared test of proportions of chest wall tract metastasis at 6 months between the control and experimental arms will be used with a 5% significance level. Secondary analysis using logistic

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regression will be used to investigate treatment after adjusting for significant baseline prognostic variables. Time to Chest Wall Tract Metastasis Kaplan-Meier curves will be drawn for each treatment group. Time to chest wall tract metastasis will be compared using a two-sided log rank test with a 5% level of significance. Cox-proportional hazards models will be used to investigate the effect of treatment after adjusting for stratification factors and other significant baseline variables. Toxicity Skin toxicity will be assessed according to NCI Common Terminology Criteria for Adverse Events v 4.0. The proportions of patients experiencing a grade of 3 or above acute toxicity, including acute radiation morbidity, or late radiation morbidity will be compared between the treatment groups using a two-sided Chi-squared test with a 5% level of significance. Acute toxicity will be defined as toxicities occurring from commencement of treatment to 3 months after completion; late toxicity will be defined as toxicities occurring between 3 months and 2 years after completion of treatment. Position of Chest Wall Tract Metastases Position of the central point of a chest wall tract metastases in relation to the reconstructed radiotherapy treatment field will be recorded as in field/out-of field recurrence. Where the central point falls on the edge of the radiotherapy treatment field this will be recoded as in-field recurrence Pain Scores Patients will be analysed using the intent-to-treat method. All tests will be 2-sided and a p-value of 0.05 or less will be considered statistically significant. In patients who develop tract metastasis, the VAS pain score from the assessment immediately before the occurrence of the tract metastasis will be considered baseline. Descriptive analysis will be performed to summarise change in pain score from baseline to subsequent pain score. Two-sample t-tests will be used to explore difference between treatments. A 20% increase in VAS pain score is considered significant. The proportion of significant increases in pain in both arms will be analysed using a 2-sided chi-squared test. No formal interim analysis is planned.

Ethics and Dissemination Protocol and Protocol amendments The trial details documented here are consistent with PIT study protocol V3.0 (dated: 19

th

April 2012). There have been two substantial amendments for the study.

i) 25/04/2012- addition of an inclusion criterion ‘Indwelling pleural catheter in-situ at the intervention site’ and several administrative updates to the protocol and patient information sheets. The amendment also included the home and outpatient VAS questionnaires.

ii) 17/04/2013- introduction of the VAS chest wall nodule page which the patient is asked to complete if they develop chest wall nodules

Trial Monitoring The trial management group (TMG) is responsible for overseeing the progress of the trial and meets twice a year. The TMG includes patient/carer representatives, respiratory physicians, thoracic surgeons, clinical oncologists, medical oncologists, and clinical nurse specialists. An Independent Data Monitoring Committee (IDMC) will not be appointed for this trial as PIT is currently widely used in clinical practice, it is not a new treatment and we not envisage that any safety issues will arise.

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Role of Study Sponsor The Christie NHS Foundation Trust is sponsoring the study. The Manchester Academic Health Science Centre Clinical Trial Unit is running the study (collection, management, analysis, and interpretation of data). The PIT TMG will write the report and will make the decision to submit the report for publication. Safety Reporting An Adverse Event (AE) is defined on this trial as any untoward medical occurrence in a clinical trial subject which does not necessarily have a causal relationship with the trial related procedures. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease. A Serious Adverse Event (SAE) for this trial is an Adverse Event only if it meets the following criteria.

• results in death (within 90 days of last dose of radiotherapy and is considered related to trial radiotherapy)

• is life-threatening (and is considered related to the trial radiotherapy)

• requires hospitalisation, or prolongation of existing hospitalisation (and is considered related to trial radiotherapy).

• results in persistent or significant disability or incapacity (and is considered related to trial radiotherapy)

• is a congenital anomaly or birth defect

• Other medically significant event. Medical judgement should be exercised in deciding whether an AE is serious in other situations. Important AEs that are not immediately life-threatening or do not result in death or hospitalisation, but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious.

Disease progressions or events related to disease progressions are not considered to be SAEs. Adverse events relating to other anti-cancer treatments that the patient may be receiving are not considered to be SAEs. All Serious Adverse Events (SAEs) are reported by site teams to the MAHSC-CTU within 24 hours of the investigator being made aware of the event. End of the trial The study will close 2 years after the 374

th patient is randomised. The Chief Investigator

and/or the trial management group have the right at any time to terminate the study for clinical or administrative reasons. The end of the study will be reported to the REC and Regulatory Authority (where applicable) within the required timeframes. Dissemination Data from all centres will be analysed together and published as soon as possible. Individual participants may not publish data concerning their patients that are directly relevant to questions posed by the trial until the TMG has published its report. The TMG will have access to the final data set, form the basis of the Writing Committee and advise on the nature of publications. The trial will be publicised at regional and national meetings, and to patient groups with the support of Mesothelioma UK. The final results will be presented at scientific meetings and published in a peer-reviewed journal (authorship will be according to the journal’s guidelines). A lay summary will be disseminated via local and national mesothelioma charities. Summary results will also be published online at clinicaltrials.gov and cancerhelp.

Current status Trial identifiers: ISRCTN: 04240319; Clinical Trials.gov: NCT01604005 60 research sites are open to and 55 have enrolled patients into the trial. It is anticipated that the recruitment will be completed by the end of 2015.

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The main analysis and publication of the primary endpoint results is planned for autumn 2016 with a further follow-up analysis and publication in 2018. The Protocol development group includes of Prof Corinne Faivre-Finn, Dr Paul Taylor, Dr Mick Peake, Dr Robert Rintoul, Prof David Baldwin, Dr Michael Snee, Dr Jason Lester, Mr John Edwards, Dr Neil Bayman, Ms Liz Darlison, Mr David Ardron, Mrs Linda Ashcroft. Dr Bayman as his role as Chief Investigator facilitated the development of the 1st version of the protocol.

Trial support The trial is being coordinated by the Manchester Academic Health Science Centre, Trials Coordination Unit (MAHSC-CTU). Additional study information can be obtained from the PIT trial manager or trial statistician Contact details Trial Manager: Brynn Chappell, [email protected], Tel +44 (0)161 918 7945 Trial Statistician: Linda Ashcroft, [email protected],

Ethics

The trial has been reviewed by NRES Committee North West - Greater Manchester West which granted ethical approval for the study on 4

th April 2012 (REC reference 12/NW/0249).

Provenance & Peer review The study was externally reviewed as part of the grant application process.

Funding This paper presents independent research commissioned by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfpB) Programme (Grant Reference Number PB-PG-1010-23232). The views expressed are those of the authors and not necessarily the NHS, the NIHR or the Department of Health.

Sponsor The Christie NHS Foundation Trust, Research & Development Department, Wilmslow Road, Manchester, M20 4BX, UK Acknowledgments We would like to thank all the patients that have agreed to participate in this trial, the principal investigators and the site teams around the UK involved in set-up, recruitment and follow-up of the study. This study was designed with patient involvement and patient representation on the protocol development committee and trial management group. We would also like to thank Alice Taylor for editorial assistance.

Dr Robert Rintoul is part funded by the Cambridge Biomedical Research Centre, Cambridge

Cancer Centre and the Clinical Research Network:Eastern. Competing interests statement The PIT Trial Management Group members have no competing interests to declare. Open access The protocol for this trial is summarised in this open access paper. There will not be open access to the participant-level dataset.

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mesothelioma--an update. Int J Occup Environ Health 2004; 10: 26-39

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6 Attanoos RL, Gibbs AR. The pathology associated with therapeutic procedures in malignant mesothelioma. Histopathology 2004; 45: 393-7

7 Adams VI, Unni KK. Diffuse malignant mesothelioma of pleura: diagnostic criteria based on an autopsy study. Am J Clin Pathol 1984; 82: 15-23

8 Brenner J, Sordillo PP, Magill GB, Golbey RB. Malignant mesothelioma of the pleura: review of 123 patients. Cancer 1982; 49: 2431-5

9 Law MR, Hodson ME, Turner-Warwick M. Malignant mesothelioma of the pleura: clinical aspects and symptomatic treatment. Eur J Respir Dis 1984; 65: 162-8

10 Ratzer ER, Pool JL, Melamed MR. Pleural mesotheliomas. Clinical experiences with thirty-seven patients. Am J Roentgenol Radium Ther Nucl Med 1967; 99: 863-80

11 Ruffie P, Feld R, Minkin S et al. Diffuse malignant mesothelioma of the pleura in Ontario and Quebec: a retrospective study of 332 patients. J Clin Oncol 1989; 7: 1157-68

12 Stewart BN, Jay BA. Subcutaneous Implantation of Cancer following Thoracentesis. Chest 1974; 66: 456-457

13 Whitwell F, Rawcliffe RM. Diffuse malignant pleural mesothelioma and asbestos exposure. Thorax 1971; 26: 6-22

14 Boutin C, Rey F, Viallat JR. Prevention of malignant seeding after invasive diagnostic procedures in patients with pleural mesothelioma. A randomized trial of local radiotherapy. Chest 1995; 108: 754-8

15 Bydder S, Phillips M, Joseph DJ et al. A randomised trial of single-dose radiotherapy to prevent procedure tract metastasis by malignant mesothelioma. Br J Cancer 2004; 91: 9-10

16 O'Rourke N, Garcia JC, Paul J et al. A randomised controlled trial of intervention site radiotherapy in malignant pleural mesothelioma. Radiother Oncol 2007; 84: 18-22

17 Lee C, Bayman N, Swindell R, Faivre-Finn C. Prophylactic radiotherapy to intervention sites in mesothelioma: a systematic review and survey of UK practice. Lung Cancer 2009; 66: 150-6

18 Ung YC, Yu E, Falkson C et al. The role of radiation therapy in malignant pleural mesothelioma: a systematic review. Radiother Oncol 2006; 80: 13-8

19 Davies HE, Musk AW, Lee YC. Prophylactic radiotherapy for pleural puncture sites in mesothelioma: the controversy continues. Curr Opin Pulm Med 2008; 14: 326-30

20 McAleer MF, Tsao AS, Liao Z. Radiotherapy in malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 2009; 75: 326-37

21 (BTS) BTS. BTS statement on malignant mesothelioma in the UK, 2007. Thorax 2007; 62: ii1-ii19

22 Ung Y, Yu E, Falkson C et al. The role of radiation therapy in malignant pleural mesothelioma: a clinical practice guideline. Program in Evidence-based Care 2006 2006; Series No.7: Section 1

23 Scherpereel A, Astoul P, Baas P et al. [Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma]. Zhongguo Fei Ai Za Zhi 2010; 13: C23-45

24 Stahel RA, Weder W, Lievens Y, Felip E, Group EGW. Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21 Suppl 5: v126-8

25 Hambleton KL, Faivre-Finn C, Baldwin DR.. Lung cancer: what’s new in diagnosis and therapies? Thorax 2009; 64: A80-A85

26 Vogelzang NJ, Rusthoven JJ, Symanowski J et al. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003; 21: 2636-44

27 (NICE) NIfHaCE. NICE technology appraisal guidance [TA135]: Pemetrexed for the treatment of malignant pleural mesothelioma volume 2015, 2008

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Figure 1 - Trial Schema / Flowchart

209x297mm (300 x 300 DPI)

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Figure 2 - PIT radiotherapy field margins 297x209mm (300 x 300 DPI)

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Appendix 1: Open and recruiting sites

Name Principal Investigator

Addenbrookes - Cambridge University Hospitals Dr David Gilligan

Alexandra Hospital Dr Asha Siva

Basingstoke & North Hampshire Hospital Dr Andrew Jackson

Blackpool Victoria Hospital Dr Muthiah Sivaramalingham

Bradford Dr Michael Snee

Calderdale & Huddersfield NHS Trust Dr Pooja Jain

Clatterbridge Cancer Centre NHS Foundation Trust Dr Aisha Tufail

Dorset Cancer Centre Dr Mike Bayne

Edinburgh Cancer Centre Prof Allan Price

George Eliot Hospital Dr Mark Hocking

Glan Clwyd Hospital Dr Niladri Ghosal

Harrogate District Foundation Trust Dr Samuel Chan

Ipswich Hospital Dr Jamey Morgan

Isle of Wight Dr Paul Fenton

James Cook University Hospital Dr Devadasan Shakespeare

Kent & Canterbury Hospital Dr Mathilda Cominos

Kidderminster General Hospital Dr Asha Siva

Kings Mill Hospital Dr Karen Foweraker

Leighton Hospital Dr Paul Burt

Llandough Hospital (Velindre) Dr Jason Lester

Macclesfield District General Hospital Dr Hamid Sheikh

Maidstone Hospital Dr Russell Burcombe

Manor Hospital Walsall Dr AD Chetiyawardana

Medway NHS Foundation Trust Dr Maher Hadaki

Mount Vernon Cancer Centre Dr Russell Moule

New Cross Hospital (Wolves) Dr Ian Sayers

Ninewells Hospital Dr Hannah Lord

North Middlesex Hospital Dr Nishi Gupta

North Midlands NHS Trust Dr Apurna Jegannathen

Northampton General Hospital Dr Anupama Gore

Northern Ireland Cancer Centre Dr Jonathan McAleese

Nottingham University Hospitals Dr Sally Morgan

Peterborough and Stamford Hospitals NHS Foundation Trust Dr Sarah Treece

Pilgrim Dr Abhro Chaudhuri

Princess Alexandra Dr Nishi Gupta

Queen's Hospital, Burton Dr AD Chetiyawardana

Royal Blackburn and Burnley Hospitals Dr Weibke Appel

Royal Bolton Hospital Dr Neil Bayman

Royal Derby Hospital Dr Manjusha Keni

Royal Oldham Hospital Dr Laura Pemberton

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Royal Preston Hospital Dr Weibke Appel

Royal Surrey Dr Veni Ezhil

Salford Royal NHS Foundation Trust Dr Hamid Sheikh

Salisbury Dr Adityanarayan Bhatnagar

South Warwickshire Dr Caroline Humber

Southampton General Hospital Dr Andrew Bates

St James Leeds Dr Michael Snee

Tameside General Hospital Dr Margaret Harris

The Christie NHS Foundation Trust Dr Neil Bayman

The Queen Elizabeth hospital, Kings Lynn Dr Kathryn Waite

United Lincolnshire Hospitals NHS Trust Dr Abhro Chaudhuri

University Hospital Birmingham Dr Qamar Ghafoor

University Hospital Coventry & Warwickshire Dr Mark Hocking

University Hospital of Leicester Dr Thiagarajan Sridhar

University Hospital of North Tees Dr Devadasan Shakespeare

University Hospitals of Morecambe Bay NHS Foundation Trust Dr Geraldine Skailes

Weston Park, Sheffield Dr Matthew Hatton

Writington Dr Neil Bayman

Wythenshawe Hospital Dr Laura Pemberton

York Teaching Hospital Dr Samuel Chan

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Appendix 2 – Patient Information Sheet (Version 4.0, 18th April 2012)

Title of the research:

A phase III study of Prophylactic Irradiation of Tracts in patients with malignant pleural

mesothelioma following invasive chest wall intervention (PIT Trial)

Invitation to participate in the trial

You are being invited to take part in a research trial. Before you decide if you want to take part, it is

important for you to understand why the research is being done and what it will involve. Please read

the following information carefully and if you wish, discuss it with friends, relatives and your General

Practitioner. Ask us if there is anything that is not clear or if you would like more information. It is

important to take time to understand this information and decide whether or not you wish to take

part.

Part 1 tells you the purpose of this trial and what will happen to you if you take part

Part 2 gives you more detailed information about the conduct of the trial

PART 1

What is the purpose of this research trial?

Mesothelioma is a rare form of cancer affecting the protective lining that covers many of the body's

internal organs. The most commonly affected areas are the lungs and internal chest wall. In the UK

over 2300 patients are diagnosed with mesothelioma each year and the numbers are increasing.

As part of the diagnosis and treatment of mesothelioma, you will undergo a procedure which

involves inserting a thin tube into the chest wall enabling an internal examination and for any

biopsies or samples of fluid to be taken. These procedures can result in the development of skin

lumps or nodules along the tract created by inserting the tube. To try and reduce the risk of these

nodules developing in the tract or at the site of the scar, some radiotherapy treatment can be given

to the chest wall at the site of the tract after the procedure has been performed; this type of

radiotherapy is known as prophylactic irradiation of tracts or PIT.

Although many hospitals already give patients radiotherapy treatment to the chest wall we still do

not know if the treatment works. This trial has been designed to answer the question about the

effectiveness of PIT. If PIT is found to be effective in preventing or delaying the development of

these skin nodules then it can be offered to all patients as part of their treatment. However, if we

discover that PIT is not effective this will save patients from undergoing ineffective treatment and

having to spend time making unnecessary extra visits to hospital.

This radiotherapy treatment will be given in addition to other mesothelioma treatment, for example,

chemotherapy.

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What is the treatment that is being tested?

The treatment being tested is radiotherapy. The trial is to compare a course of radiotherapy

treatment with no radiotherapy treatment. Radiotherapy treatment will be delivered once a day for

3 days. The radiotherapy treatment will take around 15 minutes each time.

Why have I been chosen?

You have recently been diagnosed with mesothelioma and had an internal examination of your chest

wall and a biopsy taken and/or had fluid removed from the lining around the lung with a chest drain.

Following this procedure your doctor feels that you are suitable to take part in this trial. This is a

research trial, and other patients similar to you are also being asked if they would be willing to take

part. In total approximately 400 patients will take part in the UK and Europe.

Do I have to take part?

Your participation in this research trial is entirely voluntary and you will be given sufficient time to

decide whether or not you wish to participate. You are free to decide at all times without giving a

reason that you no longer wish to participate in the trial. Withdrawal from the trial will not affect

your subsequent treatment or relationship with your treating doctor or the hospital staff in any way.

What will happen to me if I take part?

If you agree to take part, you will be asked to sign a consent form and your doctor will perform a

number of checks to ensure that you are eligible for this trial. These checks will include a physical

examination to look at your chest wall and the skin around the chest area. The doctor will also ask

you about your current levels of activity and whether you are experiencing any pain. These tests are

normally done as part of the routine checks for patients who are to be treated with radiotherapy.

Female patients may also require a pregnancy test.

If you are eligible and agree to take part in the trial you will be randomly allocated to receive

radiotherapy treatment or no radiotherapy treatment. This is done by a computer; you or your

doctor cannot choose the treatment.

Regardless of whether you are assigned to receive the PIT radiotherapy treatment or not you will be

followed up in clinic after 6 weeks, 3 months, 6 months and 12 months. You will also receive

telephone calls from a trial nurse or research radiographer every 4 weeks. During each telephone

call you will be asked to answer a question at home in a diary given to you after you have had the

radiotherapy. The research nurse or radiographer will explain to you how to answer the questions.

The telephone follow-up calls will be missed out on the months when you are seen in clinic.

Telephone follow-ups will continue until a skin nodule develops or for 2-years after you enrolled on

the trial.

The following examinations will be performed at each follow-up visit:

a) At the clinic appointment the doctor will perform:

a physical examination including inspecting the chest wall. If you develop a skin nodule, the

position of the nodule in relation to the area in which you were treated (if you were allocated to

receive the radiotherapy treatment) will be recorded at this appointment.

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an assessment of your levels of physical activity or performance status

any reaction of the skin to the radiotherapy treatment will be assessed

your levels of pain and use of painkillers will be recorded

details of any other treatment for mesothelioma will be recorded

b) At the telephone follow-up the trial nurse or research radiographer will ask you if you have

noticed any skin nodules developing. If you are concerned about a possible skin nodule then you will

be assessed in an out-patient clinic within 1 week.

Taking part in the PIT trial will not stop you from receiving any additional treatment that you may

need such as chemotherapy or radiotherapy given to control your symptoms.

Where possible any extra tests for the trial will take place during normal clinic visits. The clinical

research team can advise you how much time this will add to your visit.

What are the alternatives for treatment?

If you do not wish to take part in this trial your doctor will tell you what alternatives are available in

your particular situation.

What are the possible benefits of taking part?

If you are allocated to the group receiving PIT radiotherapy, this may help you but this cannot be

guaranteed. The information we get from this trial will help us to treat future patients with the same

disease better.

Considering that the benefit of radiotherapy cannot be guaranteed we would like you to consider

the possible side effects of the treatment, which are listed below:

What are the side effects of radiotherapy to the chest wall?

Many people who have radiotherapy to their chest wall have little or no side effects. Side effects

from radiotherapy are dependent on which part of your body is being treated and the number of

treatments you have. People who have had similar treatments can often have different side effects.

Here are some of the more common side effects:

Early side effects

These can vary according to the individual.

Tiredness - Tiredness is one of the most common side effects of cancer treatment. Although fatigue

may be a symptom that you have already due to your cancer.

Skin reactions - Approximately 10 days following radiotherapy, you will probably develop redness

and soreness of the skin within the treated area like a sun-burn. This will gradually fade over a few

weeks. We will give you E45/aqueous cream to moisturise the area and hydrocortisone cream to use

if it sensitive or sore.

Pain - There may be an ache within the treatment area lasting about one or two days and starting

just after treatment. This is nothing to worry about. It is temporary and you can take simple

painkillers such as paracetamol if necessary.

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Shortness of breath - It is extremely uncommon for radiotherapy to cause breathlessness with this

type of treatment.

Late side effects

It is possible for some types of reaction to occur months or years after the treatment has finished.

These side effects are permanent. Your doctor will discuss any possible late effects with you if they

are at all likely to occur.

Skin changes - With time, your skin (within the treated area only) may become paler than your

normal skin. Tiny ‘thread’ veins may develop on the treated skin.

Bone weakness - Rarely, radiotherapy can make some of the ribs more brittle. After a severe cough

or mild trauma this can result in chest pain and/or a minor rib fracture.

Pregnancy and Birth Control

If it is possible you may conceive (i.e. you are of child bearing age), you will be asked to have a

pregnancy test before starting treatment. Effective birth control with one of these methods should

be used during the course of treatment.

1. Tubal ligation (informally known as getting one’s “tubes tied”)

2. Insertion of an intra-uterine device (IUD or coil)

3. Diaphragm with spermicidal foam/gel/film/cream/pessary

4. Condom with spermicidal foam/gel/film/cream/pessary

5. Male partner who has had a vasectomy

6. Hormonal contraceptives

If you become pregnant while in this trial, you must tell the trial doctor immediately.

Contact Persons and Further information

The research nurses and doctors listed in this section are available to answer any questions you have

concerning this research trial. Understand that you are free to ask any questions concerning this

research trial that you wish at any time.

It is important that you contact the research nurses or trial doctor as soon as you experience any

side effects which disrupt your daily life whether you think the treatment has caused them or not. In

the event of any problem or emergency, the research nurses and doctors listed in this section may

be reached during working hours (9am to 5pm):

[Insert name & contact details of research doctor/research nurse/radiographer here]

If you have any concerns with your treatment and need to speak to someone outside these hours

(after 5pm and before 9 am), please contact [insert institution specific hotline number]

CancerHelp UK provides general information for patients about cancer and its treatment on their

website, www.cancerhelp.org.uk.

Cancer Research UK has cancer information nurses who provide a confidential service, Tel: 020 7061

8355 or email: [email protected]

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http://www.cancerhelp.org.uk/

mailto:[email protected]



Mesothelioma UK is a national resource centre dedicated to providing specialist mesothelioma

information, support & improved care and treatment.

Freephone helpline Monday - Friday 8:30 am - 4:30 pm 0800 169 2409 or visit

www.mesothelioma.uk.com

Macmillan Cancer Support provides support and counselling to help people living with cancer, ask

Macmillan Tel: 0808 808 0000 or visit www.macmillan.org.uk

UK Clinical Research Collaboration (UKCRC) publishes a leaflet entitled ‘Understanding Clinical Trials’.

This leaflet gives you more information about medical research and looks at some questions you may

want to ask. A copy may be viewed online at www.ukcrc.org or may be obtained by writing to

UKCRC, 20 Park Crescent, London, W1B 1AL.

This completes Part 1 of the information sheet.

If the information in Part 1 has interested you and you are considering participation, please

continue to read the additional information in Part 2 before making any decision

PART 2

What if relevant new information becomes available?

Sometimes during the course of a research project, new information becomes available about the

treatment that is being studied. If this happens, your trial doctor will tell you about it and discuss

whether you want to or should continue in the trial. If you decide not to carry on, or if your trial

doctor considers it to be in your best interests to withdraw you from the trial, your trial doctor will

make arrangements for your care to continue. If you decide to continue in the trial you will be asked

to sign an updated consent form. If the trial is stopped for any other reason, you will be told why

and your continuing care will be arranged.

What will happen if I don’t want to carry on with the trial?

You can withdraw your consent at any time. This will not affect the standard of care you receive.

Information collected up to your withdrawal may still be used.

If during the study you lose the capacity to consent, you will be withdrawn from the study. Any

identifiable data already collected with consent would be retained and used in the study. No further

data will be collected or any other research procedures carried out on or in relation to you.

What if something goes wrong?

Any complaint about the way you are dealt with during the trial or any possible harm you might

suffer will be addressed. The trial is being performed by your doctor and insurance against injury

will be provided by the hospital that is looking after you [insert institution name]. If you are harmed

due to someone’s negligence then you will have grounds for legal action but you may have to pay for

it. Regardless of this, if you wish to complain about any aspect of the way you have been

approached or treated during the course of this trial, the normal NHS complaints mechanisms will be

available to you. By signing a consent form you are NOT waiving any of your legal rights.

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Confidentiality

Information obtained from research will be protected and its handling will be compliant with the

Data Protection Act of 1998. The doctor in charge of the trial will keep your original signed consent

form in a secure location. Your medical records will not hold any individual results from this trial.

Your unique registration number will be used to make sure you cannot be identified outside the trial.

All information about you will be treated as confidential and nothing that might identify you will be

revealed to any other department or organisation. Your name will not appear in any publication or

report about this trial.

There will be strict control of access to the files containing clinical information. Your personal

information will be accessible to the trial doctors and others involved in the trial for the purpose of

the trial and your direct clinical care only. Direct access to your records may also be required by

members of the independent ethics committee and/or regulatory agencies.

Will My General Practitioner Be Involved?

With your permission, your GP will be notified of your participation in this trial. By signing the

consent form you are agreeing to this.

Will I be paid any costs and reimbursements?

There will be no payment to you for entering this trial, nor payment for undergoing investigations

that are additional to your standard care.

Who is organising and funding the research?

The PIT trial is being funded by the UK’s National Institute for Health Research as part of their

Research for Patient Benefit Programme. This trial is being organised and co-ordinated by

Consultant Clinical Oncologists (radiotherapy specialists) and the Trials Co-ordination Unit at The

Christie NHS Foundation Trust in Manchester. Independent international researchers in the field of

mesothelioma have been involved in developing the trial and have positively reviewed the trial.

None of the researchers will receive any payment for your participation in the trial.

What will happen to the results of the research trial?

Independent experts will review the progress of the research, and the results will be published in a

respected medical journal. The results will help to decide how to treat mesothelioma in the future.

Trials like this are often used in cancer research.

Who has reviewed the trial?

The trial was given a favourable ethical opinion for conduct in the NHS by the Greater Manchester

West Research Ethics Committee.

Thank you for taking time to read this information sheet.

You will be given a copy of the information sheet and a signed consent form to keep if you decide to

take part in the trial.

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Appendix 3 – Informed Consent Form (Version 4.0, 19th April 2012)

Patient Identification Number:

Name of Researcher: [insert local principal investigator name]

Title of the trial: A phase III trial of Prophylactic Irradiation of Tracts in patients

with malignant pleural mesothelioma following invasive chest

wall intervention (PIT Trial)

CONSENT FORM

1. I confirm that I have read and understood the information sheet Version 4.0,

dated 19 April 2012 for the above trial and have had the opportunity to

ask questions.

2. I understand that my participation is voluntary and that I am free to withdraw at

any time, without giving any reason, without my medical care or legal rights

being affected.

3. I understand that sections of any of my medical notes may be looked at by responsible

individuals from [insert institution name] and its authorised agents

or from Regulatory Authorities where it is relevant to my taking part in research.

I give permission for these individuals to have access to my records.

4. I also understand that if I withdraw from the trial early, the data collected whilst

I was on the trial will be retained to ensure the trial has been run in accordance

with all applicable rules.

5. I understand that if I lose the capacity to consent I will be withdrawn from the

study. However any identifiable data already collected with consent would be retained and

used in the study

6. I understand that I will not benefit financially if this research leads to the

development of a new treatment or medical test

7. I understand that my General Practitioner will be informed about my

participation in this trial.

8. I agree to take part in the above trial.

Please initial

in boxes

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________________________ ________________ ____________________

Name of Patient Date Signature

_________________________ ________________ ____________________

Name of Person taking consent Date Signature

(If different from researcher)

________________________ ________________ ____________________

Researcher Date Signature

1 for patient; 1 for researcher; 1 for general practitioner, 1 to be kept with hospital

notes

Thank you for taking part in this research trial

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and

related documents*

Protocol for the Isotoxic IMRT trial - Protocol for the Isotoxic Intensity Modulated

Radiotherapy (IMRT) in stage III non-small cell lung cancer (NSCLC) - A feasibility study

Section/item ItemNo Description Inc. Page in

Manuscript

Administrative information

Title 1 Descriptive title identifying the study design,

population, interventions, and, if applicable, trial

acronym

� Pg1

Trial registration 2a Trial identifier and registry name. If not yet

registered, name of intended registry

� Pg2

2b All items from the World Health Organization Trial

Registration Data Set

N/A N/A

Protocol version 3 Date and version identifier 19th

April

2012

V3.0

Pg8

Funding 4 Sources and types of financial, material, and

other support

� Pg9

Roles and

responsibilities

5a Names, affiliations, and roles of protocol

contributors

� Pg1

5b Name and contact information for the trial

sponsor

� Pg9

5c Role of study sponsor and funders, if any, in

study design; collection, management, analysis,

and interpretation of data; writing of the report;

and the decision to submit the report for

publication, including whether they will have

ultimate authority over any of these activities

� Pg8

5d Composition, roles, and responsibilities of the

coordinating centre, steering committee, endpoint

� In full

protocol

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adjudication committee, data management team,

and other individuals or groups overseeing the

trial, if applicable (see Item 21a for data

monitoring committee)

Section

13

Background and

rationale

6a Description of research question and justification

for undertaking the trial, including summary of

relevant studies (published and unpublished)

examining benefits and harms for each

intervention

� Pg3

6b Explanation for choice of comparators � Pg5-6

Objectives 7 Specific objectives or hypotheses � Pg6-7

Trial design 8 Description of trial design including type of trial

(eg, parallel group, crossover, factorial, single

group), allocation ratio, and framework (eg,

superiority, equivalence, noninferiority,

exploratory)

� Pg4

Study setting 9 Description of study settings (eg, community

clinic, academic hospital) and list of countries

where data will be collected. Reference to where

list of study sites can be obtained

� Pg4

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If

applicable, eligibility criteria for study centres and

individuals who will perform the interventions (eg,

surgeons, psychotherapists)

� Pg4-5

Interventions 11a Interventions for each group with sufficient detail

to allow replication, including how and when they

will be administered

� Pg5-6

11b Criteria for discontinuing or modifying allocated

interventions for a given trial participant (eg, drug

dose change in response to harms, participant

request, or improving/worsening disease)

� More

detail in

full

protocol

11c Strategies to improve adherence to intervention

protocols, and any procedures for monitoring

adherence (eg, drug tablet return, laboratory

tests)

N/A

11d Relevant concomitant care and interventions that N/A N/A

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are permitted or prohibited during the trial

Outcomes 12 Primary, secondary, and other outcomes,

including the specific measurement variable (eg,

systolic blood pressure), analysis metric (eg,

change from baseline, final value, time to event),

method of aggregation (eg, median, proportion),

and time point for each outcome. Explanation of

the clinical relevance of chosen efficacy and harm

outcomes is strongly recommended

� Pg6 &

more

detail in

full

protocol

Participant

timeline

13 Time schedule of enrolment, interventions

(including any run-ins and washouts),

assessments, and visits for participants. A

schematic diagram is highly recommended (see

Figure)

� Trial

schema

pg4 & PIS

Appendix

2

Sample size 14 Estimated number of participants needed to

achieve study objectives and how it was

determined, including clinical and statistical

assumptions supporting any sample size

calculations

� Pg6

Recruitment 15 Strategies for achieving adequate participant

enrolment to reach target sample size

Regular presentation of the trial at

national/international conferences, newsletters to PIs,

articles in Mesothelioma UK patient and carers

newsletters, teleconferences with PIS – please contact

trial project manager for further information.

� Contact

details

pg9 &

more

detail in

full

protocol

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence

generation

16a Method of generating the allocation sequence

(eg, computer-generated random numbers), and

list of any factors for stratification. To reduce

predictability of a random sequence, details of

any planned restriction (eg, blocking) should be

provided in a separate document that is

unavailable to those who enrol participants or

assign interventions

� Pg5 –

further

details

can be

supplied

by

MAHSC-

CTU if

required.

Allocation

concealment

mechanism

16b Mechanism of implementing the allocation

sequence (eg, central telephone; sequentially

numbered, opaque, sealed envelopes),

describing any steps to conceal the sequence

� Pg5

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until interventions are assigned

Implementati

on

16c Who will generate the allocation sequence, who

will enrol participants, and who will assign

participants to interventions

Allocation sequence generated by MAHSC-CTU.

Participants will be enrolled by the local principal

investigators and randomisation done by research

staff (eg research nurses).

� Pg5 -

MAHSC

CTU

Blinding

(masking)

17a Who will be blinded after assignment to

interventions (eg, trial participants, care providers,

outcome assessors, data analysts), and how

N/A -

No

blinding

N/A

17b If blinded, circumstances under which unblinding

is permissible, and procedure for revealing a

participant’s allocated intervention during the trial

N/A N/A

Methods: Data collection, management, and analysis

Data collection

methods

18a Plans for assessment and collection of outcome,

baseline, and other trial data, including any

related processes to promote data quality (eg,

duplicate measurements, training of assessors)

and a description of study instruments (eg,

questionnaires, laboratory tests) along with their

reliability and validity, if known. Reference to

where data collection forms can be found, if not in

the protocol

� Pg6 & In

full

protocol,

CRFs

supplied

by

MAHSC-

CTU.

18b Plans to promote participant retention and

complete follow-up, including list of any outcome

data to be collected for participants who

discontinue or deviate from intervention protocols

Data will continue to be collected on an intention-to-

treat basis for participants who discontinue or deviate

from the protocol unless they decide to withdraw

from the study, in which case no further data will be

collected.

� More

detail

available

from

MAHSC-

CTU,

contact

details

pg9

Data

management

19 Plans for data entry, coding, security, and

storage, including any related processes to

promote data quality (eg, double data entry;

range checks for data values). Reference to

where details of data management procedures

can be found, if not in the protocol

More detail available from MAHSC-CTU, contact

� In full trial

protocol

section

14.2.

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details pg9

Statistical

methods

20a Statistical methods for analysing primary and

secondary outcomes. Reference to where other

details of the statistical analysis plan can be

found, if not in the protocol

� Pg6-7 -

More

detail in

full trial

protocol

section 11

20b Methods for any additional analyses (eg,

subgroup and adjusted analyses)

N/A No

interim or

subgroup

analyses

20c Definition of analysis population relating to

protocol non-adherence (eg, as randomised

analysis), and any statistical methods to handle

missing data (eg, multiple imputation)





collected. More details also available from MAHSC-

CTU, contact details pg9

� Pg6 -

More

detail in

full trial

protocol

section 11

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee

(DMC); summary of its role and reporting

structure; statement of whether it is independent

from the sponsor and competing interests; and

reference to where further details about its charter

can be found, if not in the protocol. Alternatively,

an explanation of why a DMC is not needed

� - no

IDMC Pg7

21b Description of any interim analyses and stopping

guidelines, including who will have access to

these interim results and make the final decision

to terminate the trial

The Chief Investigator and/or the trial management

group have the right at any time to terminate the

study for clinical or administrative reasons.

� - no

interim

analyses

Pg7 & 8

Harms 22 Plans for collecting, assessing, reporting, and

managing solicited and spontaneously reported

adverse events and other unintended effects of

trial interventions or trial conduct

� Pg10-11

– further

details in

full

protocol

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section 12

Auditing 23 Frequency and procedures for auditing trial

conduct, if any, and whether the process will be

independent from investigators and the sponsor

Also MAHSC-CTU will prospectively monitor

submitted data/CRFs.

� Pg 7


Research ethics

approval

24 Plans for seeking research ethics

committee/institutional review board (REC/IRB)

approval

� Pg2 & 9

Protocol

amendments

25 Plans for communicating important protocol

modifications (eg, changes to eligibility criteria,

outcomes, analyses) to relevant parties (eg,

investigators, REC/IRBs, trial participants, trial

registries, journals, regulators)

Protocol modifications are managed through the

MAHSC-CTU.

� Pg7

Consent or

assent

26a Who will obtain informed consent or assent from

potential trial participants or authorised

surrogates, and how (see Item 32)

� Pg4-5 &

Appendi

x 2&3

26b Additional consent provisions for collection and

use of participant data and biological specimens

in ancillary studies, if applicable

N/A N/A

Confidentiality 27 How personal information about potential and

enrolled participants will be collected, shared, and

maintained in order to protect confidentiality

before, during, and after the trial

� PIS

Appendix

2

Declaration of

interests

28 Financial and other competing interests for

principal investigators for the overall trial and

each study site

� Pg9

Access to data 29 Statement of who will have access to the final trial

dataset, and disclosure of contractual agreements

that limit such access for investigators

The Trial Management group will have access to

the final trial dataset.

� Pg8

Ancillary and

post-trial care

30 Provisions, if any, for ancillary and post-trial care,

and for compensation to those who suffer harm

� PIS

Appendix

2

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from trial participation

Dissemination

policy

31a Plans for investigators and sponsor to

communicate trial results to participants,

healthcare professionals, the public, and other

relevant groups (eg, via publication, reporting in

results databases, or other data sharing

arrangements), including any publication

restrictions

� Pg8

31b Authorship eligibility guidelines and any intended

use of professional writers

No professional writer used. Also see author’s

contributions.

� Pg1

31c Plans, if any, for granting public access to the full

protocol, participant-level dataset, and statistical

code

There will not be open access to the participant-level

dataset.

� Pg9

Appendices

Informed

consent

materials

32 Model consent form and other related

documentation given to participants and

authorised surrogates

� Appendix

3

Biological

specimens

33 Plans for collection, laboratory evaluation, and

storage of biological specimens for genetic or

molecular analysis in the current trial and for

future use in ancillary studies, if applicable

N/A N/A

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Protocol for PIT: A Phase III Trial of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural

Mesothelioma Following Invasive Chest Wall Intervention.

Journal: BMJ Open

Manuscript ID bmjopen-2015-010589.R1

Article Type: Protocol

Date Submitted by the Author: 02-Dec-2015

Complete List of Authors: Bayman, Neil; The Christie NHS Foundation Trust, Clinical Oncology Ardron, David; The National Cancer Research Institute (NCRI), Consumer Liaison Group

Ashcroft, Linda; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU) Baldwin, David; Nottingham University Hospitals NHS Trust, Respiratory Medicine Unit Booton, Richard; The University of Manchester, Respiratory and Allergy Research Group Darlison, Liz; University Hospitals of Leicester NHS Trust , Department of Respiratory Medicine; Mesothelioma UK Charitable Trust, c/o Glenfield Hospital Edwards, John; Sheffield Teaching Hospitals NHS Foundation Trust UK, Department of Cardiothoracic Surgery Lang-Lazdunski, Loic; The Lister Hospital, Department of Thoracic Surgery

Lester, Jason; Velindre NHS Trust UK, Department of Clinical Oncology Peake, Michael; Glenfield Hospital, Department of Respiratory Medicine Rintoul, Robert; Papworth Hospital NHS Foundation Trust, Department of Thoracic Oncology Snee, Michael; Leeds Teaching Hospitals NHS Trust, Department of Clinical Oncology Taylor, Paul; The Christie NHS Foundation Trust, Department of Medical Oncology Lunt, Colin; The Christie NHS Foundation Trust, Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU) Faivre-Finn, Corinne; The Christie NHS Foundation Trust, Radiotherapy

Related Research; University of Manchester, Manchester Academic Health Science Centre, Institute of Cancer Sciences

<b>Primary Subject Heading</b>:

Oncology

Secondary Subject Heading: Radiology and imaging, Respiratory medicine, Evidence based practice

Keywords: Respiratory tract tumours < ONCOLOGY, Radiation oncology < RADIOLOGY & IMAGING, Clinical trials < THERAPEUTICS


BMJ Open on M

arch 9, 2020 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

BM

J Open: first published as 10.1136/bm

jopen-2015-010589 on 27 January 2016. Dow

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Protocol for PIT: A Phase III Trial of Prophylactic Irradiation of Tracts in Patients with Malignant Pleural Mesothelioma Following Invasive Chest Wall Intervention. N. Bayman

1, D. Ardron

2, L. Ashcroft

3, D.R. Baldwin

4, R. Booton

5, L. Darlison

6,10, J.G.

Edwards7, L. Lang-Lazdunski

8, J.F. Lester

9, M. Peake

10,11, R.C. Rintoul

12, M. Snee

13, P.

Taylor14,15

, C. Lunt3 C. Faivre-Finn

16,17.

Correspondence to: Dr Neil Bayman; [email protected] 0161 446 3337 1Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX UK,

2The National Cancer Research Institute (NCRI) Consumer Liaison Group, London UK,

3Manchester Academic Health Science Centre Trials Co-ordination Unit (MAHSC-CTU), The Christie NHS

Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK 4Respiratory Medicine Unit, David Evans Research Centre, , Nottingham University Hospitals NHS Trust, Nottingham

City Hospital Campus, , Nottingham, NG5 1PB, UK, 5 Respiratory and Allergy Research Group, Institute of Inflammation & Repair, The University of Manchester North

West Lung Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK 6Mesothelioma UK Charitable Trust, c/o Glenfield Hospital, Leicester, LE3 9QP, UK

7Department of Cardiothoracic Surgery, Chesterman Unit, Northern General Hospital, Sheffield Teaching Hospitals

NHS Foundation Trust UK, Herries Rd, Sheffield, S5 7AU, UK 8Department of Thoracic Surgery, The Lister Hospital, Chelsea Bridge Road, London SW1W 8RH

9Department of Clinical Oncology, Velindre NHS Trust UK, Velindre Rd, Cardiff, South Glamorgan CF14 2TL, UK

10Department of Respiratory Medicine, University Hospitals of Leicester NHS Trust, Glenfield Hospital, Leicester, LE3

9QP, UK 11

National Cancer Intelligence Network, (NCIN), Public Health England, 2nd

Floor, Skipton House, 80 London Road, London, SE1 6LH 12

Department of Thoracic Oncology, Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK, 13

Department of Clinical Oncology, Leeds Teaching Hospital NHS Trust, St James Hospital, Leeds, LS9 7TF UK, 14

Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK 15

Department Pulmonary Oncology, Wythenshawe Hospital Manchester M23 9LT 16

The University of Manchester, Manchester Academic Health Science Centre, Institute of Cancer Sciences, Manchester Cancer Research Centre (MCRC), Wilmslow Road, Manchester, M20 4BX 17

Radiotherapy Related Research, The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK

Author’s contributions CFF and NB conceived of the study. CFF, NB, DA, LA, DRB, RB, LD, JGE, LLL, JFL, MP, RCR, MS, PT, initiated the study design and helped with implementation. CFF is the grant holder. LA provided statistical expertise in clinical trial. All authors contributed to refinement of the study protocol and approved the final manuscript. Keywords: mesothelioma, prophylactic radiotherapy, chemotherapy, phase III, tracts Word Count: 3,853 (excluding title page, abstract, references, figures and tables)

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Abstract

Introduction

Histological diagnosis of malignant mesothelioma requires an invasive procedure such as CT

guided needle biopsy, thoracoscopy, video-assisted thorascopic surgery (VATs) or

thoracotomy. These invasive procedures encourage tumour cell seeding at the intervention

site and patients can develop tumour nodules within the chest wall. In an effort to prevent

nodules developing, it has been widespread practice across Europe to irradiate intervention

sites post-procedure – a practice known as prophylactic irradiation of tracts (PIT). To date

there has not been a suitably powered randomised trial to determine whether PIT is effective

at reducing the risk of chest wall nodule development.

Methods and Analysis

In this multicentre phase III randomised controlled superiority trial, 374 patients who can

receive radiotherapy within 42 days of a chest wall intervention will be randomised to receive

PIT or no PIT. Patients will be randomised on a 1:1 basis. Radiotherapy in the PIT arm will

be 21 Gy in 3 fractions. Subsequent chemotherapy is given at the clinicians’ discretion. A

reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy 6

months after randomisation would be clinically significant. All patients will be followed up for

up to 2 years with monthly telephone contact and at least 4 outpatient visits in the first year.


PIT was approved by NRES Committee North West - Greater Manchester West (REC

reference 12/NW/0249) and recruitment is currently on-going, the last patient is expected to

be randomised by the end of 2015. The analysis of the primary endpoint, incidence of chest

wall nodules 6 months after randomisation, is expected to be published in 2016 in a peer

reviewed journal and results will also be presented at scientific meetings and summary results

published online. A follow-up analysis is expected to be published in 2018.

Trial identifiers: ISRCTN: 04240319; Clinical Trials.gov: NCT01604005

Summary of strengths and limitations of study

Strengths:

• Largest, adequately powered randomised controlled study of prophylactic

radiotherapy in this population

• Radiotherapy fields reflect current practice for thoracoscopy and drain insertion

• Monthly telephone follow-up to supplement out-patient follow-upClinical significance

of chest wall metastases measured with VAS pain score

Limitations:

• Will not determine role of prophylactic radiotherapy at the site of an indwelling pleural catheter

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Introduction Malignant pleural mesothelioma (MPM) is almost exclusively linked to asbestos exposure with a latency period that is usually more than 30 years and prognosis is poor.

1-4 The median

survival in the UK is 8.8 months and the 1 year survival 38.5%.5

Diagnosis of mesothelioma is usually made by pleural biopsy either via computerised tomography (CT) guided needle biopsy, thoracoscopy, video assisted thoracic surgery (VATs), or thoracotomy. Patients often have associated pleural effusions and require chest drains to relieve symptoms such as chest pain and difficulty breathing. These invasive procedures encourage tumour cell seeding at the site of the intervention, which can result in formation of a subcutaneous tumour. The rate of chest wall metastases ranges from 2-50%, and depends on the procedure performed.

4, 6-14 In an effort to minimise tumour seeding and prevent nodule development, it has been widespread practice for more than 20 years in the UK to irradiate intervention sites post-procedure – a practice known as prophylactic irradiation of tracts (PIT). Only three randomised controlled trials, the largest with 61 patients, have assessed the role of PIT with conflicting results reported.

14-19 One study reported a statistically significant reduction

in the frequency of malignant seeding of tracts in the PIT arm compared to the control arm14

; the other two studies did not

15, 16. Systematic reviews of the literature have concluded that the

randomised trials conducted to date were considered the best available evidence for PIT, but that there was insufficient evidence to definitively recommend PIT.

17-20 Inconsistencies are

also evident in current national recommendations on the use of PIT. The British Thoracic Society

21 recommends the use of PIT to prevent chest wall nodule formation following an

interventional procedure. In contrast, the Cancer Care Ontario Program22

stated that a recommendation for PIT in MPM could not be made due to inconsistent evidence, reflecting a lack of high quality data. Similarly, in 2010 the European Respiratory Society stated “The value of prophylactic radiotherapy is questionable”

23 and the European Society of Medical

Oncology (ESMO) clinical recommendations for diagnosis, treatment and follow-up of MPM state that “it remains impossible to draw definitive conclusions regarding its efficacy”

24.

Currently in the UK the routine use of PIT in patients with MPM depends on locality. A 2008 UK survey showed that 75% of radiotherapy centres are routinely using PIT.

17 In addition, the

small number of patients recruited to each arm, the high death rates, and overestimation of the rate of chest wall metastasis in the control arms, question whether the three previous randomised controlled trials were adequately powered. Furthermore, recent evidence shows that portal tracts are not always perpendicular to the skin

25 and thus the small radiation fields

centred on the chest wall scar employed by the previous negative studies may have been suboptimal. There is now strong evidence to support the role of palliative chemotherapy in patients with MPM

26 which is approved in the UK by the National Institute of Clinical Excellence (NICE)

27.

Importantly, the previous studies were conducted before palliative chemotherapy was widely used in MPM. Therefore, the role of PIT in the era of effective palliative chemotherapy remains undefined. In addition, no previous studies have used validated pain scoring tools to assess pain from tract metastases. We believe a trial is essential for the following reasons: firstly an adequately powered RCT employing radiotherapy techniques ensuring adequate coverage of the entire portal tract will establish whether PIT should be offered routinely to MPM patients after chest wall intervention in the era of palliative chemotherapy; secondly to establish whether chest wall metastases are symptomatic and thus, whether PIT, if effective, is clinically significant.

The hypothesis for this trial is that prophylactic irradiation of tracts will reduce the incidence of chest wall nodules from 15% to 5%. The primary objective of the PIT study is to determine the efficacy, as assessed by the incidence of chest wall metastasis, of prophylactic irradiation of tracts following invasive chest wall intervention in malignant pleural mesothelioma compared to no prophylactic radiotherapy. Secondary objectives include: the description of the toxicity of

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prophylactic irradiation of tracts; time from randomisation to chest wall tract metastasis in patients undergoing prophylactic irradiation of tracts compared with the no prophylactic radiotherapy; the assessment of pain from chest wall metastasis.

Methods and Analysis Trial Design This is a 2-arm, phase III multi-centre (list of centres can be found in Appendix 1 including a mix of academic centres and community hospitals) randomised superiority trial comparing radiotherapy vs. no radiotherapy in patients with a histological diagnosis of Malignant Pleural Mesothelioma following chest wall intervention (see Figure 1). 374 patients will be randomised on a 1:1 basis to receive PIT (experimental arm) or no PIT (control arm). Patients can receive chemotherapy post radiotherapy/randomisation at the discretion of the treating physician. The follow-up period for the study is up to 2 years post randomisation which includes regular telephone follow-up and a minimum of 4 outpatient visits in the first year. Figure 1 – Trial Schema / Flowchart Patient Selection Potential participants will be identified by the principal investigator and his/her team at each centre, via the discussion of cases in a multidisciplinary team meeting (MDT). If a patient is identified as a potential participant in the PIT trial they will be approached at their next clinic visit, as part of discussions with the patient about their options for treatment. Patients who are interested in receiving further information about the trial will be given a copy of the patient information sheet (see online supplementary appendix 2) and consent form (see online supplementary appendix 3), and will have the opportunity to discuss the trial in detail before deciding whether to participate.

Inclusion criteria

• Either sex, age ≥ 18 years. • Diagnosis of mesothelioma by multi-disciplinary team (MDT) • All histological subtypes. Where the histological diagnosis is unclear, a specialist thoracic

pathologist should be consulted. • ECOG performance status 0-2. • Inoperable disease or operable disease in patients unsuitable for surgery as decided by a

MDT. • Chest wall intervention with video-assisted thoracoscopy (VATS), open surgical biopsy,

local anaesthetic thoracoscopy or chest drain. • Able to start radiotherapy within 42 days (6 weeks) from most recent chest wall

intervention. • Chest wall intervention scar visible at time of randomisation. • No indwelling pleural catheters in-situ at the intervention site • Radiotherapy target volume acceptable by the local radiotherapist. • No previous open thoracotomy. • No previous radiotherapy to the region of the chest wall intervention site. • Not currently receiving chemotherapy and not received chemotherapy for mesothelioma

before randomisation • No other previous or concomitant illness or treatment which in the opinion of the clinician

will interfere with the trial treatments or comparisons. • Patients enrolled on other clinical trials could be considered after discussion with the chief

investigators.

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• Female patients must satisfy the investigator that they are not pregnant, or are not of childbearing potential, or are using adequate contraception.

• Patients must not be breastfeeding • Absence of any psychological, familial, sociological or geographical condition potentially

hampering compliance with the trial protocol and follow-up schedule; those conditions should be discussed with the patient before randomisation in the trial

• Patients can only be randomised in this trial once. Exclusion criteria • Patients who underwent a thoracotomy (as large thoracotomy scars may not be

adequately covered by this radiotherapy technique) • Previous radiotherapy to the region of the chest wall intervention site • Indwelling pleural catheter in-situ at the intervention site • Patients currently receiving chemotherapy Consent All patients will be informed of the aims of the trial, the procedures and possible adverse effects, and the mechanism of treatment allocation. Patients will be informed as to the strict confidentiality of their patient data, but that their medical records may be reviewed for trial purposes by authorised individuals other than their treating physician. It will be emphasized that the participation is voluntary and that the patient is allowed to decline further participation in the protocol whenever he/she wants. This will not prejudice the patient’s subsequent care. Documented informed consent will be obtained by local principal investigators or a delegated member of staff for all patients included in the trial before they are registered or randomised in the trial in accordance with the national and local regulatory requirements. Randomisation Procedure Patients will be randomised by phone or fax on a 1:1 basis to one of two treatment arms. A variant of an adaptive biased coin randomisation method will be used to favour balance between treatment arms in the four strata formed from the following two factors:

• histology (epithelIoid or not)

• Intention to give chemotherapy Randomisation will be undertaken centrally by Manchester Academic Health Science Centre Clinical Trials Unit (MAHSC-CTU). Radiotherapy Patients are treated on a linear accelerator using a single electron field. Treatment fields can be shaped using individualised lead cut-outs of the appropriate thickness. The total dose of radiotherapy in the PIT arm is 21 Gy in 3 fractions, once daily over 3 consecutive days. The patient can be treated supine, prone, or in the lateral position depending on the position of the chest wall intervention site. To ensure > 90 percent of the prescribed dose is delivered to the skin surface, 0.5 cm tissue-equivalent bolus can be applied to the whole treatment field. The field position for radiotherapy is recorded so that if the patient develops chest wall nodules it can be determined if the nodules are inside or outside the treatment field. The Clinical Target Volume (CTV) comprises the visible and palpable scar with a 1 cm margin of clinically normal tissue in the lateral, medial and inferior directions at the skin surface. The Planning Target Volume (PTV) comprises the CTV with a 1 cm margin in all directions at the skin surface. The CTV to PTV expansion allows for set up errors, changes in the electron beam profile at depth and patient motion. The treatment field is defined by adding a further 1 cm margin in all directions to account for the beam penumbra. The superior margin will vary and should be the determined by counting 3 ribs superiorly. The upper border of the 3rd rib superior to the scar will be the superior border of the treatment field. This will take into account microscopic spread but also ensure that chest wall intervention tracts (which will commonly run over the rib superior to the scar) are covered at depth (see Figure 2).

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No organs at risk need to be identified and if a patient has two intervention sites, and therefore two scars (e.g. a VATS scar and adjacent chest drain scar) these can be treated within a single treatment field or two separate fields. A gap of > 1cm must separate two treatment fields. Figure 2 - PIT radiotherapy field margins

Chemotherapy Patients can be treated with palliative chemotherapy at the physician’s discretion after completion of radiotherapy (experimental arm) or after randomisation (control arm). The efficacy and/or safety of chemotherapy is not being investigated as part of the study. The chemotherapy regimen used should be cisplatin or carboplatin plus pemetrexed, although alternative chemotherapy regimens (including clinical trial agents) may be considered after discussion with the chief investigators. The number of cycles given is left to the physician’s discretion. A gap of at least 1-week must separate the completion of radiotherapy and the start of palliative chemotherapy. The chemotherapy regimen, start and stop dates and total number of cycles administered should be recorded. No further data needs to be collected concerning the patients chemotherapy treatment. Concomitant medication-not applicable for this trial. Discontinuation or withdrawal of patients In the case of disease progression, the patient will be treated according to each centre’s policy. For patients allocated to the treatment arm, radiotherapy can be stopped at the participants request or if too unwell to continue at the discretion of the treating clinician Outpatient visits The patient is reviewed in clinic 6, 12, 26 and 52 weeks following randomisation to assess for any signs of chest wall metastasis and to record any treatment related toxicities. In addition, telephone follow-up at 4-weekly intervals following randomisation will determine if the patient has noted any chest wall nodules. If a patient is suspicious that a nodule has appeared, they will be invited to clinic for assessment. If a chest wall metastases is confirmed, the position of the metastases is recorded in relation to the reconstructed radiotherapy treatment field. Patients are asked to complete a Visual Analogue Score (VAS) for pain at baseline, and at each telephone and clinic follow-up. Patients are specifically asked to only consider pain at the original site of chest wall intervention. If the patient develops chest wall nodules they will be asked to complete a VAS for pain at the site of the chest wall intervention at for the 3 nodules closest to the original intervention. Outcome measures The primary end point is the incidence of chest wall tract metastasis 6 months from randomisation. If a patient raises suspicion that a chest wall nodule had developed at telephone follow-up, they will be invited to attend an out-patient appointment with the investigator. If there is clinical evidence of a chest wall metastases, a chest wall metastasis CRF is completed using the clinic date as date of chest wall metastasis. The secondary endpoints are: • Time from randomisation to chest wall tract metastasis (recorded on chest wall

metastasis CRF) • Position of chest wall tract metastasis recurrence in relation to radiotherapy field in

patients randomised to experimental arm (in field/out-of-field, recorded on chest wall metastasis CRF)

• Acute and late skin radiotherapy toxicity (recorded by CTCAE v4.0 at baseline and at each out-patient visit on CRF)

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• Pain from chest wall tract metastasis (recorded by Visual Analogue Scale (VAS) pain scores recorded on chest wall metastasis CRF)

Sample size calculation The crude rate of tract metastases following chest wall intervention until death, based on historical data, is expected to be 15%. It is estimated that the majority of events will occur within 6 months of the intervention. A reduction in the incidence of chest wall nodules from 15% to 5% in favour of radiotherapy would be clinically significant. Based on a 2-arm trial with a 5% significance level, 2-sided test, and 80% power this would require 280 patients. Furthermore it is anticipated that 25% of patients will not survive for 6 months therefore an additional 94 patients will be required, making the total number of patients to be enrolled 374.. Analysis Incidence of Chest Wall Tract Metastasis All patients randomised will be analysed on an intention to treat basis. A two-sided chi-squared test of proportions of chest wall tract metastasis at 6 months between the control and experimental arms will be used with a 5% significance level. Secondary analysis using logistic regression will be used to investigate treatment after adjusting for significant baseline prognostic variables. Time to Chest Wall Tract Metastasis Kaplan-Meier curves will be drawn for each treatment group. Time to chest wall tract metastasis will be compared using a two-sided log rank test with a 5% level of significance. Cox-proportional hazards models will be used to investigate the effect of treatment after adjusting for stratification factors and other significant baseline variables. Toxicity Skin toxicity will be assessed according to NCI Common Terminology Criteria for Adverse Events v 4.0. The proportions of patients experiencing a grade of 3 or above acute toxicity, including acute radiation morbidity, or late radiation morbidity will be compared between the treatment groups using a two-sided Chi-squared test with a 5% level of significance. Acute toxicity will be defined as toxicities occurring from commencement of treatment to 3 months after completion; late toxicity will be defined as toxicities occurring between 3 months and 2 years after completion of treatment. Position of Chest Wall Tract Metastases Position of the central point of a chest wall tract metastases in relation to the reconstructed radiotherapy treatment field will be recorded as in field/out-of field recurrence. Where the central point falls on the edge of the radiotherapy treatment field this will be recoded as in-field recurrence Pain Scores Patients will be analysed using the intent-to-treat method. All tests will be 2-sided and a p-value of 0.05 or less will be considered statistically significant. In patients who develop tract metastasis, the VAS pain score from the assessment immediately before the occurrence of the tract metastasis will be considered baseline. Descriptive analysis will be performed to summarise change in pain score from baseline to subsequent pain score. Two-sample t-tests will be used to explore difference between treatments. A 20% increase in VAS pain score is considered significant. The proportion of significant increases in pain in both arms will be analysed using a 2-sided chi-squared test. No formal interim analysis is planned. Protocol adherence No major problems are anticipated in terms of adherence to intervention protocols as the experimental arm only involves 3 fractions of standard radiotherapy delivered over approximately 5 minutes on 3 consecutive days.

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Data Handling & Analysis All forms will be entered in a trial defined database for which some consistency checking will be programmed in. Data managers will check for missing and invalid data using SQL queries and statistical programs. Any queries will be highlighted on trial specific query forms and returned to the centre for correction and/or clarification. The data will be stored on a secure server access to which is restricted to MAHSC-CTU staff. The data management procedures can be found in the PIT Data Management Manual, this is an internal document created for use by the Data Manager within the MAHSC-CTU and contains all procedures defined to ensure the data management and validation procedures are properly carried out.

Ethics and Dissemination Protocol and Protocol amendments The trial details documented here are consistent with PIT study protocol V3.0 (dated: 19

th

April 2012, available on request from the trial manager, MAHSC-CTU). There have been two substantial amendments for the study.

i) 25/04/2012- addition of an inclusion criterion ‘Indwelling pleural catheter in-situ at the intervention site’ and several administrative updates to the protocol and patient information sheets. The amendment also included the home and outpatient VAS questionnaires.

ii) 17/04/2013- introduction of the VAS chest wall nodule page which the patient is asked to complete if they develop chest wall nodules

Trial Monitoring The trial management group (TMG) is responsible for reviewing the trial’s day-to-day activities, the overall supervision of the trial and ensure that it is being conducted in accordance with the principles of GCP and relevant regulations. The group should agree any protocol amendments and provide advice to the investigators on all aspects of the trial. The TMG meets twice a year and includes patient/carer representatives, respiratory physicians, thoracic surgeons, clinical oncologists, medical oncologists, and clinical nurse specialists. Three additional members who are independent of the trial have been appointed and will be available to advise the TMG should any issues arise requiring an independent viewpoint. An Independent Data Monitoring Committee (IDMC) will not be appointed for this trial as PIT is currently widely used in clinical practice, it is not a new treatment and we not envisage that any safety issues will arise. Trial Sponsorship The study is sponsored by The Christie NHS Foundation Trust, Research & Development Department, Wilmslow Road, Manchester, M20 4BX, UK Trial Management The Manchester Academic Health Science Centre Clinical Trial Unit is co-ordinating the study. This includes data collection, management, monitoring, analysis, and interpretation of data. The PIT TMG will write the report and will make the decision to submit the report for publication. Safety Reporting An Adverse Event (AE) is defined on this trial as any untoward medical occurrence in a clinical trial subject which does not necessarily have a causal relationship with the trial related procedures. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease. A Serious Adverse Event (SAE) for this trial is an Adverse Event only if it meets the following criteria.

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• results in death (within 90 days of last dose of radiotherapy and is considered related to trial radiotherapy)

• is life-threatening (and is considered related to the trial radiotherapy)

• requires hospitalisation, or prolongation of existing hospitalisation (and is considered related to trial radiotherapy).

• results in persistent or significant disability or incapacity (and is considered related to trial radiotherapy)

• is a congenital anomaly or birth defect

• Other medically significant event. Medical judgement should be exercised in deciding whether an AE is serious in other situations. Important AEs that are not immediately life-threatening or do not result in death or hospitalisation, but may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in the definition above, should also be considered serious.

Disease progressions or events related to disease progressions are not considered to be SAEs. Adverse events relating to other anti-cancer treatments that the patient may be receiving are not considered to be SAEs. All Serious Adverse Events (SAEs) are reported by site teams to the MAHSC-CTU within 24 hours of the investigator being made aware of the event. End of the trial The study will close 2 years after the 374

th patient is randomised. The Chief Investigator,

TMG and/or the 3 independent members have the right at any time to terminate the study for clinical or administrative reasons. The end of the study will be reported to the REC and Regulatory Authority (where applicable) within the required timeframes. Investigators will inform participants of any premature termination of the trial and ensure that the appropriate follow up is arranged for all involved. Dissemination Data from all centres will be analysed together and published as soon as possible. Individual participants may not publish data concerning their patients that are directly relevant to questions posed by the trial until the TMG has published its report. The TMG will have access to the final data set, form the basis of the Writing Committee and advise on the nature of publications. The trial will be publicised at regional and national meetings, and to patient groups with the support of Mesothelioma UK. The final results will be presented at scientific meetings and published in a peer-reviewed journal (authorship will be according to the journal’s guidelines). A lay summary will be disseminated via local and national mesothelioma charities. Summary results will also be published online at clinicaltrials.gov and cancerhelp.

Current status Trial identifiers: ISRCTN: 04240319; Clinical Trials.gov: NCT01604005 60 research sites are open to and 55 have enrolled patients into the trial. It is anticipated that the recruitment will be completed by the end of 2015. The main analysis and publication of the primary endpoint results is planned for autumn 2016 with a further follow-up analysis and publication in 2018. The Protocol development group includes of Prof Corinne Faivre-Finn, Dr Paul Taylor, Dr Mick Peake, Dr Robert Rintoul, Prof David Baldwin, Dr Michael Snee, Dr Jason Lester, Mr John Edwards, Dr Neil Bayman, Ms Liz Darlison, Mr David Ardron, Mrs Linda Ashcroft. Dr Bayman as his role as Chief Investigator facilitated the development of the 1st version of the protocol.

Trial support

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The trial is being coordinated by the Manchester Academic Health Science Centre, Trials Coordination Unit (MAHSC-CTU). Additional study information can be obtained from the PIT trial manager or trial statistician Contact details Trial Manager: Brynn Chappell, [email protected], Tel +44 (0)161 918 7945 Trial Statistician: Linda Ashcroft, [email protected],

Ethics

The trial has been reviewed by NRES Committee North West - Greater Manchester West which granted ethical approval for the study on 4

th April 2012 (REC reference 12/NW/0249).

Provenance & Peer review The study was externally reviewed as part of the grant application process.

Funding This paper presents independent research commissioned by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfpB) Programme (Grant Reference Number PB-PG-1010-23232). The views expressed are those of the authors and not necessarily the NHS, the NIHR or the Department of Health. Acknowledgments We would like to thank all the patients that have agreed to participate in this trial, the principal investigators and the site teams around the UK involved in set-up, recruitment and follow-up of the study. This study was designed with patient involvement and patient representation on the protocol development committee and trial management group. We would also like to thank Alice Taylor for editorial assistance.

Dr Robert Rintoul is part funded by the Cambridge Biomedical Research Centre, Cambridge

Cancer Centre and the Clinical Research Network:Eastern. Competing interests statement The PIT Trial Management Group members have no competing interests to declare. Open access The protocol for this trial is summarised in this open access paper. There will not be open access to the participant-level dataset.

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