Study of Chemoradiotherapy in Oesophageal Cancer Including PET Response and Dose Escalation (SCOPE2)

SCOPE2 - A Randomised Phase II/III Trial to Study Radiotherapy Dose Escalation in Patients With Oesophageal Cancer Treated With Definitive Chemo-radiation With an Embedded Phase II Trial for Patients With a Poor Early Response Using Positron Emission Tomography (PET)

Research has shown that increasing the dose of radiotherapy improves outcomes in patients with lung and head and neck cancers. This study aims to see whether this is also the case for patients with tumour of the oesophagus. This trial will compare the effects of the standard dose of radiotherapy to a higher dose whilst closely monitoring the side effects.

A comparison will also be made regarding the effects of the standard drugs used in chemotherapy (cisplatin and capecitabine) with an alternative combination (carboplatin and paclitaxel) in patients that do not show a response to chemotherapy with standard drugs early on in treatment.

All patients will receive 6 weeks of chemotherapy and 5 weeks of chemoradiotherapy.

How the study will be conducted:

Prior to the commencement of treatment each patient will have a special scan called a PET scan. Patients will receive a second PET scan two weeks after the start of standard chemotherapy. The changes between the two scans will then be used to allocate treatment into the different arms of the study. All study subjects will be randomised to receive either the standard radiotherapy dose or the high radiotherapy dose. The participants that do not respond to the first cycle of standard chemotherapy will be eligible to take part in the aspect of the trial looking at an alternative chemotherapy regimen. Patients will be randomised as follows;

On the basis of the second PET scan, patients who are not responding to standard chemotherapy will be allocated by a computer to one of the four groups detailed below:

• Standard chemotherapy and standard dose of radiotherapy
• Standard chemotherapy and higher dose of radiotherapy
• Alternative chemotherapy and standard dose of radiotherapy
• Alternative chemotherapy and higher dose of radiotherapy

Patients who are responding to standard chemotherapy (or where the response is unknown or those who were not eligible for PET scan portion of the study) will be allocated by a computer to one of two groups detailed below:

• Standard chemotherapy and standard dose of radiotherapy
• Standard chemotherapy and higher dose of radiotherapy

The arms within each of the groups above (responders and non-responders) will be equal in size and patients will be allocated randomly by a computer.

This study will also compare the way that this treatment affects the two different cell types found in oesophageal tumours.

The effects of the different treatment, together with the costs of the different treatment and the effects on quality of life will be analysed to see which is more effective for each of the different groups.

Study Overview

• Status: Recruiting
• Conditions: Oesophageal Cancer
• Intervention / Treatment: Drug: Carboplatin; Drug: Paclitaxel; Drug: Cisplatin; Drug: Capecitabine; Radiation: Radiotherapy

• Study Type: Interventional
• Enrollment (Anticipated): 584
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Sarah Bridges; Phone Number: +44 2920 687869; Email: scope2@cardiff.ac.uk
• Study Contact Backup: Name: Lisette Nixon, PhD; Phone Number: +44 2920687459; Email: nixonls@cardiff.ac.uk

Study Locations

• United Kingdom
  • Aberdeen, United Kingdom
    • Recruiting
    • Aberdeen Royal Infirmary
    • Contact: Lucy Wells
  • Bristol, United Kingdom
    • Recruiting
    • Bristol Haematology & Oncology
    • Contact: Stephen Falk
  • Cambridge, United Kingdom
    • Recruiting
    • Addenbrooke's Hospital
    • Contact: Susan Harden
  • Canterbury, United Kingdom
    • Not yet recruiting
    • Kent and Canterbury
    • Contact: Mathilda Cominos
  • Cardiff, United Kingdom, CF14 2TL
    • Recruiting
    • Velindre Cancer Care Centre
    • Contact: Carys Morgan; Phone Number: 02920 615 888; Email: carys.morgan6@wales.nhs.uk
  • Cheltenham, United Kingdom
    • Recruiting
    • Cheltenham General Hospital
    • Contact: Charles Candish
  • Coventry, United Kingdom
    • Recruiting
    • University Hospital Coventry
    • Contact: Sharmila Sothi
  • Derby, United Kingdom
    • Recruiting
    • Derby Teaching Hospitals NHS Trust
    • Contact: Prantik Das
  • Glan Clwyd, United Kingdom
    • Recruiting
    • Glan Clwyd Hospital
    • Contact: Angel Garcia
  • Glasgow, United Kingdom
    • Recruiting
    • Beatson West of Scotland Cancer Centre
    • Contact: David McIntosh
  • Gloucester, United Kingdom
    • Recruiting
    • Gloucestershire Royal Hospital
    • Contact: Charles Candish
  • Hull, United Kingdom
    • Recruiting
    • Castle Hill Hospital
    • Contact: Raj Roy
  • Liverpool, United Kingdom
    • Recruiting
    • The Clatterbridge Cancer Centre NHS Foundation Trust
    • Contact: Raj Sripadam
  • London, United Kingdom
    • Recruiting
    • North Middlesex Hospital
    • Contact: Lucinda Melcher
  • London, United Kingdom
    • Recruiting
    • Imperial College Healthcare NHS Trust
    • Contact: Danielle Power
  • London, United Kingdom
    • Recruiting
    • Guy's and St Thomas'
    • Contact: Asad Qureshi
  • London, United Kingdom
    • Recruiting
    • The Royal Marsden Hospitals (Fulham)
    • Contact: Katharine Aitken
  • Middlesbrough, United Kingdom
    • Recruiting
    • The James Cook University Hospital
    • Contact: David Wilson
  • Oxford, United Kingdom
    • Recruiting
    • Churchill Hospital
    • Contact: Somnath Mukherjee
  • Peterborough, United Kingdom
    • Recruiting
    • Peterborough and Stamford Hospitals NHS Foundation Trust
    • Contact: Catherine Jephcott
  • Sheffield, United Kingdom
    • Recruiting
    • Sheffield Teaching Hospitals - Weston Park Hospital
    • Contact: Jon Wadsley
  • Southampton, United Kingdom
    • Recruiting
    • University Hospital Southampton NHS Foundation Trust
    • Contact: Andrew Bateman
  • Sutton, United Kingdom
    • Recruiting
    • The Royal Marsden Hospitals (Sutton, Surrey)
    • Contact: Katharine Aitken
  • Swansea, United Kingdom
    • Recruiting
    • Singleton Hospital
    • Contact: Sarah Gwynne
  • Worcester, United Kingdom
    • Recruiting
    • Worcestershire Royal Hospital
    • Contact: Cheng Boon
  • Wrexham, United Kingdom
    • Recruiting
    • Wrexham Maelor
    • Contact: Simon Gollins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 15 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Main inclusion criteria:

1. 17 years of age or older.
2. Have been selected to receive potentially curative definitive chemoradiotherapy by a specialist Upper GI MDT.
3. Histologically confirmed adenocarcinoma, undifferentiated cancer or squamous cell carcinoma.
4. Tumours of the cervical, thoracic oesophagus, or gastro-oesophageal junction (GOJ) with proximal extent of disease no more proximal than 15cm ab oral and distal extent of primary tumour no more than 2 cm beyond the GOJ.
5. Tumours staged with endoscopic ultrasound*, CT and PET-CT to be T1-4 and N+/- (provided total tumour length including nodes is ≤10).
6. Total contiguous disease length ≤10cm defined by CT, EUS and/or PET. The primary tumour should also be ≤8cm.
7. WHO performance status 0 or 1.
8. Adequate cardiovascular function for safe delivery of chemo-radiation in the opinion of the principal investigator. Where there is clinical concern patients should have an adequate cardiac ejection fraction ≥ 40% as determined by MUGA scan or ECHO (within 4 weeks prior to enrolment).
9. Adequate respiratory function for safe delivery of chemo-radiation in the opinion of the Principal Investigator. Where there is clinical concern FEV1 ≥ 1 litre as determined by spirometry (within 4 weeks prior to enrolment).
10. Patients with clinically significant hearing impairment (hearing loss with hearing aid, or hearing loss where intervention indicated, or limiting daily activities or tinnitus limiting daily activities or sensory-motor neuropathy are eligible, however, cisplatin will be replaced by carboplatin (AUC 5)
11. Adequate haematological, hepatic and renal function
12. Patients agree to use effective forms of contraception during the trial (if applicable to patient).

13. Patients who have provided written informed consent prior to enrolment.

    Additional inclusion criteria for patient eligibility for PET randomisation (cisplatin/capecitabine vs carboplatin/paclitaxel) as assessed at local centre:

14. Baseline SUVmax ≥ 5.
15. PET scan 14 days after start of chemo (-2/+3 days from this date is acceptable)
16. Not responding to early cis/cape chemotherapy (this is defined as patients having a <35% reduction in SUVmax)

18. To be eligible for PET randomisation, the baseline PET-CT must have been within 4 weeks prior to start date of treatment.

Patients that are eligible for the trial but are ineligible for PET randomisation will be randomised to receive 50/60Gy radiotherapy plus cisplatin and capecitabine.

* Patients where the EUS scope is unable to pass are eligible.

Main exclusion criteria:

1. Patients who have had previous treatment for invasive oesophageal carcinoma or gastro-oesophageal junction carcinoma (not including PDT or laser therapy for high grade dysplasia/carcinoma in-situ).
2. Patients with metastatic disease i.e. M1a or M1b according to UICC TNM version 7.
3. Patients with other active malignancy or past malignancy in remission for less than 3 years are not eligible for the trial. However, patients with the following conditions which have been curatively treated will NOT be excluded: basal cell carcinoma, carcinoma-in-situ breast and carcinoma-in-situ cervix.
4. Patients with >2cm mucosal extension of tumour into the stomach or where the superior extent is proximal to 15 cm ab oral.
5. Patients with unstable angina or uncontrolled hypertension or cardiac failure or other clinically significant cardiac disease.
6. Patients who need continued treatment with a contraindicated concomitant medication or therapy.
7. Patients with known dihydropyrimidine dehydrogenase (DPD) deficiency.

9. Patients with serious infections

10. Known hypersensitivity to IMPs.

11. Women who are pregnant or breastfeeding.

12. Oesophageal stent (patients requiring a PEG/RIG/feeding jejunostomy for nutritional purposes are eligible).

13. Any other situation, which in the opinion of the local PI, makes the patient an unsuitable candidate for this trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1 (carboplatin/paclitaxel+standard RT dose); Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: carboplatin AUC 5 on D1 and paclitaxel 175mg/m2 on D1 Week 7-11: Weekly carboplatin AUC 2 and paclitaxel 50mg/m2 concomitant with radiotherapy (50Gy/25 fractions)	Drug: Carboplatin; For more information please see the arm descriptions section.; Drug: Paclitaxel; For more information please see the arm descriptions section.; Drug: Cisplatin; For more information please see the arm descriptions section.; Drug: Capecitabine; For more information please see the arm descriptions section.; Radiation: Radiotherapy; For more information please see the arm descriptions section.
Experimental: Arm 2 (cisplatin/capecitabine+standard RT dose); Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 3: Week 7-9: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 4: Week 10-11: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-14 Cycles 3 and 4 are given concomitantly with radiotherapy (50Gy/25 fractions). Capecitabine stops on last day of RT.	Drug: Cisplatin; For more information please see the arm descriptions section.; Drug: Capecitabine; For more information please see the arm descriptions section.; Radiation: Radiotherapy; For more information please see the arm descriptions section.
Experimental: Arm 3 (carboplatin/paclitaxel+high RT dose); Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: carboplatin AUC 5 on D1 and paclitaxel 175mg/m2 on D1 Week 7-11: Weekly carboplatin AUC 2 and paclitaxel 50mg/m2 concomitant with radiotherapy (60Gy/25 fractions)	Drug: Carboplatin; For more information please see the arm descriptions section.; Drug: Paclitaxel; For more information please see the arm descriptions section.; Drug: Cisplatin; For more information please see the arm descriptions section.; Drug: Capecitabine; For more information please see the arm descriptions section.; Radiation: Radiotherapy; For more information please see the arm descriptions section.
Experimental: Arm 4 (Cisplatin+Capecitabine+high RT dose); Cycle 1: Week 1-3: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 2: Week 4-6: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 3: Week 7-9: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-21 Cycle 4: Week 10-11: cisplatin 60mg/m2 on D1 and capecitabine 625mg/m2 bd D1-14 Cycles 3 and 4 are given concomitantly with radiotherapy (60Gy/25 fractions). Capecitabine stops on last day of RT.	Drug: Cisplatin; For more information please see the arm descriptions section.; Drug: Capecitabine; For more information please see the arm descriptions section.; Radiation: Radiotherapy; For more information please see the arm descriptions section.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary endpoint phase II in squamous cell carcinoma comparing standard dose radiotherapy to high dose radiotherapy	24 week treatment failure free survival (TFFS).	24 weeks
Primary endpoint phase III in squamous cell carcinoma: Overall survival (OS) comparing standard dose radiotherapy to high dose radiotherapy	Overall survival (OS)	24 weeks
Primary endpoint in squamous cell carcinoma when switching chemotherapy	24 week treatment failure free survival (TFFS).	24 weeks
Primary endpoint phase in adenocarcinoma phase II comparing standard dose radiotherapy to high dose radiotherapy	24 week treatment failure free survival (TFFS).	24 weeks
Primary endpoint in adenocarcinoma when switching chemotherapy	24 week treatment failure free survival (TFFS).	24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	Overall survival assessed at each visit. Additionally patients will be flagged with the HSCIC to reduce loss to follow up.	5 years follow up
Progression free survival	Progression free survival (PFS), additionally patients will be flagged with the HSCIC to reduce loss to follow up.	5 years
Quality of Life	Quality of Life (QoL): EORTC QLQ-C30 and EORTC QLQ-OES18 questionnaires	Baseline, week 7, end of treatment, 6, 12 and 24 months
Toxicity	CTCAE v4.03 at baseline, after each treatment cycle, and follow up visits. Patients in the dose escalation arm will have additional assessment and 6 and 9 weeks post RT to monitor toxicities.	After each treatment cycle and at follow up visits
Health economics	Health economic data will be collected using health resource utilisation log plus data on health resource usage	Baseline, end of treatment, 6, 12 and 24 months

Collaborators and Investigators

• Sponsor: Lisette Nixon
• Collaborators: Cancer Research UK
• Investigators: Principal Investigator: Tom Crosby, Velindre University NHS Trust

Publications and helpful links

General Publications

• Sakanaka K, Ishida Y, Fujii K, Ishihara Y, Nakamura M, Hiraoka M, Mizowaki T. Radiation Dose-escalated Chemoradiotherapy Using Simultaneous Integrated Boost Intensity-Modulated Radiotherapy for Locally Advanced Unresectable Thoracic Oesophageal Squamous Cell Carcinoma: A Single-institution Phase I Study. Clin Oncol (R Coll Radiol). 2021 Mar;33(3):191-201. doi: 10.1016/j.clon.2020.07.012. Epub 2020 Aug 4.

Study record dates

Study Major Dates

• Study Start (Actual): November 4, 2016
• Primary Completion (Anticipated): April 1, 2021
• Study Completion (Anticipated): April 1, 2023

Study Registration Dates

• First Submitted: April 12, 2016
• First Submitted That Met QC Criteria: April 12, 2016
• First Posted (Estimate): April 18, 2016

Study Record Updates

• Last Update Posted (Actual): October 25, 2018
• Last Update Submitted That Met QC Criteria: October 24, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Esophageal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel; Cisplatin; Capecitabine
• Other Study ID Numbers: 2014/VCC/0015; 2015-001740-11 (EudraCT Number); Ethics Reference Number (Other Identifier: 15/WA/0395)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided