Standardisation of Radiotherapy (START) Trial

Lead Research Organisation: Institute of Cancer Research
Department Name: Division of Radiotherapy and Imaging

Abstract

The patient advocate group Radiotherapy Action Group Exposure (R.A.G.E.) has become a strong supporter of the START initiative over the years, with 2 members represented on the Trial Management Group. Issues relating to radiotherapy fractionation have emerged repeatedly in the media over the last 20 years. The understanding of scientific issues by the majority of lay people and a minority of professionals has been poor. The trial has achieved a high public profile across the UK including a discussion on Panorama. A highly productive debate has changed the climate, with the importance of evidence based medicine acknowledged by all parties.

Technical Summary

Breast radiotherapy is delivered as a series of small
doses (fractions). The international standard delivers
25 fractions of 2.0 Gy over 5 weeks (Gy = unit of
radiation dose). Alternative UK schedules give a
smaller number of slightly larger fractions e.g.
15 fractions of 2.67 Gy over 3 weeks.
If simpler schedules prove to be at least as safe
and effective as the international standard, their
adoption will benefit patients and health services.
The START trial tests the hypothesis that schedules
using fractions slightly larger than 2.0 Gy are safe
and effective alternatives to the international
standard.

Publications

10 25 50
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Barnett GC (2014) A genome wide association study (GWAS) providing evidence of an association between common genetic variants and late radiotherapy toxicity. in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

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Barnett GC (2012) Individual patient data meta-analysis shows no association between the SNP rs1800469 in TGFB and late radiotherapy toxicity. in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

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Bartlett FR (2013) The UK HeartSpare Study: randomised evaluation of voluntary deep-inspiratory breath-hold in women undergoing breast radiotherapy. in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

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Bartlett FR (2013) Breast radiotherapy and heart disease - where are we now? in Clinical oncology (Royal College of Radiologists (Great Britain))

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Bartlett FR (2014) Response to D. Woolf and M. Keshtgar's reply to: breast radiotherapy and heart disease - where are we now? in Clinical oncology (Royal College of Radiologists (Great Britain))

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Bartlett FR (2014) Voluntary breath-hold technique for reducing heart dose in left breast radiotherapy. in Journal of visualized experiments : JoVE

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Bartlett FR (2015) The UK HeartSpare Study (Stage IB): randomised comparison of a voluntary breath-hold technique and prone radiotherapy after breast conserving surgery. in Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology

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Bartlett FR (2013) Multileaf collimation cardiac shielding in breast radiotherapy: Cardiac doses are reduced, but at what cost? in Clinical oncology (Royal College of Radiologists (Great Britain))

 
Guideline Title Recommendations for hypofractionated whole-breast irradiation
Description Citation in Brazilian Society of Radiotherapy (SBRT) guidelines
Geographic Reach South America 
Policy Influence Type Citation in clinical guidelines
Impact START cited in guideline as an evidence-base for the adopted of hypofractionated radiotherapy for breast cancer.
URL http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0104-42302018000900770
 
Description Citation in Cochrane Review
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
Impact The new radiotherapy regimen delivers a curative post-surgical treatment for localised breast cancer that is gentler on the healthy tissues and non-inferior in terms of cancer cure. A shorter treatment regimen has allowed more patients to be treated at radiotherapy centres. It has also saved the NHS money as many fewer treatment sessions have been needed.
URL http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003860.pub4/abstract
 
Guideline Title NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer
Description Citation in NCCN Guidelines
Geographic Reach North America 
Policy Influence Type Citation in clinical guidelines
Impact The National Comprehensive Cancer Network (NCCN) is a nonprofit alliance of 27 cancer centers throughout the U.S. Experts from NCCN cancer centers diagnose and treat all cancers, with a particular focus on complex, aggressive, or uncommon cancers. The National Comprehensive Cancer Network also develops the NCCN Clinical Practice Guidelines in Oncology, a set of recommendations designed to help health care professionals diagnose, treat, and manage cancer patient care. These guidelines reference START in their recommendations for hypofractionation in early breast cancer.
URL https://jnccn.org/view/journals/jnccn/15/5S/article-p682.xml
 
Description Citation in meta-analysis
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in systematic reviews
Impact The meta-analysis included the results of six RCTs, including START A, START B and FAST and concluded that there is no difference between conventional fractionation and hypofractionation in terms of efficacy (recurrence, disease free survival and mortality).
URL https://www.sciencedirect.com/science/article/pii/S0960977619305399
 
Guideline Title Smith et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline.
Description Hypofractionated whole breast irradiation recommended for patients with breast cancer regardless of age, tumour stage, and previous chemotherapy treatment
Geographic Reach North America 
Policy Influence Type Citation in clinical guidelines
Impact This guideline offers recommendations on fractionation for whole breast irradiation (WBI) and guidance on treatment planning and delivery. It recommends hypofractionated whole breast irradiation (HF-WBI) for patients with breast cancer regardless of age, tumour stage, and previous chemotherapy treatment. It replaced previous ASTRO guideline published on dose-fractionation for WBI published in 2011 which recommended hypofractionation for early-stage breast cancer patients meeting specific criteria. The START trial is quoted in the supplemental material as evidence for the recommendation regarding the preferred dose-fractionation scheme.
URL https://www.sciencedirect.com/science/article/pii/S1879850018300511?via%3Dihub
 
Guideline Title Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline
Description Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The results of research I have led, involving a series of phase 3 clinical trials in patients with early breast cancer, have been incorporated as a standard of care in international practice in UK, mainland Europe, North America, South America, India and China
 
Guideline Title NICE: Early and locally advanced breast cancer: diagnosis and treatment
Description Replacement of standard 5-week course of curative radiotherapy with a 3-week course
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact A 3-week course of curative radiotherapy for women with early breast cancer has replaced the 5-week standard of care in UK since 2009 and is currently a standard of care in most European countries, North America, India and South America. Apart from a proportional (40%) reduction in hospital resource costs, which are applicable to approximately 40,000 women per year in the UK, and many hundreds of thousands of women worldwide, there are fewer travel costs and lost days of work for patients.
 
Description Clinical Trials Award - HOT II/Cancer Research UK (CRUK) and Department of Health
Amount £234,385 (GBP)
Funding ID C181/A9694 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2011
 
Description Clinical Trials Award - HOT II/Cancer Research UK (CRUK) and Department of Health
Amount £230,000 (GBP)
Funding ID C181/A9694 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 01/2009 
End 12/2011
 
Description Clinical Trials Awards & Advisory Committee - Late Phase Study
Amount £1,000,000 (GBP)
Funding ID C1491/A16831 
Organisation Cancer Research UK 
Department CTAAC Clinical Trials Advisory & Awards
Sector Charity/Non Profit
Country United Kingdom
Start 08/2012 
End 07/2020
 
Description EC FP6 (EURATOM)
Amount £185,500 (GBP)
Funding ID FI6R-036452 
Organisation Sixth Framework Programme (FP6) 
Sector Public
Country European Union (EU)
Start 09/2006 
End 08/2009
 
Description Health Protection Agency
Amount £182,524 (GBP)
Organisation Public Health England 
Sector Public
Country United Kingdom
Start 04/2012 
End 03/2014
 
Description NIHR Health Technology Assessment programme FAST-Forward
Amount £3,639,054 (GBP)
Funding ID 09/01/47 
Organisation National Institute for Health Research 
Department Health Technology Assessment Programme (HTA)
Sector Public
Country United Kingdom
Start 09/2011 
End 03/2016
 
Description NIHR Research Capability Funding
Amount £27,179 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 08/2013 
End 03/2014
 
Description Research Grant
Amount £160,257 (GBP)
Funding ID PR11 
Organisation Breast Cancer Campaign (BCC) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2007 
End 02/2010
 
Description Translational Grant - RACE(S)
Amount £126,783 (GBP)
Funding ID C181/A6976 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2006 
End 04/2008
 
Description DNA double-strand break repair and induction of apoptosis in ex vivo irradiated blood lymphocytes in relation to late normal tissue reactions following breast radiotherapy 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution I drafted the original research proposal, and the research subjects were patients under my care who has participated in national clinical trial led by myself. My team also collected the blood samples for fresh transport to Didcot
Collaborator Contribution A clinical research fellow performed the laboratory assays as part of his PhD.
Impact PMID: 21620495 PMID: 21704405 PMID: 24622963 PMID: 26944319 PMID: 27106550 PMID: 27197782
Start Year 2008
 
Description NIH 01: A genome wide association study for the identification of radiation-induced normal tissue toxicity in breast cancer patients treated with radiotherapy 
Organisation Mount Sinai Hospital (USA)
Country United States 
Sector Hospitals 
PI Contribution We have jointly submitted this grant application to the NIH in America.
Collaborator Contribution Co-applicant on an NIH grant application.Co-applicant on an NIH grant application.
Impact This grant application was rejected but we are intending reapplying in 2011.
Start Year 2008
 
Description NIH 01: A genome wide association study for the identification of radiation-induced normal tissue toxicity in breast cancer patients treated with radiotherapy 
Organisation New York University
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution We have jointly submitted this grant application to the NIH in America.
Collaborator Contribution Co-applicant on an NIH grant application.Co-applicant on an NIH grant application.
Impact This grant application was rejected but we are intending reapplying in 2011.
Start Year 2008
 
Description The Relationship Between Homologous Recombination Repair and the Sensitivity of Human Epidermis to the Size of Daily Doses Over a 5-Week Course of Breast Radiotherapy 
Organisation Public Health England
Department Public Health England Porton Down
Country United Kingdom 
Sector Public 
PI Contribution The research plan was designed by me, and the breast cancer patients contributing serial skin biopsies to the research were treated under my care. A clinical research fellow collected the skin samples and analysed them at Oxford and Didcot as part of her PhD degree
Collaborator Contribution Partners were responsible for the laboratory aspects of this correlative research
Impact PMID: 22855580 PMID: 23746696
Start Year 2007
 
Description The Relationship Between Homologous Recombination Repair and the Sensitivity of Human Epidermis to the Size of Daily Doses Over a 5-Week Course of Breast Radiotherapy 
Organisation University of Oxford
Department Department of Oncology
Country United Kingdom 
Sector Academic/University 
PI Contribution The research plan was designed by me, and the breast cancer patients contributing serial skin biopsies to the research were treated under my care. A clinical research fellow collected the skin samples and analysed them at Oxford and Didcot as part of her PhD degree
Collaborator Contribution Partners were responsible for the laboratory aspects of this correlative research
Impact PMID: 22855580 PMID: 23746696
Start Year 2007
 
Title START clinical trial 
Description This is a clinical trial testing hypofractionated radiotherapy for the treatment of early breast cancer. 
Type Therapeutic Intervention - Radiotherapy
Current Stage Of Development Late clinical evaluation
Development Status Closed
Clinical Trial? Yes
Impact The reduced fractionation in the START trials is now UK standard of care. 
URL http://www.isrctn.com/ISRCTN59368779
 
Description ECC 2013 press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact The organisers of the conference ECC2013 decided to release a press statement for the poster presentation as the results were thought to be highly significant for the radotherapy community.

There was a lot of press coverage for the results of this poster.
Year(s) Of Engagement Activity 2013
 
Description Lancet Oncology press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact This was the press release for the 10 year results of the START trial which was written by Lancet Oncology.

There were a lot of articles in national press.
Year(s) Of Engagement Activity 2013
 
Description Lay Summary for patients 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact We wrote a lay summary of the published trial results for the participants in the trial. This was then circulated to the recruiting centres to send or give out to the patients.

We are not aware of any impact of this policy.
Year(s) Of Engagement Activity 2008
 
Description Poster presentation at European Cancer Congress 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Poster Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact The poster was selected for a poster presentation at ECC 2013 and presented important results about wasted radiotherapy dose during treatment for breast cancer. The title and authors of the poster were: Estimation of an overall treatment time factor for local relapse after adjuvant radiotherapy for early breast cancer in the START hypofractionation trials (CRUK/96/001); JS Haviland, SM Bentzen, M Sydenham, JR Owen, JM Bliss, JR Yarnold on behalf of the START Trialists' Group.

There was a lot of press coverage of these results.
Year(s) Of Engagement Activity 2013
 
Description Press Release San Antonio Dec 2012 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The START trial 10 year results were chosen by the San Antonio Conference for their press conference.

The press conference was attended by press from North America and Europe
Year(s) Of Engagement Activity 2012
 
Description Press release from CRUK 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact This was a press release from the funders to accompany the 10 year results of the START trial when published in Lancet Oncology

Lots of coverage of the trial results in the national press.
Year(s) Of Engagement Activity 2013
 
Description Press release to accompany ASCO presentation 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? Yes
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact The START trial presentation was selected for ASCO press coverage, which comprised a press conference and a press release. This is only for those presentations considered "Best at ASCO".

We were approached by Lancet to pubish the results in their journal.
Year(s) Of Engagement Activity 2008
 
Description San Antonio Breast Cancer Conference 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Paper Presentation
Geographic Reach International
Primary Audience Health professionals
Results and Impact The conference attracts nearly 10000 participants from 100 countries, all breast cancer specialists. The abtract title and authors are:
The UK START (Standardisation of Breast Radiotherapy) Trials; 10-year follow-up results. Joanne S Haviland, Rajiv Agrawal, Edwin Aird, Jane Barrett, Peter Barrett-Lee, Jackie Brown, John Dewar, Jane Dobbs, Penelope Hopwood, Peter Hoskin, Pat Lawton, Brian Magee, Judith Mills, David Morgan, Roger Owen, Joyce Pritchard, Sandra Simmons, Mark Sydenham, Karen Venables, Judith M Bliss, John R Yarnold.

The results of the START trial will be used in a meta analysis with other hypofractionation trials.
Year(s) Of Engagement Activity 2012