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www.thelancet.com Published online April 28, 2020 https://doi.org/10.1016/S0140-6736(20)30932-6
1
Hypofractionated breast radiotherapy for 1 week versus
3 weeks (FAST-Forward): 5-year efficacy and late normal
tissue effects results from a multicentre, non-inferiority,
randomised, phase 3 trial
Adrian Murray Brunt*, Joanne S Haviland*, Duncan A Wheatley, Mark A Sydenham, Abdulla Alhasso, David J Bloomfield, Charlie Chan,
Mark Churn, Susan Cleator, Charlotte E Coles, Andrew Goodman, Adrian Harnett, Penelope Hopwood, Anna M Kirby, Cliona C Kirwan,
Carolyn Morris, Zohal Nabi, Elinor Sawyer, Navita Somaiah, Liba Stones, Isabel Syndikus, Judith M Bliss†, John R Yarnold†, on behalf of the
FAST-Forward Trial Management Group
Summary
Background We aimed to identify a five-fraction schedule of adjuvant radiotherapy (radiation therapy) delivered in
1 week that is non-inferior in terms of local cancer control and is as safe as an international standard 15-fraction
regimen after primary surgery for early breast cancer. Here, we present 5-year results of the FAST-Forward trial.
Methods FAST-Forward is a multicentre, phase 3, randomised, non-inferiority trial done at 97 hospitals (47 radiotherapy
centres and 50 referring hospitals) in the UK. Patients aged at least 18 years with invasive carcinoma of the breast
(pT1–3, pN0–1, M0) after breast conservation surgery or mastectomy were eligible. We randomly allocated patients to
either 40 Gy in 15 fractions (over 3 weeks), 27 Gy in five fractions (over 1 week), or 26 Gy in five fractions (over 1 week)
to the whole breast or chest wall. Allocation was not masked because of the nature of the intervention. The primary
endpoint was ipsilateral breast tumour relapse; assuming a 2% 5-year incidence for 40 Gy, non-inferiority was
predefined as ≤1·6% excess for five-fraction schedules (critical hazard ratio [HR] of 1·81). Normal tissue eects were
assessed by clinicians, patients, and from photographs. This trial is registered at isrctn.com, ISRCTN19906132.
Findings Between Nov 24, 2011, and June 19, 2014, we recruited and obtained consent from 4096 patients from 97 UK
centres, of whom 1361 were assigned to the 40 Gy schedule, 1367 to the 27 Gy schedule, and 1368 to the 26 Gy
schedule. At a median follow-up of 71·5 months (IQR 71·3 to 71·7), the primary endpoint event occurred in 79 patients
(31 in the 40 Gy group, 27 in the 27 Gy group, and 21 in the 26 Gy group); HRs versus 40 Gy in 15 fractions were 0·86
(95% CI 0·51 to 1·44) for 27 Gy in five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five fractions. 5-year incidence of
ipsilateral breast tumour relapse after 40 Gy was 2·1% (1·4 to 3·1); estimated absolute dierences versus 40 Gy in
15 fractions were –0·3% (–1·0 to 0·9) for 27 Gy in five fractions (probability of incorrectly accepting an inferior five-
fraction schedule: p=0·0022 vs 40 Gy in 15 fractions) and –0·7% (–1·3 to 0·3) for 26 Gy in five fractions (p=0·00019 vs
40 Gy in 15 fractions). At 5 years, any moderate or marked clinician-assessed normal tissue eects in the breast or
chest wall was reported for 98 of 986 (9·9%) 40 Gy patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of 1020 (11·9%)
26 Gy patients. Across all clinician assessments from 1–5 years, odds ratios versus 40 Gy in 15 fractions were 1·55
(95% CI 1·32 to 1·83, p<0·0001) for 27 Gy in five fractions and 1·12 (0·94 to 1·34, p=0·20) for 26 Gy in five fractions.
Patient and photographic assessments showed higher normal tissue eect risk for 27 Gy versus 40 Gy but not for
26 Gy versus 40 Gy.
Interpretation 26 Gy in five fractions over 1 week is non-inferior to the standard of 40 Gy in 15 fractions over 3 weeks
for local tumour control, and is as safe in terms of normal tissue eects up to 5 years for patients prescribed adjuvant
local radiotherapy after primary surgery for early-stage breast cancer.
Funding National Institute for Health Research Health Technology Assessment Programme.
Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
Introduction
The Early Breast Cancer Trialists’ Collaborative Group
systematic overview confirms that radiotherapy after
primary surgery in women with early-stage cancers
reduces locoregional cancer recurrence and breast cancer
deaths, including patients with positive lymph nodes
treated by mastectomy and axillary clearance.1,2 For many
decades, schedules of adjuvant radiotherapy for these
patients delivered 25 fractions of 2 Gy over 5 weeks.
Randomised controlled trials with long-term follow-up
have since confirmed that fewer, larger fractions giving a
lower total dose are at least as safe and eective as the
previously used international standard.3–10 Specifically,
mature data confirm the safety and non-inferiority of 15 or
Published Online
April 28, 2020
https://doi.org/10.1016/
S0140-6736(20)30932-6
See Online/Comment
https://doi.org/10.1016/
S0140-6736(20)30978-8
*Joint first authors
†Joint senior authors
University Hospitals of
North Midlands and University
of Keele, Stoke on Trent, UK
(Prof A Murray Brunt FRCR);
Clinical Trials and Statistics
Unit, The Institute of Cancer
Research, Sutton, London, UK
(Prof A Murray Brunt,
J S Haviland MSc,
M A Sydenham BSc,
Prof P Hopwood MD,
L Stones BA, Prof J M Bliss MSc);
Royal Cornwall Hospital,
Treliske, Truro, UK
(D A Wheatley FRCR); Beatson
West of Scotland Cancer
Centre, Glasgow, UK
(A Alhasso FRCR); Brighton and
Sussex University Hospitals,
Brighton, UK
(D J Bloomfield FRCR); Nuffield
Health Cheltenham Hospital,
Cheltenham, UK (C Chan FRCS);
Worcestershire Acute Hospitals
NHS Trust, Worcester, UK
(M Churn FRCR); Imperial
Healthcare NHS Trust, London,
UK (S Cleator FRCR); University
of Cambridge, Cambridge, UK
(Prof C E Coles FRCR); Royal
Devon and Exeter NHS
Foundation Trust, Exeter, UK
(A Goodman FRCR); Torbay
Hospital NHS Foundation
Trust, Torquay, UK
(A Goodman); Norfolk and
Norwich University Hospital,
Norwich, UK (A Harnett FRCR);
The Royal Marsden NHS
Foundation Trust and The
Institute of Cancer Research,
London, UK (A M Kirby MD,
N Somaiah FRCR,
Articles
2
www.thelancet.com Published online April 28, 2020 https://doi.org/10.1016/S0140-6736(20)30932-6
Prof J R Yarnold FRCR);
University of Manchester,
Manchester, UK
(Prof C C Kirwan FRCS);
Independent Cancer Patients’
Voice, London, UK (C Morris);
Mount Vernon Cancer Centre,
Northwood, UK (Z Nabi BSc);
King’s College London, London,
UK (Prof E Sawyer FRCR); and
Clatterbridge Cancer Centre,
Bebington, Wirral, UK
(I Syndikus FRCR)
Correspondence to:
Professor A Murray Brunt,
c/o Clinical Trials and Statistics
Unit, The Institute of Cancer
Research, Sutton,
London SM2 5NG, UK
fastforward-icrctsu@icr.ac.uk
16 fractions of about 2·7 Gy to total doses of 40·0 Gy or
42·5 Gy.5,8 A 3-week schedule of 15 fractions has been
the UK standard of care for adjuvant locoregional radio-
therapy for early breast cancer since 2009 and is now an
international standard for adjuvant local radiotherapy.11,12
There is no reason to assume that 15 fractions represent
the lower limits of this hypofractionated and accelerated
approach. We report outcomes of the FAST-Forward
randomised phase 3 trial testing two dose levels of a five-
fraction regimen delivered in 1 week against 40 Gy in
15 fractions over 3 weeks for patients prescribed local
radiotherapy after breast conservation surgery or
mastectomy for early breast cancer. The objectives are to
identify a 1-week schedule non-inferior to a standard
3-week regimen for 5-year local tumour control and
similar in terms of late adverse eects. FAST-Forward was
informed by the FAST trial that tested two dose levels of
five once-weekly fractions;13,14 FAST trial results to 10-year
follow-up are to be published soon. The trial design used
dose levels estimated to be the upper and lower bounds
that are isoeective with the control schedule in terms of
tumour control and normal tissue eects.
Methods
Study design
FAST-Forward is a multicentre, non-blinded, phase 3,
randomised, non-inferiority trial, done at 97 hospitals
(47 radiotherapy centres and 50 referring hospitals) in
the UK, testing the safety and ecacy of five-fraction
schedules of adjuvant radiotherapy to the whole breast
or chest wall delivered in 1 week compared with the UK
standard 15-fraction 3-week schedule. Substudies
included a published acute toxicity study,15 photo -
graphic assess ments of late adverse eects, and patient-
reported outcomes; not all centres participated in the
substudies. Following recruitment into the main trial a
further substudy opened, testing the same fractionation
schedules for patients requiring radiotherapy to the
axilla or supraclavicular fossa lymph nodes after sentinel
node biopsy or supraclavicular fossa only (levels 3–4)
after axillary dissection with a primary endpoint
focusing on safety. Patients and results from this
substudy are not reported here because follow-up is not
yet mature. FAST-Forward was approved by the national
South East Coast Kent research ethics committee
(11/LO/0958) and local research and development
oces of all participating centres. The trial protocol is
in the appendix (pp 15–78).
Patients
Eligible patients were women or men aged at least 18 years
with invasive carcinoma of the breast (pT1–3, pN0–1, M0)
following complete microscopic excision of the primary
tumour by breast conservation surgery or mastectomy
(reconstruction allowed), recruited in the UK from
47 radiotherapy centres and 50 referral centres. A protocol
amendment on Feb 15, 2013, excluded the lowest-risk
patients (aged ≥65 years, pT1, grade 1 or 2, oestrogen
Research in context
Evidence before this study
We searched PubMed on April 22, 2020, using the search terms
“breast cancer”, “adjuvant radiotherapy”, “hypofractionation”,
and “randomised clinical trials”. We searched for primary
research and reviews published in English between Jan 1, 1980,
and April 22, 2020. We found 13 randomised studies testing
adjuvant breast hypofractionated radiotherapy regimens
against standard fractionation ranging in sample size from 30 to
2236 patients. All offered consistent support for the
experimental approach.
Radiotherapy (radiation therapy) after primary surgery for early
breast cancer has historically been delivered in five daily doses
(fractions) of 1·8–2·0 Gy per week over at least 5 weeks,
but randomised phase 3 clinical trials done in Canada, the UK,
and subsequently, China and Denmark have confirmed the
safety and efficacy of 15-fraction or 16-fraction schedules using
daily fractions of 2·7 Gy. Four of these trials published 10-year
follow-up data on a total of 7000 patients, and 3-week
schedules have replaced traditional regimens in many countries
over the past decade for most, if not all, patients prescribed
local or locoregional radiation therapy after breast conservation
surgery or mastectomy. Most recently, long-term outcome data
for a five-fraction schedule delivered by once-weekly
treatments has been reported, which suggests further scope for
simplifying curative radiotherapy for women with early breast
cancer.
Added value of this study
15 or 16 fractions over 3·0–3·2 weeks are unlikely to represent
the limits of this approach, called hypofractionation.
The FAST-Forward trial shows that 26 Gy in five fractions of
5·2 Gy to the conserved breast or post-mastectomy chest wall
after primary surgery is non-inferior in terms of 5-year
ipsilateral local tumour relapse to 40 Gy in 15 fractions over
3 weeks within an absolute 1·6% non-inferiority margin
compared with 2% incidence with 40 Gy. The 5-day schedule
causes milder early skin reaction and similar rates of late
adverse effects. When mature, a randomised FAST-Forward
substudy will report the safety of the five-fraction regimen for
patients prescribed radiotherapy to breast or chest wall
combined with axilla or supraclavicular fossa.
Implications of all the available evidence
FAST-Forward results confirm that 26 Gy in five fractions is as
effective and safe as an international standard 15-fraction
regimen after primary surgery for early breast cancer.
The 1-week schedule has major benefits over the 3-week or
5-week regimens in terms of convenience and cost for patients
and for health services globally.
See Online for appendix
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3
receptor [ER] positive, HER2 negative, pN0, M0) to
increase the overall primary event rate. All patients
had axillary surgery (sentinel node biopsy or axillary
dissection); nodal radiotherapy was not allowed in the
main study. Concurrent endocrine therapy or trastu-
zumab, or both, were permitted but not concurrent
chemotherapy. For the patient-reported outcomes sub-
study all patients at participating centres were eligible.
All patients who had breast conservation surgery were
eligible for the photographic substudy at participating
centres. A small number of patients who had had
mastectomy were recruited into the photographic
substudy to validate the scoring method in patients who
had chest wall radiotherapy, but are not reported here
because photographs were only available for 76 patients.
All patients provided written informed consent.
Randomisation and masking
Patients were randomly assigned (1:1:1) to receive either
40 Gy in 15 fractions of 2·67 Gy; 27 Gy in five fractions of
5·4 Gy; or 26 Gy in five fractions of 5·2 Gy. A sequential
tumour bed radiotherapy boost to the conserved breast
was allowed, with centres required to specify boost
intention and dose (10 Gy or 16 Gy in 2-Gy fractions)
before randomisation. Randomisation was done by
telephone or fax from the recruiting centre to the
Institute of Cancer Research-Clinical Trials and Statistics
Unit (ICR-CTSU), Sutton, London, UK, and used an in-
house bespoke trial-specific randomisation system set-
up by the ICR-CTSU IT team. Computer-generated
random permuted blocks were used (block sizes 6 and
9), stratified by radiotherapy centre and risk group (high
[age <50 years or grade 3] vs low [age ≥50 years and
grade 1 or 2]). Treatment allocation was not masked to
clinicians or patients.
Test dose levels were informed by START8 and FAST15
trials generating α/β values for late normal tissue eects.
Assuming an α/β value of 3 Gy and no eect of overall
time on outcomes, 27 Gy in five fractions of 5·4 Gy was
predicted to match late normal tissue eects of 40 Gy in
15 fractions of 2·7 Gy or 46 Gy in 23 fractions of 2 Gy.
Allowance for a possible eect of treatment time informed
the choice of the slightly lower 26 Gy dose level.
Radiotherapy
The whole breast clinical target volume, including the
soft tissues from 5 mm below the skin surface to the deep
fascia, was either established from field-based tangential
fields or the volume was contoured prospectively. Post-
mastectomy chest wall clinical target volume encom-
passed post-surgical skin flaps and underlying soft tissues
to the deep fascia; both excluded underlying muscle and
rib cage. Surgeons were strongly encouraged to mark the
tumour cavity walls with titanium clips or gold seeds at
the time of breast conservation surgery in order to aid
placement of tangential fields and delineation of tumour
bed. A typical margin of 10 mm was added around the
breast or chest wall clinical target volume accounting for
set-up error, breast swelling, and breathing to create a
planning target volume (PTV). For all patients, a full
3D CT set of outlines covering the whole breast and
organs at risk was collected with a slice separation up to
5 mm, and organs at risk were outlined prospectively. A
tangential opposing pair beam arrangement encompassed
the whole breast or chest wall PTV, minimising the
ipsilateral lung and heart exposure. The treatment plan
was optimised with 3D dose compensation to achieve the
Figure 1: FAST-Forward trial profile
*One patient had no radiotherapy as they were unable to get into a stable position; three were given 40 Gy in
15 fractions (one because of concern for brachial plexus, one decided on a different treatment plan, and one
because of constraints of treatment planning). †One patient had no radiotherapy because they were diagnosed
with pemphigoid and eight were given 40 Gy in 15 fractions (one because dose constraints were not met, one was
unable to plan within protocol constraints because of tumour bed position, one had poor planning target volume
coverage, one had technical difficulties in planning, one was transferred to direct electron field, one had a simulator
plan because 3D images were not possible, one had a small pericardial effusion found at planning, and one gave no
reason).
4110 patients enrolled and
randomly assigned
1370 patients allocated to
27 Gy in five fractions
(1 week)
12 did not receive
allocated therapy
2 ineligible
4 patient choice
4 investigator
decision*
1 withdrawal of
consent
1 incorrect dose
given
3 withdrew consent
for use of their data
1367 included in the
intention-to-treat
population
1355 patients received
allocated therapy
(per-protocol population)
1231 patients with 5-year visit
form available
136 with no 5-year visit
form available
93 died
3 withdrew
0 lost to
follow-up
40 forms not
received
1372 patients allocated to
26 Gy in five fractions
(1 week)
21 did not receive
allocated therapy
4 ineligible
6 patient choice
9 investigator
decision†
2 treatment stopped
early
4 withdrew consent
for use of their data
1368 included in the
intention-to-treat
population
1347 patients received
allocated therapy
(per-protocol population)
1232 patients with 5-year visit
form available
136 with no 5-year visit
form available
75 died
4 withdrew
0 lost to follow-up
57 forms not
received
1368 patients allocated to
40 Gy in 15 fractions
(3 weeks)
7 withdrew consent
for use of their data
1361 included in the
intention-to-treat
population
7 did not receive
allocated therapy
2 patient choice
2 treatment
prolonged
because of patient
illness
3 treatment stopped
early
1354 patients received
allocated therapy
(per-protocol population)
1218 patients with 5-year visit
form available
143 with no 5-year visit
form available
72 died
15 withdrew
1 lost to
follow-up
55 forms not
received
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following PTV dose distribution: more than 95% of PTV
received 95% of prescribed dose, less than 5% of PTV
received 105% or more, less than 2% of PTV received
107% or more, and a global maximum of less than 110%.
Dose constraints for the control group were as follows:
volume of ipsilateral lung receiving 12 Gy less than 15%,
and volume of heart receiving 2 Gy less than 30% and
that receiving 10 Gy less than 5%. Dose constraints for
the five-fraction schedules were as follows: volume of
ipsilateral lung receiving 8 Gy less than 15%, and volume
of heart receiving 1·5 Gy less than 30% and that receiving
7 Gy less than 5%. X-ray beam energies for treatment
were 6 MV or 10 MV, but a mixture of energies—eg, 6 MV
and 10–15 MV—was allowed for larger patients, assessed
on a case-by-case basis. Tumour bed boost was delivered
via electrons or photons. Verification was done using
electronic portal imaging using MV or kV x-rays. Control
group treatment verification was required for at least
three fractions in the first week with correction for any
systematic error and then once weekly with a tolerance of
5 mm. The five-fraction schedules required verification
imaging for each fraction with recommendations to
correct all measured displacements. A comprehensive
quality assurance programme involved every radiotherapy
centre before trial activation and continued throughout
trial accrual; this was coordinated by the UK Radiotherapy
Trials Quality Assurance team based at Mount Vernon
Hospital, Northwood, UK. The radiotherapy planning
pack is in the appendix (pp 79–103).
Assessments
Patients were assessed by clinicians for ipsilateral breast
tumour relapse and late normal tissue eects at annual
follow-up visits. Starting 12 months after trial entry,
late-onset normal tissue eects in ipsilateral breast or
chest wall (breast distortion, shrinkage, induration and
telangiectasia; and breast or chest wall oedema and
discomfort) were graded by clinicians on a four-point
scale (none, a little, quite a bit, or very much), interpreted
as none, mild, moderate, or marked. Symptomatic rib
fracture, symptomatic lung fibrosis, and ischaemic
heart disease were recorded. Clinical assessments of
acute skin toxicity have been previously reported.15
In the patient-reported outcomes substudy, ques-
tionnaires were administered at baseline (before ran-
domisation) and at 3, 6, 12, 24, and 60 months, including
the European Organisation for Research and Treatment
of Cancer QLQ-BR23 breast cancer module, body image
scale, and protocol-specific questions relating to changes
to the aected breast after treatment (including breast
appearance changed, smaller, harder or firmer, and skin
appearance changed). Patient assess ments used a four-
point scale (not at all, a little, quite a bit, and very much).
In the photographic substudy, photographs were taken
at baseline and at 2 and 5 years after radiotherapy.
Change in photographic breast appearance compared
with baseline (after surgery and before radiotherapy) was
40 Gy in
15 fractions
(n=1361)
27 Gy in
five fractions
(n=1367)
26 Gy in
five fractions
(n=1368)
Age, years
Median (IQR) 60 (53–66) 61 (53–67) 61 (52–66)
Range 29–89 25–90 25–89
<40 12 (0·9%) 16 (1·2%) 28 (2·0%)
40–49 186 (13·7%) 173 (12·7%) 189 (13·8%)
50–59 440 (32·3%) 423 (30·9%) 414 (30·3%)
60–69 506 (37·2%) 511 (37·4%) 524 (38·3%)
70–79 175 (12·9%) 197 (14·4%) 172 (12·6%)
≥80 42 (3·1%) 47 (3·4%) 41 (3·0%)
Sex
Female 1355 (99·6%) 1365 (99·9%) 1362 (99·6%)
Male 6 (0·4%) 2 (0·1%) 4 (0·3%)
Unknown 0 0 2 (0·1%)
Tumour grade
1 315 (23·1%) 315 (23·0%) 300 (21·9%)
2 660 (48·5%) 663 (48·5%) 690 (50·4%)
3 386 (28·4%) 389 (28·5%) 378 (27·6%)
Risk group
Low (age ≥50 and grade 1 or 2) 843 (61·9%) 854 (62·5%) 854 (62·4%)
High (age <50 or grade 3, or both) 518 (38·1%) 513 (37·5%) 514 (37·6%)
Primary surgery
Breast conservation surgery 1270 (93·3%) 1278 (93·5%) 1284 (93·9%)
Breast conservation surgery with
oncoplastic technique
42 (3·1%) 33 (2·4%) 42 (3·1%)
Mastectomy 91 (6·7%) 89 (6·5%) 84 (6·1%)
Mastectomy with immediate
reconstruction
8 (0·6%) 11 (0·8%) 7 (0·5%)
Autologous reconstruction 5/8 (62·5%) 7/11 (63·6%) 3/7 (42·9%)
Implant-based reconstruction 2/8 (25·0%) 4/11 (27·3%) 4/7 (57·1%)
Reconstruction type not specified 1/8 (12·5%) 0 0
Side of primary tumour
Left 726 (53·3%) 674 (49·3%) 662 (48·4%)
Right 635 (46·7%) 693 (50·7%) 704 (51·5%)
Unknown 0 0 2 (0·1%)
Maximal extent of axillary staging
Sentinel node biopsy or guided
axillary sampling
1157 (85·0%) 1184 (86·6%) 1164 (85·1%)
Axillary clearance 200 (14·7%) 181 (13·2%) 201 (14·7%)
Other 4 (0·3%) 2 (0·1%) 1 (0·1%)
Unknown 0 0 2 (0·1%)
Pathological node status
Positive 257 (18·9%) 243 (17·8%) 256 (18·7%)
Negative 1103 (81·0%) 1124 (82·2%) 1110 (81·1%)
Unknown 1 (0·1%) 0 2 (0·1%)
Histological type
Infiltrating ductal 1084 (79·6%) 1096 (80·2%) 1086 (79·4%)
Lobular 144 (10·6%) 139 (10·2%) 127 (9·3%)
Mixed 51 (3·7%) 63 (4·6%) 65 (4·8%)
Other 82 (6·0%) 69 (5·0%) 87 (6·4%)
Unknown 0 0 3 (0·2%)
Pathological tumour size, cm
Median (IQR) 1·6 (1·1–2·2) 1·6 (1–2·2) 1·6 (1·1–2·4)
(Table 1 continues on next page)
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5
scored on a three-point scale (none, mild, or marked)
based on changes in breast size and shape relative to the
contralateral breast. Patients were ineligible for further
photographic assessments after breast reconstruction
surgery and further ipsilateral disease. Digital photo-
graphs were scored by three observers who were masked
to patient identity and treatment allocation, following
scoring procedures established in the START trials.16
Breast size and surgical deficit were assessed from the
baseline photographs on a three-point scale (small,
medium, and large).
Outcomes
The primary endpoint was ipsilateral breast tumour
relapse, defined as invasive carcinoma or ductal carci-
noma in situ presenting anywhere in the ipsilateral
breast parenchyma or overlying skin or post-mastectomy
chest wall, whether considered local recurrence or new
primary tumour. Data on first regional relapse (axilla,
supraclavicular fossa, and internal mammary chain),
distant metastases, new primary cancer, and death were
collected. Key secondary endpoints were late normal
tissue eects assessed by clinicians, patients, and from
photographs, and other disease-related and survival
outcomes (locoregional relapse, distant relapse, disease-
free survival, and overall survival; appendix p 29).
Statistical analysis
The target sample size was 4000 patients (balanced
allocation between groups). This provided 80% power
(one-sided α of 0·025 allowing for non-inferiority
hypothesis and a simple Bonferroni correction taking into
account comparisons between each test schedule and the
control group17) to exclude an absolute increase of 1·6% in
5-year ipsilateral breast tumour relapse incidence for a
five-fraction schedule compared with control, assuming
2% 5-year incidence in the 40 Gy group (START data,7 and
allowing for reduced ipsilateral breast tumour relapse due
to evolution of surgical techniques and systemic therapy).
The 1·6% absolute non-inferiority margin was defined at
the trial design stage by the protocol development group,
which included clinicians and patient advocates and was
considered to be acceptable and appropriate. Binary
proportions were used for the sample size calculations
because event rates are so low. Estimates allowed for
10% loss to follow-up or unevaluable patients, expected to
be largely due to development of metastatic disease.
2196 patients (732 per group) was estimated for the
photographic and patient-reported outcomes substudies
to provide 80% power to detect an 8% dierence in the
5-year prevalence of late normal tissue eects between the
five-fraction schedules (assuming 35% with 5-year mild
or marked change in photographic breast appear ance
from START-B 40 Gy results7), allowing for 10% loss to
follow-up or unevaluable patients.
Kaplan-Meier estimates (with 95% CIs) of 5-year
ipsilateral breast tumour relapse incidence were
40 Gy in
15 fractions
(n=1361)
27 Gy in
five fractions
(n=1367)
26 Gy in
five fractions
(n=1368)
(Continued from previous page)
Pathological T stage
T1mi 4 (0·3%) 5 (0·4%) 6 (0·4%)
T1a 69 (5·1%) 68 (5·0%) 51 (3·7%)
T1b 258 (19·0%) 270 (19·8%) 256 (18·7%)
T1c 612 (45·0%) 601 (44·0%) 602 (44·0%)
T2 394 (28·9%) 389 (28·5%) 424 (31·0%)
T3 21 (1·5%) 30 (2·2%) 25 (1·8%)
Unknown 3 (0·2%) 4 (0·3%) 4 (0·3%)
ER and HER2 status
ER positive HER2 positive 103 (7·6%) 103 (7·5%) 93 (6·8%)
ER positive HER2 negative 1108 (81·4%) 1130 (82·7%) 1097 (80·2%)
ER negative HER2 positive 32 (2·4%) 34 (2·5%) 42 (3·1%)
ER negative HER2 negative 111 (8·2%) 96 (7·0%) 128 (9·4%)
Not known 7 (0·5%) 4 (0·3%) 8 (0·6%)
Progesterone receptor status
Positive 577 (73·1%)†541 (70·3%)†566 (69·8%)†
Negative 212 (26·9%)†229 (29·7%)†245 (30·2%)†
Not done 571 (42·0%) 596 (43·6%) 555 (40·6%)
Missing on form 1 (0·1%) 1 (0·1%) 2 (0·1%)
Lymphovascular invasion
Present 186 (13·7%) 178 (13·0%) 202 (14·8%)
Absent 1085 (79·7%) 1084 (79·3%) 1055 (77·1%)
Uncertain 34 (2·5%) 40 (2·9%) 51 (3·7%)
Unknown 56 (4·1%) 65 (4·8%) 60 (4·4%)
Neoadjuvant chemotherapy received‡
Yes 48 (3·5%) 56 (4·1%) 43 (3·1%)
No 1312 (96·4%) 1311 (95·9%) 1323 (96·7%)
Unknown 1 (0·1%) 0 2 (0·1%)
Adjuvant therapy received: all patients
Chemotherapy§ 333/1360 (24·5%) 324/1367 (23·7%) 370/1366 (27·1%)
Adjuvant therapy received:‡ HER2-positive patients
Chemotherapy and trastuzumab 84/135 (62·2%) 85/137 (62·0%) 100/135 (74·1%)
Trastuzumab, no chemotherapy 16/135 (11·9%) 13/137 (9·5%) 13/135 (9·6%)
Chemotherapy, no trastuzumab 2/135 (1·5%) 2/137 (1·5%) 0
No chemotherapy, no trastuzumab 33/135 (24·4%) 37/137 (27·0%) 22/135 (16·3%)
Adjuvant therapy received:‡ ER-positive patients
Endocrine therapy 1169/1216 (96·1%) 1186/1237 (95·9%) 1157/1196 (96·7%)
Boost given
Yes 342 (25·1%) 337 (24·7%) 332 (24·3%)
No 1017 (74·7%) 1027 (75·1%) 1031 (75·4%)
Not known 2 (0·1%) 3 (0·2%) 5 (0·4%)
Boost dose
10 Gy in five fractions 260/342 (76·0%) 273/337 (81·0%) 257/332 (77·4%)
16 Gy in eight fractions 80/342 (23·4%) 64/337 (19·0%) 75/332 (22·6%)
Unknown 2/342 (0·6%) 0 0
Data are n (%) or n/N (%) unless otherwise stated. ER=oestrogen receptor. *14 patients withdrew consent for any of
their data to be used in analysis. †These percentages are calculated out of total patients who had available results for
this test. ‡Patients could have more than one type of adjuvant systemic therapy. §Chemotherapy type (for those
specified): anthracyclines (n=584), taxane and anthracyclines (n=348), taxane and other—eg, docetaxel, carboplatin,
and trastuzumab (n=83), and other (n=3).
Table 1: Demographic, clinical, and treatment characteristics at randomisation (n=4096)*
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calculated, and hazard ratios (HRs; with 95% CIs)
comparing fractionation schedules obtained from Cox
proportional hazards regression, censoring patients at
date of death or last follow-up. Absolute dierences (with
95% CIs) in 5-year ipsilateral breast tumour relapse
incidence were estimated by applying the HRs (and
95% CIs) to the control group 5-year event-free estimate.18
Primary assessment of non-inferiority was based on
whether the upper limit of the two-sided 95% CI
(corresponding to one-sided 97·5% CI) for the absolute
dierence in 5-year ipsilateral breast tumour relapse was
less than 1·6%. Non-inferiority of each five-fraction
schedule versus control was also tested using the a priori
critical HR of 1·81 (ln0·964/ln0·98, from protocol-
specified incidence); p<0·025 was deemed statistically
signifi cant (probability of incorrectly accepting an infer-
ior five-fraction schedule). An exploratory competing
risks analysis was done for ipsilateral breast tumour
relapse, with death from any cause as a competing event
in a Fine–Gray competing risks regression model.
Clinician and patient assessments of late normal tissue
eects were analysed as follows: (1) 5-year cross-sectional
analyses compared prevalence of moderate or marked
eects versus none or mild eects between groups using
risk ratios and risk dierences and Fisher’s exact test; and
(2) longitudinal analyses of moderate or marked eects
(vs none or mild) using generalised estimating equations19
including all assessments, comparing groups across the
whole follow-up period using odds ratios (ORs) and the
Wald test. Generalised estimating equations models
included a term for years of follow-up, enabling time
trends to be modelled. Additionally, to enable comparison
of clinician-assessed normal tissue eects with results
reported from other trials, survival analysis methods
analysed time to first moderate or marked event, including
Kaplan-Meier estimates of cumulative incidence, and
groups compared using HRs from Cox proportional
hazards regression and the pairwise log-rank test.
Scores for change in photographic breast appearance at
2 and 5 years were modelled using generalised estimating
equations. Categories of mild and marked change in
photographic breast appearance were combined for
analysis because very few had marked changes. Pairwise
comparisons of mild or marked change at 2 or 5 years
between groups were described by ORs obtained from
the generalised estimating equations models and the
Wald test. Because of multiple testing, a significance
level of 0·005 was used for the clinician and patient
normal tissue eects assessments; all hypotheses for the
normal tissue eects endpoints were two-sided.
Estimates of fractionation sensitivity (α/β values) in
FAST-Forward were obtained for the primary endpoint of
ipsilateral breast tumour relapse and late normal tissue
eects as per methods in the START and FAST trials.3
The α/β estimate for breast cancer was obtained from a
Cox proportional hazards regression model of time to
first ipsilateral breast tumour relapse, and for late normal
tissue eects from generalised estimating equations
models including all follow-up assessments (separate
models for photographic and clinician assessments).
Each model included terms for total dose and total dose
multiplied by fraction size; the α/β ratio was calculated by
dividing the two parameter estimates respectively, with a
95% CI estimated from the model using the covariance of
the two estimates (lower confidence limits were truncated
at zero). Isoeect doses in 2 Gy equivalents (EQD2) were
calculated for the five-fraction schedules, together with an
estimate of the five-fraction schedule that would be
isoeective with 40 Gy in 15 fractions in terms of local
tumour control and late normal tissue eects. No
correction was made for dierence in treatment time.
No formal interim analyses were done; accumulating
data were monitored annually by the independent data
monitoring committee. All analyses were performed on
an intention-to-treat basis that included all patients
Cumulative
number of
events
Estimated
cumulative
incidence by
5 years (95% CI)
Hazard ratio (95% CI);
p value
Estimated absolute
difference vs 40 Gy
at 5 years (95% CI)
Ipsilateral breast tumour (local) relapse*
40 Gy (n=1361) 31 (2·3%) 2·1% (1·4 to 3·1) 1 (ref) ··
27 Gy (n=1367) 27 (2·0%) 1·7% (1·2 to 2·6) 0·86 (0·51 to 1·44);
0·56
–0·3% (–1·0 to 0·9)
26 Gy (n=1368) 21 (1·5%) 1·4% (0·9 to 2·2) 0·67 (0·38 to 1·16);
0·15
–0·7% (–1·3 to 0·3)
Locoregional relapse†
40 Gy (n=1361) 43 (3·2%) 2·8% (2·0 to 3·9) 1 (ref) ··
27 Gy (n=1367) 35 (2·6%) 2·3% (1·6 to 3·3) 0·80 (0·51 to 1·25);
0·33
–0·5% (–1·4 to 0·7)
26 Gy (n=1368) 29 (2·1%) 1·8% (1·2 to 2·7) 0·66 (0·41 to 1·06);
0·083
–0·9% (–1·6 to 0·2)
Distant relapse
40 Gy (n=1361) 59 (4·3%) 3·8% (2·9 to 5·0) 1 (ref) ··
27 Gy (n=1367) 69 (5·0%) 4·7% (3·7 to 6·0) 1·16 (0·82 to 1·64);
0·41
0·6% (–0·7 to 2·3)
26 Gy (n=1368) 76 (5·6%) 5·1% (4·0 to 6·4) 1·27 (0·90 to 1·79);
0·17
1·0% (–0·4 to 2·9)
Any breast cancer-related event‡
40 Gy (n=1361) 119 (8·7%) 7·8% (6·5 to 9·4) 1 (ref) ··
27 Gy (n=1367) 112 (8·2%) 7·2% (5·9 to 8·7) 0·93 (0·71 to 1·20);
0·56
–0·6% (–2·2 to 1·5)
26 Gy (n=1368) 114 (8·3%) 7·5% (6·2 to 9·0) 0·94 (0·73 to 1·22);
0·65
–0·4% (–2·1 to 1·6)
All-cause mortality
40 Gy (n=1361) 92 (6·8%) 5·4% (4·3 to 6·8) 1 (ref) ··
27 Gy (n=1367) 105 (7·7%) 6·9% (5·7 to 8·4) 1·12 (0·85 to 1·48);
0·42
0·6% (–0·8 to 2·5)
26 Gy (n=1368) 90 (6·6%) 5·6% (4·5 to 7·0) 0·96 (0·72 to 1·28);
0·78
–0·2% (–1·5 to 1·5)
Hazard ratios less than 1 favour five-fraction schedules. p values were calculated by log-rank test (two-sided). *Includes
three patients with angiosarcoma in ipsilateral breast (one in the 40 Gy group and two in the 26 Gy group). †Defined
as ipsilateral breast tumour relapse or regional relapse (axilla, supraclavicular fossa, and internal mammary chain).
‡Includes local, regional, or distant relapse, breast cancer death, or contralateral breast cancer (disease-free survival).
Table 2: Relapse and mortality by fractionation schedule: time-to-event analysis (n=4096)
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7
according to their allocated treatment regardless of what
was actually received. Because the main hypothesis was
non-inferiority, the primary endpoint was also tested in
the per-protocol population, which excluded patients for
whom a major deviation was reported. The database
snapshot was taken on Nov 22, 2019; Stata, version 15
(StataCorp), was used for analyses. The trial is registered
at isrctn.com, ISRCTN19906132.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report. The corresponding author had full access to
all data in the study and had final responsibility for the
decision to submit for publication.
Results
Between Nov 24, 2011, and June 19, 2014, 4110 patients
were enrolled in the FAST-Forward trial. After ran-
domisation, 14 patients withdrew consent for use of
data and were removed from the intention-to-treat popula-
tion; thus, 4096 patients were included in the intention-
to-treat anlaysis (1361 assigned to 40 Gy in 15 fractions;
1367 assigned to 27 Gy in five frac tions; and 1368 assigned
to 26 Gy in five fractions; figure 1). Seven patients in the
40 Gy group, 12 in the 27 Gy group, and 21 in the 26 Gy
group did not receive the allocated therapy and were not
included in the per-protocol popu lation. Compliance with
allocated treatment was 99%. Demographic and clinical
charac teristics at baseline were well balanced between
groups (table 1). 5-year visit forms were available for
3681 (96%) patients of 3833 still in follow-up (not died,
withdrawn, or lost).
After a median follow-up of 71·5 months (IQR 71·3 to
71·7), ipsilateral breast tumour relapse was recorded in
79 patients (31 in the 40 Gy group, 27 in the 27 Gy group,
and 21 in the 26 Gy group); HRs versus 40 Gy in
15 fractions were 0·86 (95% CI 0·51 to 1·44) for 27 Gy in
five fractions and 0·67 (0·38 to 1·16) for 26 Gy in five
fractions. Estimated cumulative incidence of ipsilateral
breast tumour relapse up to 5 years was 2·1% (95% CI
1·4 to 3·1) for 40 Gy (expected incidence 2%), 1·7%
(1·2 to 2·6) for 27 Gy and 1·4% (0·9 to 2·2) for 26 Gy
(table 2, figure 2). Estimated absolute dierences in
ipsilateral breast tumour relapse versus 40 Gy were –0·3%
(–1·0 to 0·9) for 27 Gy and –0·7% (–1·3 to 0·3) for 26 Gy.
The upper confidence limits excluded an increase in
ipsilateral breast tumour relapse of 1·6% or more so non-
inferiority can be claimed for both five-fraction schedules
compared with 40 Gy in 15 fractions. A test against the
Figure 2: Cumulative risk of ipsilateral breast tumour relapse by fractionation schedule
40 Gy
Number at risk
Censored
Events
27 Gy
Number at risk
Censored
Events
26 Gy
Number at risk
Censored
Events
0
1361
0
0
1367
0
0
1368
0
0
1
1347
13
1
1352
11
4
1347
17
4
2
1307
46
8
1328
27
12
1325
34
9
3
1281
65
15
1303
48
16
1302
54
12
4
1230
109
22
1255
90
22
1257
95
16
5
1045
289
27
1066
278
23
1070
280
18
6
486
844
31
508
833
26
524
824
20
7
91
1239
31
90
1250
27
89
1258
21
Time since randomisation (years)
0
1
2
3
100
Ipsilateral breast tumour relapse (%)
40 Gy in 15 fractions
27 Gy in five fractions
26 Gy in five fractions
27 Gy vs 40 Gy: hazard ratio 0·86 (95% CI 0·51 to 1·44);
5-year difference –0·3% (95% CI –1·0 to 0·9); non-inferiority p=0·0022
26 Gy vs 40 Gy: hazard ratio 0·67 (95% CI 0·38 to 1·16);
5-year difference –0·7% (95% CI –1·3 to 0·3); non-inferiority p=0·00019
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critical HR greater than 1·81 confirmed the result, with a
p value of 0·0022 for 27 Gy and 0·00019 for 26 Gy
compared with 40 Gy. Analyses in the per-protocol
population were consistent (estimated absolute dierence
vs 40 Gy –0·4% [–1·0 to 0·8], p=0·0017 for 27 Gy and
–0·6% [–1·2 to 0·4], p=0·00037 for 26 Gy; full data
for per-protocol analyses not shown because treatment
compliance was 99%). Comparing the five-fraction
schedules, the estimated absolute dierence in ipsilateral
breast tumour relapse cumulative incidence up to 5 years
was –0·4% (–1·0 to 0·6) for 26 Gy versus 27 Gy. The
unadjusted α/β estimate for ipsilateral breast tumour
relapse was 3·7 Gy (0·3 to 7·1), with EQD2 estimates of
44·7 Gy for 40 Gy, 43·1 Gy for 27 Gy, and 40·6 Gy for 26 Gy
with no correction for treatment time. Adjusting for risk
group and ER and HER2 status made minimal dierence
(adjusted α/β estimate 3·7 Gy [95% CI 0·4 to 6·9]). HRs
obtained from a competing risks analysis of ipsilateral
breast tumour relapse with death from any cause as a
competing event were almost identical to those from the
primary analysis (HRs from competing risks model were
0·85 [95% CI 0·51 to 1·43] for 27 Gy vs 40 Gy; and 0·67
[0·38 to 1·16] for 26 Gy vs 40 Gy).
Regional relapses occurred in 34 (0·8%) of 4096 patients
(13 [1·0%] of 1361 in the 40 Gy group, 11 [0·8%] in the
27 Gy group, and ten [0·7%] in the 26 Gy group;
table 3), six of which were concurrent with ipsilateral
breast tumour relapse. Incidence of locoregional relapse,
distant relapse, dis ease-free survival, and overall survival
were similar between groups, with no statistically
significant dierences (table 2; appendix pp 3–4). No
formal subgroup analyses were done because of the low
number of primary endpoint events, but frequencies of
ipsilateral breast tumour relapse, regional relapse, and
distant relapse were tabulated according to age, grade,
and ER and HER2 status for descriptive purposes; as
expected, ipsilateral breast tumour relapse occurred in
more of the patients with higher-grade primary tumours
(appendix p 7). Invasive contralateral breast cancer
was reported for 55 (1·3%) of 4096 patients (18 [1·3%] in
the 40 Gy group, 17 [1·2%] in the 27 Gy group, and
20 [1·5%] in the 26 Gy group; table 3), and non-breast
second primary cancers were reported for 123 (3·0%) of
4096 patients (42 [3·1%] in the 40 Gy group, 37 [2·7%] in
the 27 Gy group, and 44 [3·2%] in the 26 Gy group;
table 3), the most common being colorectal cancer
(25 cases).
287 (7·0%) of 4096 patients died, 151 (3·7%) from breast
cancer, 125 (3·1%) from other causes, and 11 (0·3%) with
unknown cause of death and no evidence of disease
relapse (table 3). Of 27 patients with a cardiac-related death,
15 had a history of cardiac disease reported at random-
isation or were a current or ex-smoker in the past year.
At least one annual clinical assessment of normal
tissue eects was available for 3975 (97·0%) of
4096 patients. At 5 years, any moderate or marked
clinician-assessed normal tissue eects in the breast or
chest wall was reported for 98 of 986 (9·9%) 40 Gy
patients, 155 (15·4%) of 1005 27 Gy patients, and 121 of
1020 (11·9%) 26 Gy patients (appendix pp 5–6, 8–9), with
a significant dierence between 40 Gy and 27 Gy
(p=0·0003) but not between 40 Gy and 26 Gy (p=0·17).
Breast shrinkage was the most prevalent moderate or
marked eect at 5 years, reported in 50 (5·5%) of
916 40 Gy patients, 78 (8·2%) of 948 27 Gy patients, and
65 (6·8%) of 954 26 Gy patients (appendix pp 8–9).
Longitudinal analysis of all annual clinical assessments
of normal tissue eects over follow-up showed a
significantly increased risk of any moderate or marked
eect in the breast or chest wall for the 27 Gy group
compared with 40 Gy (OR 1·55 [95% CI 1·32 to 1·83],
p<0·0001), with no significant dierence between 26 Gy
and 40 Gy (1·12 [0·94 to 1·34], p=0·20; table 4). This
pattern was similar for the individual eects of breast
distortion, shrinkage, induration, and breast or chest
wall oedema, with significantly higher risk for 27 Gy
than 40 Gy but not for 26 Gy (table 4; appendix pp 5–6).
Comparing the two five-fraction schedules, 26 Gy had
significantly lower risk of any moderate or marked
breast or chest wall normal tissue eects (p=0·0001) and
breast shrinkage (p=0·0018) compared with 27 Gy. Esti-
mates of 5-year cumulative incidence of any mode rate or
marked clinician-assessed normal tissue eects in the
breast or chest wall were 26·8% (95% CI 24·4 to 29·4)
for 40 Gy, 35·1% (32·4 to 37·9) for 27 Gy, and 28·5%
(26·0 to 31·1) for 26 Gy (appendix p 10). Results for
40 Gy in
15 fractions
(n=1361)
27 Gy in
five fractions
(n=1367)
26 Gy in
five fractions
(n=1368)
Local tumour control event (primary
endpoint)*
31 (2·3%) 27 (2·0%) 21 (1·5%)
Local relapse 23 (1·7%) 22 (1·6%) 17 (1·2%)
Ipsilateral breast, new primary 6 (0·4%) 3 (0·2%) 4 (0·3%)
Cannot differentiate 2 (0·1%) 2 (0·1%) 0
Regional relapse 13 (1·0%) 11 (0·8%) 10 (0·7%)
Distant relapse 59 (4·3%) 69 (5·0%) 76 (5·5%)
Contralateral breast, second primary 23 (1·7%) 20 (1·5%) 23 (1·7%)
Invasive 18 (1·3%) 17 (1·2%) 20 (1·5%)
Ductal carcinoma in situ 5 (0·4%) 3 (0·2%) 2 (0·1%)
Unknown 0 0 1 (0·1%)
Non-breast, second primary 42 (3·1%) 37 (2·7%) 44 (3·2%)
Death 92 (6·8%) 105 (7·7%) 90 (6·6%)
Breast cancer† 47 (3·5%) 51 (3·7%) 53 (3·9%)
Second cancer 12 (0·9%) 16 (1·2%) 10 (0·7%)
Cardiac 10 (0·7%) 9 (0·7%) 8 (0·6%)
Other cause 17 (1·7%) 27 (2·0%) 16 (1·2%)
Unknown 6 (1·2%) 2 (0·1%) 3 (0·2%)
Data are n (%). Patients reporting events of more than one type are included in each relevant row. *Includes angiosarcoma
in ipsilateral breast (one in the 40 Gy group and two in the 26 Gy group) and six patients with ductal carcinoma in situ
(three in the 40 Gy group, two in the 27 Gy group, and one in the 26 Gy group). †Includes 13 patients with distant relapse
before death from other causes (four in the 40 Gy group, four in the 27 Gy group, and five in the 26 Gy group).
Table 3: Relapses, second primary cancers, and deaths by fractionation schedule (n=4096)
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9
comparison of schedules from the analyses of time to
first moderate or marked eect were similar to those
from the long itudinal modelling of all annual clinical
assessments (appendix p 10).
1796 patients consented to the patient-reported
outcomes substudy, 18 of whom withdrew consent
immediately after randomisation or were not given the
baseline booklet. Questionnaires returned from those
expected (patients alive and well, not withdrawn)
were 1771 (99·6%) of 1778 at baseline, 1668 (96·2%) of
1733 at 3 months, 1622 (94·2%) of 1722 at 6 months,
1599 (93·7%) of 1707 at 1 year, 1531 (91·7%) of 1669 at
2 years, and 1334 (84·0%) of 1589 at 5 years. Of the
1774 patients with at least one completed questionnaire,
1634 had breast conservation surgery and 140 had
mastectomy. Change in breast appearance had the
highest 5-year prevalence, with moderate or marked
change reported in 140 (32·4%) of 432 for 40 Gy,
Number of moderate or
marked events/total
number of assessments
over follow-up
Odds ratio for schedule
(95% CI)
p value for comparison
with 40 Gy
p value for
comparison
between 27 Gy
and 26 Gy
Odds ratio for years of
follow-up (95% CI); p value
Any adverse event in the
breast or chest wall*
·· ·· ·· ·· 0·98 (0·96–1·00); 0·055
40 Gy 651/6121 (10·6%) 1 (ref) ·· ·· ··
27 Gy 1004/6303 (15·9%) 1·55 (1·32–1·83) <0·0001 ·· ··
26 Gy 774/6327 (12·2%) 1·12 (0·94–1·34) 0·20 0·0001 ··
Breast distortion† ·· ·· ·· ·· 0·99 (0·95–1·02); 0·38
40 Gy 232/5724 (4·0%) 1 (ref) ·· ·· ··
27 Gy 363/5953 (6·1%) 1·51 (1·15–1·97) 0·0028 ·· ··
26 Gy 299/5945 (5·0%) 1·20 (0·91–1·60) 0·19 0·083 ··
Breast shrinkage† ·· ·· ·· ·· 1·03 (1·00–1·06); 0·023
40 Gy 330/5728 (5·8%) 1 (ref) ·· ·· ··
27 Gy 503/5944 (8·5%) 1·50 (1·20–1·88) 0·0004 ·· ··
26 Gy 369/5943 (6·2%) 1·05 (0·82–1·33) 0·71 0·0018 ··
Breast induration
(tumour bed)†
·· ·· ·· ·· 1·00 (0·96–1·04); 0·95
40 Gy 185/5713 (3·2%) 1 (ref) ·· ·· ··
27 Gy 304/5948 (5·1%) 1·56 (1·19–2·05) 0·0013 ·· ··
26 Gy 236/5937 (4·0%) 1·19 (0·90–1·59) 0·23 0·047 ··
Breast induration
(outside tumour bed)†
·· ·· ·· ·· 0·96 (0·90–1·02); 0·17
40 Gy 45/5712 (0·8%) 1 (ref) ·· ·· ··
27 Gy 137/5943 (2·3%) 2·79 (1·74–4·50) <0·0001 ·· ··
26 Gy 97/5930 (1·6%) 1·90 (1·15–3·14) 0·013 0·059 ··
Telangiectasia ·· ·· ·· ·· 1·21 (1·14–1·29); <0·0001
40 Gy 63/6087 (1·0%) 1 (ref) ·· ·· ··
27 Gy 100/6272 (1·6%) 1·68 (1·07–2·65) 0·025 ·· ··
26 Gy 102/6300 (1·6%) 1·53 (0·96–2·43) 0·070 0·65
Breast or chest wall
oedema
·· ·· ·· ·· 0·73 (0·69–0·78); <0·0001
40 Gy 89/6097 (1·5%) 1 (ref) ·· ·· ··
27 Gy 217/6287 (3·4%) 2·18 (1·57–3·03) <0·0001 ·· ··
26 Gy 155/6318 (2·4%) 1·47 (1·03–2·09) 0·032 0·0097 ··
Breast or chest wall
discomfort
·· ·· ·· ·· 0·93 (0·89–0·97); 0·0003
40 Gy 234/6086 (3·8%) 1 (ref) ·· ·· ··
27 Gy 269/6285 (4·3%) 1·10 (0·86–1·40) 0·44 ·· ··
26 Gy 250/6309 (4·0%) 0·98 (0·76–1·26) 0·86 0·35 ··
Results for years of follow-up show trend in normal tissue effects over follow-up across all fractionation schedules. p values are calculated by Wald test; odds ratios are
estimated from the generalised estimating equations model including all follow-up data and show relative odds of moderate or marked adverse event (vs none or mild) for
each pairwise comparison of fractionation schedules across all follow-up assessments. *Includes shrinkage, induration, telangiectasia, or oedema. †Patients who had breast
conservation surgery or mastectomy with reconstruction.
Table 4: Longitudinal analysis of moderate or marked clinician-assessed late normal tissue effects for patients with at least one annual clinical assessment
(n=3975)
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158 (35·9%) of 440 for 27 Gy, and 136 (31·7%) of 429 for
26 Gy. 5-year prevalence of patient-reported adverse
eects were not significantly dierent between the
schedules (appendix pp 5–6, 11–12). Patient-reported
moderate or marked breast hardness or firmness at
5 years was not significantly increased for 27 Gy
compared with 40 Gy and breast swelling was not more
prevalent in both five-fraction schedules than the 40 Gy
Number of patients
reporting moderate
or marked event at
baseline/total*
Number of moderate or
marked events/total
number of assessments
over 3–60 months of
follow-up
Odds ratio for
schedule (95% CI)
p value for
comparison
with 40 Gy
p value for
comparison
between
27 Gy and
26 Gy
Odds ratio for years of
follow-up (95% CI);
p value
Protocol-specific items
Breast appearance
changed
·· ·· ·· ·· ·· 1·03 (1·01–1·05);
0·0010
40 Gy 170/573 (29·7%) 778/2480 (31·4%) 1 (ref) ·· ·· ··
27 Gy 177/583 (30·4%) 929/2550 (36·4%) 1·22 (1·02–1·46) 0·033 ·· ··
26 Gy 155/581 (26·7%) 770/2563 (30·0%) 0·91 (0·75–1·10) 0·33 0·0018 ··
Breast smaller ·· ·· ·· ·· ·· 1·11 (1·09–1·13);
<0·0001
40 Gy 96/560 (17·1%) 585/2445 (23·9%) 1 (ref) ·· ·· ··
27 Gy 106/576 (18·4%) 606/2520 (24·0%) 1·05 (0·85–1·29) 0·67 ·· ··
26 Gy 90/574 (15·7%) 515/2542 (20·3%) 0·81 (0·65–1·00) 0·053 0·017 ··
Breast harder or firmer ·· ·· ·· ·· 0·95 (0·93–0·97);
<0·0001
40 Gy 94/558 (16·8%) 499/2446 (20·4%) 1 (ref) ·· ·· ··
27 Gy 105/572 (18·4%) 690/2512 (27·5%) 1·42 (1·17–1·72) 0·0003 ·· ··
26 Gy 95/566 (16·8%) 626/2534 (24·7%) 1·22 (1·00–1·48) 0·048 0·1007 ··
Skin appearance
changed
·· ·· ·· ·· ·· 0·96 (0·93–0·99);
0·0080
40 Gy 78/577 (13·5%) 345/2505 (13·8%) 1 (ref) ·· ·· ··
27 Gy 61/586 (10·4%) 392/2571 (15·2%) 1·03 (0·83–1·28) 0·77 ·· ··
26 Gy 67/580 (11·5%) 338/2576 (13·1%) 0·90 (0·72–1·13) 0·37 0·23 ··
European Organisation for Research and Treatment of Cancer QLQ-BR23 items
Breast pain ·· ·· ·· ·· ·· 0·96 (0·94–0·99);
0·011
40 Gy 53/583 (9·1%) 338/2538 (13·3%) 1 (ref) ·· ·· ··
27 Gy 42/590 (7·1%) 428/2601 (16·5%) 1·23 (0·98–1·54) 0·068 ·· ··
26 Gy 53/588 (9·0%) 417/2597 (16·1%) 1·23 (0·98–1·53) 0·074 0·96 ··
Breast swollen ·· ·· ·· ·· ·· 0·84 (0·80–0·89);
<0·0001
40 Gy 56/583 (9·6%) 122/2538 (4·8%) 1 (ref) ·· ·· ··
27 Gy 43/589 (7·3%) 236/2597 (9·1%) 1·46 (1·10–1·94) 0·0080 ·· ··
26 Gy 47/589 (8·0%) 192/2599 (7·4%) 1·27 (0·95–1·69) 0·11 0·22 ··
Breast oversensitive ·· ·· ·· ·· ·· 0·96 (0·93–0·99);
0·0097
40 Gy 57/579 (9·8%) 283/2528 (11·2%) 1 (ref) ·· ·· ··
27 Gy 42/584 (7·2%) 334/2596 (12·9%) 1·10 (0·87–1·40) 0·43 ·· ··
26 Gy 62/586 (10·6%) 319/2587 (12·3%) 1·11 (0·88–1·41) 0·37 0·91 ··
Skin problems in breast ·· ·· ·· ·· ·· 0·96 (0·92–1·01);
0·11
40 Gy 26/582 (4·5%) 156/2539 (6·1%) 1 (ref) ·· ·· ··
27 Gy 24/290 (4·1%) 209/2596 (8·0%) 1·25 (0·95–1·65) 0·11 ·· ··
26 Gy 18/590 (3·0%) 164/2592 (6·3%) 0·98 (0·73–1·31) 0·90 0·084 ··
Arm or shoulder pain ·· ·· ·· ·· ·· 1·00 (0·97–1·03);
>0·99
40 Gy 66/582 (11·3%) 401/2537 (15·8%) 1 (ref) ·· ·· ··
27 Gy 78/591 (13·2%) 441/2601 (17·0%) 1·12 (0·91–1·37) 0·29 ·· ··
26 Gy 81/589 (13·7%) 455/2599 (17·5%) 1·14 (0·93–1·40) 0·2006 0·83 ··
(Table 5 continues on next page)
Articles
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11
schedule, at the prespecified cuto of p=0·005.
Longitudinal analyses of all patient assessments from
baseline to 5 years showed a significantly higher risk of
moderate or marked breast hardness or firmness for
27 Gy compared with 40 Gy (OR 1·42, 1·17, 1·72,
p=0·0003), and a lower risk of change in breast
appearance for 26 Gy compared with 27 Gy (p=0·0018),
but no significant dierences between schedules for the
other normal tissue eects (table 5; appendix pp 5–6).
Of the 1737 patients who consented to the photographic
substudy, baseline photographs were received for
1634 (94·1%), and 2-year or 5-year photo graphs were
available for 1385 (79·7%). 1309 (75·4%) were patients who
had breast conservation surgery; for these patients, 2-year
photographs were assessed in 1267 and 5-year photographs
were assessed in 875 (appendix p 13). 226 patients died or
withdrew from the photographic substudy by year 5; for
the remainder, the most common reasons for photographs
not being taken were appointments not made because
of clerical errors at the centres, patients not attending
clinic visits, and patients withdrawing consent from the
substudy. At 2 years, mild or marked change in photo-
graphic breast appearance was reported in 35 (8·5%) of
411 for 40 Gy, 67 (15·6%) of 429 for 27 Gy, and 46 (10·8%) of
427 for 26 Gy; corresponding results at 5 years were
34 (12·0%) of 283 for 40 Gy, 83 (26·9%) of 308 for 27 Gy,
and 37 (13·0%) of 284 for 26 Gy (appendix p 13). Modelling
2-year and 5-year photographic assessments together,
27 Gy had a significantly increased risk of mild or marked
change in breast appearance compared with 40 Gy
(OR 2·29 [95% CI 1·60 to 3·27], p<0·0001), with no
significant dierence between 26 Gy and 40 Gy (OR 1·26
[0·85 to 1·86], p=0·24; appendix p 13). 26 Gy had a
significantly lower risk of change in photographic breast
appearance than 27 Gy (p=0·0006).
The unadjusted α/β estimate for any moderate or
marked clinician-assessed normal tissue eects in the
breast or chest wall was 1·7 Gy (95% CI 1·2 to 2·3),
giving EQD2 estimates of 47·1 Gy for 40 Gy in 15 frac tions,
51·6 Gy for 27 Gy in 5 fractions, and 48·3 Gy for 26 Gy
in 5 fractions; adjusting for prognostic factors (age,
boost, and whole-breast planning treatment volume as
a proxy for breast size) made very little dierence.
The α/β estimated from the photographic endpoint
(adjusting for breast size and surgical deficit assessed
from the baseline photographs) was very similar (1·8 Gy
[1·1 to 2·4]). The unadjusted α/β estimate for patient-
reported change in breast appearance was 2·3 Gy
(1·8 to 2·9), resulting in EQD2 estimates of 46·1 Gy for
40 Gy, 48·2 Gy for 27 Gy, and 45·2 Gy for 26 Gy; adjusting
for covariates made minimal dierence.
The most common specialist referral for radiotherapy-
related adverse eects during follow-up was to lympho-
edema clinics (appendix p 14). Incidence of ischaemic
heart disease, symptomatic rib fracture, and symptomatic
lung fibrosis was very low at this stage of follow-up
(appendix p 14).
Discussion
We demonstrated non-inferiority, measured in terms of
ipsilateral breast tumour relapse, of 27 Gy and 26 Gy five-
fraction schedules compared with 40 Gy in 15 fractions at
5 years’ follow-up for patients with early breast cancer,
most of whom were treated by local tumour excision and
sentinel node biopsy for node-negative disease. Normal
tissue eects up to 5 years for the 26 Gy in five fractions
schedule were similar to those with the 40 Gy in
15 fractions schedule. Low rates of ipsilateral breast
tumour relapse and of moderate or marked late normal
tissue eects can be attributed to improvements in all
Number of patients
reporting moderate
or marked event at
baseline/total*
Number of moderate or
marked events/total
number of assessments
over 3–60 months
follow-up
Odds ratio for
schedule (95% CI)
p value for
comparison
with 40 Gy
p value for
comparison
between
27 Gy and
26 Gy
Odds ratio for years of
follow-up (95% CI);
p value
(Continued from previous page)
Arm or hand swollen ·· ·· ·· ·· ·· 1·06 (1·00–1·11);
0·031
40 Gy 24/582 (4·1%) 101/2536 (4·0%) 1 (ref) ·· ·· ··
27 Gy 17/588 (2·9%) 103/2600 (4·0%) 0·95 (0·66–1·36) 0·77 ·· ··
26 Gy 22/590 (3·7%) 124/2592 (4·8%) 1·14 (0·80–1·62) 0·46 0·31 ··
Difficulty raising arm ·· ·· ·· ·· ·· 1·04 (0·99–1·08);
0·089
40 Gy 27/582 (4·6%) 171/2533 (6·7%) 1 (ref) ·· ·· ··
27 Gy 36/589 (6·1%) 209/2599 (8·0%) 1·24 (0·94–1·63) 0·12 ·· ··
26 Gy 37/587 (6·3%) 188/2596 (7·2%) 1·12 (0·85–1·48) 0·42 0·46 ··
Results for years of follow-up show trend in normal tissue effects over follow-up across all fractionation schedules. p values are calculated by Wald test; odds ratios are
estimated from the generalised estimating equations model including all questionnaires (baseline to 5 years) and show relative odds of moderate or marked adverse events
(vs none or mild) for each pairwise comparison of fractionation schedules across all questionnaires. *Total is those who completed the corresponding question.
Table 5: Longitudinal analysis of moderate or marked patient-assessed late normal tissue effects from baseline to 5 years for patients with at least one
completed questionnaire (n=1774)
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12
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diagnostic and treat ment modalities and to the com-
mitment of patients to early diagnosis and randomised
trials.20
The 10-year analyses of ipsilateral breast tumour
relapse and normal tissue eects reported by earlier
Canadian5 and UK trials3,4,6–8 confirm that although
normal tissue eects continue to accumulate beyond
5 years, there is evidence that relative dierences between
test and control groups change very little over time.21 In
the START-B trial, the HR for clinician-assessed breast
shrinkage after 40 Gy in 15 fractions compared with
50 Gy in 25 fractions was 0·83 (95% CI 0·66–1·04) at
5 years and 0·80 (0·67–0·96) at 10 years, by which
time the proportion of patients with breast shrinkage
increased from 11·4% (9·5–13·6) at 5 years to 26·2%
(23·2–29·6) at 10 years.8 The findings of FAST-Forward
can be applied to dierent prognostic groups in view of
the very low overall ipsilateral breast tumour relapse
incidence, a conclusion consistent with a meta-analysis
of the 5861 patients entered into the three START trials,
which identified no inconsistency of eect in terms of
normal tissue eects or recurrence risk across any of the
prognostic or treatment subgroups investigated.8
The absence of a detectable dose response for local
tumour control between 26 Gy and 27 Gy in five frac-
tions is a potential limit to precision, but this feature
reflects the shallowness of the dose response curve for
subclinical breast cancer that is around the 98% local
tumour control level, so the –0·4% estimated dierence
in absolute levels of ipsilateral breast tumour relapse
between 27 Gy and 26 Gy probably reflects random
sampling variability in the ipsilateral breast tumour
relapse rate or chance imbalances in unmeasured
prognostic factors between test groups. For late normal
tissue eects, the dose response is much steeper,
enabling detection of clinically and statistically signifi-
cant dier ences in event rates between 26 Gy and 27 Gy
in five fractions. The five-fraction schedule isoeective
with 40 Gy in 15 fractions allows direct estimation of
α/β for late normal tissue eects, which is consistent
with values generated from our other trials. The
α/β value of 3·7 Gy (95% CI 0·3–7·1) for tumour control
in FAST-Forward is similar to the 3·5 Gy (1·2–5·7)
estimated from the START pilot and START-A trials.8
Point estimates of α/β values, assuming no eect of
time, for late normal tissue eects in FAST-Forward
scored by clinicians, patients, and photographic assess-
ments are closer to 2 Gy than the 3 Gy estimated in the
earlier START8 and FAST trials,14 but 95% CIs overlap
for each endpoint in all trials. In FAST, 915 women were
randomly assigned after breast conservation surgery for
node negative disease to 50 Gy in 25 fractions versus
two dose levels of a five-fraction regimen delivered once
weekly, thereby ensuring complete repair between
fractions and controlling for overall treatment time.13,14
The α/β value for change in photographic breast
appearance in FAST was 2·6 Gy (1·4–3·7). Uncertainty
about biological processes, which include a time factor
in FAST-Forward, does not interfere with clinical evalu-
ation and decisions on implementation of FAST-Forward
results in similar patient groups.
The five-fraction regimen is relevant to partial-breast
radiotherapy, the preferred alternative to whole-breast
radiotherapy for many women after recent phase 3
trials.22–25 Beyond its safety and eectiveness, the 26 Gy
FAST-Forward schedule is convenient and substantially
less expensive for patients and for health services. It is
also likely to be safe for patients requiring regional radio-
therapy, an approach that is under formal assessment in
a randomised FAST-Forward substudy comparing 40 Gy
in 15 fractions and 26 Gy in five fractions. Assuming no
eect of time, 26 Gy in five fractions is equivalent to
46·8 Gy and 53·7 Gy in 2-Gy fractions assuming
α/β values of 2 Gy and 1 Gy, respectively, dose intensities
well within the limits of tolerance for these structures.26,27
In terms of limitations of our study, there is no reason to
consider the heart more sensitive to fraction size than
most other soft tissues. It is undoubtedly sensitive to
total dose but the tiny number of cardiac events in FAST-
Forward prevents meaningful analysis.28 Any heart
exposure is potentially harmful even after 2 Gy fractions,
so the priority is to exclude the heart from the treatment
volume as far as possible using deep inspiration breath
hold or a similar technique,29,30 or partial breast
radiotherapy.23 The size of the trial prevents reliable
subgroup analyses by patient age, tumour grade, receptor
status, and systemic therapies, but consistent with our
10-year analyses of almost 6000 patients in the START
hypofractionation trials, there is no suggestion of
heterogeneity.8 Finally, synchronous boost regimens
were avoided despite current interest in this application
of hypofractionation. It is safer to consider boost as an
independent treatment variable such as tumour grade or
adjuvant systemic therapy whose impacts are randomly
distributed across treatment groups. This allows a pure
assessment of whole-breast hypofractionation without
having to con sider the partial volume eects of dierent
breast dose levels. Routine implementation of 26 Gy in
five fractions can more naturally incorporate appropriate
five-fraction synchronous boost regimens.
In conclusion, 5-year ipsilateral breast tumour relapse
incidence after a 1-week course of adjuvant breast
radiotherapy delivered in five fractions is non-inferior to
the standard 3-week schedule according to the predefined
inferiority threshold. The 26 Gy dose level is similar to
40 Gy in 15 fractions in terms of patient-assessed normal
tissue eects, clinician-assessed normal tissue eects,
and photographic change in breast appearance, and is
similar to normal tissue eects expected after 46–48 Gy in
2 Gy fractions. The consistency of FAST-Forward results
with earlier hypofractionation trials supports the adoption
of 26 Gy in five daily fractions as a new standard for
women with operable breast cancer requiring adjuvant
radiotherapy to partial or whole breast.
Articles
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13
Contributors
AMB and JRY are the current and previous chief investigators
respectively, and DAW is the chief clinical coordinator for the trial.
JMB is the trials methodology lead within the Institute of Cancer
Research-Clinical Trials and Statistics Unit (ICR-CTSU) and provided
oversight and guidance for trial management throughout the trial.
JRY, JMB, and JSH were responsible for the study design. AMB, JRY,
and JSH wrote the first draft of the manuscript. JSH was responsible for
statistical analyses and contributed to data interpretation. AA, DJB, CC,
MC, SC, CEC, AG, AH, PH, AMK, CCK, CM, ZN, ES, NS, and IS are
members of the FAST-Forward trial management group (TMG),
which contributed to study design, was responsible for oversight
throughout the trial and contributed to data interpretation and
manuscript preparation. MAS and LS managed the study and data
collection at ICR-CTSU. CM is a patient advocate member of the TMG
and provided guidance for study documentation and reports. PH was
the lead for the patient-reported outcomes substudy. ZN was
responsible for radiotherapy quality assurance. All authors reviewed
and approved the manuscript.
Declaration of interests
JMB, JSH, MAS, and LS report grants from National Institute for Health
Research Health Technology Assessment and Cancer Research UK during
the conduct of the study. JMB reports grants and non-financial support
from Novartis (previously GlaxoSmithKline), AstraZeneca, Clovis
Oncology, Janssen-Cilag, Merck Sharpe and Dohme, Puma Biotechnology,
Pfizer, and Roche; and grants from Medivation, outside the submitted
work. DAW reports travel grants from Roche Pharmaceuticals outside the
submitted work. CCK reports personal fees from Roche Pharmaceutical
outside the submitted work. All other authors declare no competing
interests.
Data sharing
Deidentified individual participant data, together with a data dictionary
defining each field in the set, will be made available to other researchers
on request. Trial documentation including the protocol are available
online. The Institute of Cancer Research-Clinical Trials and Statistics
Unit (ICR-CTSU) supports wider dissemination of information from the
research it conducts and increased cooperation between investigators.
Trial data are obtained, managed, stored, shared, and archived according
to ICR-CTSU standard operating procedures to ensure the enduring
quality, integrity, and utility of the data. Formal requests for data sharing
are considered in line with ICR-CTSU procedures, with due regard given
to funder and sponsor guidelines. Requests are via a standard proforma
describing the nature of the proposed research and extent of data
requirements. Data recipients are required to enter a formal data sharing
agreement, which describes the conditions for release and requirements
for data transfer, storage, archiving, publication, and intellectual property.
Requests are reviewed by the trial management group in terms of
scientific merit and ethical considerations, including patients’ consent.
Data sharing is undertaken if proposed projects have a sound scientific or
patients’ benefit rationale, as agreed by the trial management group and
approved by the independent data monitoring and steering committee,
as required. Restrictions relating to patients’ confidentiality and consent
will be limited by aggregating and anonymising identifiable patients’
data. Additionally, all indirect identifiers that could lead to deductive
disclosures will be removed in line with ICR-CTSU data sharing
guidelines.
Acknowledgments
We thank the patients who participated in this trial and sta at the
participating centres and at the Institute of Cancer Research-Clinical Trials
and Statistics Unit (ICR-CTSU); we also thank FAST-Forward trial
management group members past and present, and the independent data
monitoring committee and trial steering committee for overseeing the trial
(appendix pp 1–2). The trial is sponsored by The Institute of Cancer
Research (London, UK). The FAST-Forward trial is funded by the National
Institute for Health Research (NIHR) Health Technology Assessment
programme (UK; 09/01/47), with programme grants from Cancer
Research UK to support the work of ICR-CTSU (C1491/A15955;
C1491/A25351). We acknowledge NHS funding to the NIHR Biomedical
Research Centre at the Royal Marsden NHS Foundation Trust (London,
UK) and The Institute of Cancer Research (London, UK). The views
expressed are those of the authors and not necessarily those of the NIHR
or the Department of Health and Social Care.
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