Clinical Oncology 33 (2021) 430e439

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Clinical Oncology
journal homepage: www.clinicaloncologyonline.net

Original Article
Five-fraction Radiotherapy for Breast Cancer: FAST-Forward to
Implementation
A.M. Brunt *y, J.S. Haviland y, A.M. Kirby zx, N. Somaiah xz, D.A. Wheatley {, J.M. Bliss y,
J.R. Yarnold x
* David Weatherall Building, School of Medicine, University of Keele, Keele, UK
y
Clinical Trials and Statistics Unit (ICR-CTSU), The Institute of Cancer Research, London, UK
z
Department of Radiotherapy, Royal Marsden NHS Foundation Trust, Sutton, UK
x
Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK
{
Sunrise Centre, Royal Cornwall Hospital, Truro, UK

Abstract
Introduction: The phase 3 FAST-Forward trial reported outcomes for 26 and 27 Gy schedules delivered in 5 fractions over 1 week versus 40 Gy in 15 fractions
over 3 weeks in 4000 patients. We discuss concerns raised by the radiotherapy community in relation to implementing this schedule.
Ipsilateral Breast Tumour Relapse (IBTR): Published estimated 5-year IBTR with 95% CI after 40 Gy in 15 fractions was 2.1% (95% CI 1.4e3.1), 1.7% (1.2e1.6) after
27 Gy and 1.4% (0.2e2.2) after 26 Gy, emphatically showing non-inferiority of the 5-fraction regimens. Subgroup analyses comparing IBTR in 26 Gy versus 40 Gy
show no evidence of differential effect regarding age, grade, pathological tumour size, nodal status, tumour bed boost, adjuvant chemotherapy, HER2 status and
triple negative status. The number of events in these analyses is small and results should be interpreted with caution. There was only 1 IBTR event post-
mastectomy.
Normal tissue effects: The 26 Gy schedule, on the basis of similar NTE to 40 Gy in 15 fractions, is the recommended regimen for clinical implementation. There is
a low absolute rate of moderate/marked NTE, these are predominantly moderate not severe change. Subgroup analyses comparing clinician-assessed moderate
or marked adverse effect for 26 Gy versus 40 Gy show no evidence of differential effects according to age, breast size, surgical deficit, tumour bed boost, or
adjuvant chemotherapy.
Radiobiological considerations: The design of the FAST-Forward trial does not control for time-related effects, and the ability to interpret clinical outcomes in
terms of underlying biology is limited. There could conceivably be a time-effect for tumour control. A slight reduction in a/b estimate for the late normal tissue
effects of test regimens might be a chance effect, but if real could reflect fewer consequential late effects due to lower rates of moist desquamation.
Conclusion: The 26 Gy 5-fraction daily regimen for breast radiotherapy can be implemented now.
Ó 2021 The Authors. Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).

Key words: Breast cancer; hypofractionation; non-inferiority RCT; radiobiology; radiotherapy; tumour control

Introduction become a new standard of care. The phase III randomised

FAST-Forward trial [4] reported outcomes, in relation to
Over the last 30 years, breast radiotherapy fractionation both tumour control and normal tissue effects (NTE), for 26
has been systematically investigated and debated. Moder- and 27 Gy in five fractions over 1 week versus 40 Gy in 15
ate hypofractionation, using 15 or 16 fractions over 3 weeks fractions over 3 weeks in more than 4000 patients. Selec-
delivering total doses in the range 40e42.5 Gy, has become tion of total doses for the five-fraction schedules was
the widespread international standard [1e3]. Recent pub- informed by earlier trials, including the FAST trial of 915
lished studies of five-fraction breast radiotherapy describe patients testing 28.5 and 30 Gy in five fractions delivered
safe, effective and simpler regimens that will probably once weekly versus 50 Gy in 25 fractions over 5 weeks,
which has now published 10-year results [5].
At a consensus meeting held in October 2020 under the
Author for correspondence: A.M. Brunt, David Weatherall Building, auspices of The Royal College of Radiologists, the UK breast
School of Medicine, University of Keele, Keele, Staffordshire ST5 5BG, UK. cancer radiotherapy community voted for five-fraction breast
E-mail address: m.brunt@keele.ac.uk (A.M. Brunt).

https://doi.org/10.1016/j.clon.2021.04.016
0936-6555/Ó 2021 The Authors. Published by Elsevier Ltd on behalf of The Royal College of Radiologists. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439 431

radiotherapy as its new national standard for breast radio- increased risk of IBTR at a young age were cited, but no
therapy (https://www.rcr.ac.uk/publication/postoperative- evidence of an adverse outcome by age after hypofractio-
radiotherapy-breast-cancer-hypofractionation-rcr-consensus- nation has been reported. A post-hoc analysis of tumour
statements). However, some commentators suggest caution in grade in the Ontario Clinical Oncology Group trial [11]
adopting the schedule now. In the Editorial accompanying the suggested an interaction of grade and randomisation group,
FAST-Forward results, Levy and Rivera [6] agree that results are but subsequent central analysis of tumour blocks reported
practice-changing for low-risk patients, but want longer-term no trend for patients with high-grade tumours to be
disease outcomes and clinically defined subgroup analyses. disadvantaged after 42.5 Gy in 16 fractions [13]. They also
Offersen et al. [7] argued that 26 Gy in five fractions is expected found that tumour grade and molecular subtype did not
to be less effective than 40 Gy in 15 fractions based on con- predict response to hypofractionation. A subgroup meta-
ventional a/b estimates. We explore these issues, together with analysis of locoregional relapse was carried out of the
recurring themes that have come up when presenting the data START-P [14], -A [8] and -B [9] trials in 5861 patients
since publication. reporting 10-year results [10]. Treatment effects of hypo-
fractionation in terms of tumour control were not signifi-
cantly different from 50 Gy in 25 fractions when examined
Ipsilateral Breast Tumour Relapse by age, type of primary surgery, axillary node status, tumour
grade, use of adjuvant chemotherapy or boost radiotherapy.
FAST-Forward is a non-inferiority trial with ipsilateral The 2018 American Society for Radiation Oncology
breast tumour relapse (IBTR) as the primary end point. evidence-based guidelines approved hypofractionated
Based on START trial data [8,9] and incorporating subse- breast radiotherapy with 40/42.5 Gy in 15/16 fractions over
quent improvements in surgical technique and systemic 3 weeks, irrespective of age, tumour grade or receptor sta-
therapy, it was anticipated that the incidence of IBTR by 5 tus [1].
years in the FAST-Forward control group giving 40 Gy in 15 Wang et al. [15] reported on 810 patients in a single
fractions would be 2%. Following discussions with clinicians institution randomised non-inferiority trial of hypofractio-
and patient advocates, a non-inferiority margin of 1.6% was nated radiotherapy post-mastectomy. All patients under-
prespecified in the protocol, which required a sample size of went axillary dissection and were at least four-node positive
4000 patients. The estimated 5-year incidence of IBTR after or T3e4, unless they received neoadjuvant chemotherapy, in
40 Gy in 15 fractions was 2.1% (95% confidence interval which case either clinical stage III or pathological axillary
1.4e3.1), 1.7% (1.2e1.6) after 27 Gy and 1.4% (0.2e2.2) after node-positive patients were eligible. The hypofractionated
26 Gy. These upper confidence limits excluded an increase schedule was 43.5 Gy in 15 fractions over 3 weeks versus 50
in IBTR of >1.6% after both five-fraction schedules, with P ¼ Gy in 25 fractions over 5 weeks as standard. The radio-
0.0022 and P ¼ 0.00019 for non-inferiority of 27 and 26 Gy therapy target volume included the chest wall, level 3 axilla
schedules, respectively, compared with 40 Gy in 15 and supraclavicular fossa. The 5-year locoregional recur-
fractions. rence rate was 8.3% (90% confidence interval 5.8e10.7) with
These results on IBTR are definitive. However, one the 15-fraction schedule and 8.1% (90% confidence interval
requirement proposed by commentators is longer follow- 5.4e10.6) with the 25-fraction schedule. With a P < 0.0001
up, as IBTR continues beyond 5 years. Other trials of hypo- for non-inferiority they concluded that the hypofractionated
fractionation have reported almost identical hazard ratios regimen was non-inferior to standard.
for IBTR at 5 and 10 years, the relevant metrics for com- FAST-Forward reported non-inferior IBTR for both five-
parisons of effect. For example, START-B [10] incidence rates fraction schedules and given the preceding arguments we
of IBTR at 5/10 years after 40 Gy in 15 fractions versus 50 Gy would not expect inferiority to be observed in any sub-
in 25 fractions were 1.9%/3.8% versus 3.3%/5.2%, respec- groups, but what did we find? In total, 1545 (37.8%) patients
tively, reflecting crude hazard ratios of 0.72 (95% confidence were in the high-risk category as defined by age <50 years,
interval 0.43e1.21) and 0.70 (95% confidence interval grade 3 tumour or both, and this was a stratification factor
0.46e1.07), i.e. unchanged between 5 and 10 years. The at randomisation. Retrospective subgroup analyses
Ontario Clinical Oncology Group [11] reported IBTR rates at comparing IBTR in 26 Gy versus 40 Gy provided no evidence
5/10 years after 50 Gy in 25 fractions versus 42.5 Gy in 16 of a differential effect according to age, grade, pathological
fractions of 3.2%/6.7% and 2.8%/6.2%, respectively, giving an tumour size, nodal status, tumour bed boost, adjuvant
absolute difference of 0.4% (95% confidence interval chemotherapy, HER2 status and in triple-negative patients
e1.5e2.4%) and 0.5% (95% confidence interval e2.5e3.5%) at (Figure 1). Confidence intervals for the hazard ratios over-
5- and 10-year timepoints. lapped for the subgroups, although the number of events in
Commentators refer to subgroups for whom hypo- these analyses was small (52); hence, results should be
fractionation may not be so effective, but the empirical data interpreted with caution, as the statistical power was low.
are reassuring. The 2011 American Society for Radiation Subgroup analysis according to type of primary surgery was
Oncology evidence-based guidelines [12] were unable to not possible as there was only one IBTR event post-
confirm agreement on hypofractionation in patients <50 mastectomy in a control group patient (out of 91) and
years. The small number of patients included in trials and an none in the 173 patients treated with five fractions. Table 1
432 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439

Fig 1. Subgroup analyses of time to ipsilateral breast tumour relapse for (a) 26 Gy in five fractions versus 40 Gy in 15 fractions and (b) 27 Gy in
five fractions versus 40 Gy in 15 fractions.

shows the frequencies and number of patients in each boost and dose/fractionation, both declared prior to ran-
category of age <50 years, grade 3, post-mastectomy, triple- domisation, was balanced between the three treatment
negative and HER2-positive tumours. No evidence to signal groups, minimising the risk of bias in dose intensity be-
concern was seen for the five-fraction schedules. The use of tween trial groups.
 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439 433

Table 1
Ipsilateral breast tumour relapse by higher risk subgroup in FAST-Forward

Subgroup Event/number 40 Gy/15 fractions 27 Gy/5 fractions 26 Gy/5 fractions

Age under 50 years at randomisation Events 3 7 4
Number at risk 198 189 217
Grade 3 Events 20 15 8
Number at risk 386 389 378
Mastectomy Events 1 0 0
Number at risk 91 89 84
ER-negative/HER2-negative* Events 10 5 3
Number at risk 111 96 128
HER2-positive Events 4 7 2
Number at risk 135 137 135
* PR status was not mandatory in the UK or the trial but when ER/HER2 were negative PR status was negative/positive/unknown in 265/
18/52, respectively.

Normal Tissue Effects more important [16]. FAST-Forward offers a good example
in that breast erythema was less intense and also settled a
In FAST-Forward, late NTE assessed by clinicians, patients fortnight earlier after five-fraction than 15-fraction sched-
and photographs were key secondary end points. The 26 Gy ules [17]. In this context, the milder erythema was a
in five daily fractions schedule, on the basis of similar NTE to response to 26 and 27 Gy total dose levels much more than
40 Gy in 15 fractions, is the recommended regimen for to fraction sizes of 5.2 and 5.4 Gy. Acute reactions were also
clinical implementation. By ‘similar’ we mean that NTE milder in both five-fraction arms (total doses 28.5 and 30
were neither statistically nor clinically significantly Gy) of the FAST trial than the 50 Gy schedule [18].
different from 40 Gy in 15 fractions with respect to clini- Induration is a key late NTE that is expected to increase
cian- or patient-assessed outcomes, including photographic with the passage of time, irrespective of radiation schedule.
assessments conducted blind to treatment allocation. The Other factors contributing to breast appearance include fat
27 Gy five-fraction schedule was statistically significantly necrosis and oedema, particularly in the early years [19].
different to the 40 Gy standard for many late NTE and also to Table 2 shows FAST-Forward breast assessments recorded
the 26 Gy schedule, confirming the sensitivity of trial separately by patients and clinicians. It is important to
outcome measures to detect a difference in dose intensity consider the absolute frequencies of events as well as the
corresponding to 3 Gy in 2 Gy equivalents assuming a/b ¼ 2 relative comparisons between schedules. For example, for
Gy (see below). The 27 Gy five-fraction regimen exhibited breast shrinkage, the most frequent of the clinician-
late NTE rates of comparable magnitude to 50 Gy in 25 daily assessed effects, the prevalence of moderate or marked ef-
fractions. To provide some perspective for the late NTE after fects at 5 years was 5.5% in 40 Gy and 6.8% in 26 Gy, and the
five-fraction regimens, 40 Gy in 15 fractions is equivalent to 5-year prevalence of moderate or marked induration
about 46 Gy in 2 Gy fractions in terms of late NTE compared outside the tumour bed was only 0.1% and 2.1% in 40 and 26
with 50 Gy in 25 fractions according to START trial out- Gy, respectively. For all clinician-assessed events docu-
comes [11]. In FAST-Forward, the 26 Gy regimen is compa- mented in the moderate/marked change categories, most
rable to 47 Gy in 2 Gy equivalents in terms of late NTE. were moderate rather than marked in severity.
Early NTE are much less responsive to fraction size than With regards to increasing frequency of late NTE with
late NTE, the contribution of total dose being relatively time, stability of the hazard ratio at longer timepoints is

Table 2
Breast clinician and patient assessment in FAST-Forward

Normal tissue effect Clinician or Moderate or marked Moderate or marked Odds ratio comparison P-value
patient assessed events in 40 Gy at 5 events in 26 Gy at 5 with 40 Gy across comparison
years (%) years (%) follow-up* (95% CI) with 40 Gyy
Breast distortion Clinician 32/916 (3.5) 53/955 (5.5) 1.20 (0.91e1.60) 0.19
Breast shrinkage Clinician 50/916 (5.5) 65/954 (6.8) 1.05 (0.82e1.33) 0.71
Breast induration Clinician 1/911 (0.1) 20/955 (2.1) 1.90 (1.15e3.14) 0.013
outside tumour bed
Breast appearance changed Patient 140/432 (32.4) 136/429 (31.7) 0.91 (0.75e1.10) 0.33
Breast smaller Patient 122/428 (28.5) 103/429 (24.0) 0.81 (0.65e1.00) 0.053
Breast harder or firmer Patient 61/428 (14.2) 74/425 (17.4) 1.22 (1.00e1.48) 0.048
* Clinician assessment is longitudinal all years. Patient assessment is longitudinal 3 months to 5 years, adjusting for baseline assessment.
y
Statistical significance defined in the statistical analysis plan for normal tissue end points as P < 0.005 to allow for multiple testing.
434 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439

clinically relevant, as shown for START-B [10] and FAST [5] whole-breast planning treatment volume as the proxy for
in Table 3. The principle of the relative difference between breast size. The same lack of change was found with
test and control group changing little with time can there- photographic assessment and breast size. We can conclude
fore be applied to FAST-Forward, again noting the low ab- that breast size is an established factor for increased NTE
solute levels of marked and moderate events. following breast radiotherapy but that hypofractionation,
The Danish-led HYPO trial of 1864 patients tested the including five-fraction schedules, is not an additional
non-inferiority of 40 Gy in 15 fractions in terms of breast concern for larger breasted patients.
induration at 3 years compared with 50 Gy in 25 fractions In FAST-Forward, retrospective subgroup analyses
[7]. This important study reproduced the START-B results comparing the time to first clinician-assessed moderate or
with 3-year rates of induration of 11.8% (95% confidence marked adverse effect in the breast or chest wall for 26 Gy
interval 9.7e14.1%) in the 50 Gy group and 9.0% (95% con- versus 40 Gy provided no evidence of a differential effect of
fidence interval 7.2e11.1%) in the 40 Gy group (risk differ- the five-fraction schedule according to age, breast size,
ence 22.7%; 95% confidence interval 25.6e0.2%; P ¼ 0.07). surgical deficit, tumour bed boost or adjuvant chemo-
Low uptake of hypofractioned whole-breast radiotherapy in therapy, as confidence intervals for subgroups overlapped,
the USA, due in part to concerns of safety for patients although the power for these retrospective subgroup ana-
receiving a tumour bed boost, chemotherapy or having lyses was low (Figure 2).
large breast size, led to a randomised non-inferiority trial What about other organs at risk? The heart is often
[20]. The standard treatment of 50 Gy in 25 daily fractions mentioned, particularly as a very long follow-up is required
with a 10e14 Gy boost in five to seven fractions was tested to assess the full risk, although there is no specific reason to
against 42.56 Gy in 16 daily fractions with a 10e12.5 Gy expect an increased cardiac sensitivity to hypofractionation.
boost in four to five fractions. In total, 106 (36.9%) of the 287 Darby et al. [22] have shown that there is no safe dose to the
patients were defined as large breast size, with a bra cup heart and therefore the effort is to reduce or eliminate
size of at least D. Adverse patient-reported cosmetic cardiac dose. At this early stage, after imaging and further
outcome, the primary end point, was 5.4% lower (8.2% investigation, excluding cases confirmed not to be
versus 13.6%, P ¼ 0.002 for non-inferiority) in the hypo- radiotherapy-related, for left-sided radiotherapy there were
fractionated arm overall and 18.6% lower (90% upper con- six cases of ischaemic heart disease in the 40 Gy group and
fidence limit 8% lower) for large breasted patients. They three cases in the 26 Gy group. The most frequent specialist
concluded that this offers strong reassurance for hypo- referral we have seen is to lymphoedema clinics for breast
fractionation not compromising cosmetic outcome based lymphoedema: 90 patients (6.6%) following 40 Gy, 122
on large breast size. (8.9%) after 27 Gy and 106 (7.7%) after 26 Gy. Breast oedema
Tsang et al. [21] looked at dose heterogeneity with is predominantly an early side-effect, which we have seen
regards to the FAST trial and the risk of ‘triple trouble’. In settling, such that at 5 years the moderate/marked inci-
total, 390 full computed tomography planning data sets dence on clinician assessment was seven (0.7%) patients
were reviewed for patients where there was a baseline and after 40 Gy, 18 (1.8%) after 27 Gy and 17 (1.7%) patients after
a 2-year photographic assessment, the primary end point of 26 Gy, with no oedema in 94, 92 and 93%, respectively.
FAST. The two five-fraction groups were combined for These rates are low and not clinically or statistically signif-
analysis and there was no significant difference between icantly different.
these and the control for breast volume or for patient
tumour and treatment characteristics from the whole FAST Some Radiobiological Considerations: Tumours
population. Multiple logistic regression analyses showed
that after adjusting for breast size (and surgical deficit), In a review of the linear-quadratic model and implica-
there was no evidence of late NTE associated with dose tions for practice, Brand and Yarnold [23] present FAST-
inhomogeneity using various definitions of hotspots. The Forward as an example of a trial evaluating five-fraction
effect of inhomogeneity was not significantly different for hypofractionated accelerated radiotherapy. To make sense
any of the dosimetric parameters between control and five- of FAST-Forward in terms of fraction size effects, the START
fraction schedules. In FAST-Forward, the a/b estimate for trials offer a good entry point. The START-P/-A trials
any clinician-assessed moderate or marked NTE was barely [8,10,14] (1986e2003) each compared 50 Gy in 25 fractions
different unadjusted or when adjusted for breast size, using over 5 weeks (control) with two test dose levels of a 13-

Table 3
Treatment comparisons for moderate or marked breast shrinkage at 5 and 10 years of follow-up in previous breast radiotherapy trials

Trial Risk ratio (95%CI) at 5 years Risk ratio (95%CI) at 10 years

START-B:
40 Gy/15 fractions versus 50 Gy/25 fractions 0.77 (0.56e1.07) 0.87 (0.59e1.26)
FAST:
30 Gy/5 fractions versus 50 Gy/25 fractions 2.03 (1.15e3.58) 1.83 (0.88e3.81)
28.5 Gy/5 fractions versus 50 Gy/25 fractions 1.20 (0.63e2.27) 1.83 (0.88e3.81)
 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439 435

Fig 2. Subgroup analyses of time to first moderate or marked clinician-assessed adverse event in breast/chest wall for (a) 26 Gy in five fractions
versus 40 Gy in 15 fractions and (b) 27 Gy in five fractions versus 40 Gy in 15 fractions.
436 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439

fraction regimen over 5 weeks (five fractions per fortnight). chemotherapy. In the context of the START-B result, if the
By controlling for time-related effects and assuming com- post-hoc analysis (hypothesis generating) estimated 0.6 Gy/
plete repair of sublethal damage between fractions in all day (95% confidence interval 0.1e1.8, P ¼ 0.02) ‘wasted’ dose
groups, an unconfounded estimate of sensitivity to fraction in control group patients during weeks 4 and 5 is true, it
size (a/b) is possible. This simply involves identifying the implies about 14  0.6 ¼ 8 Gy of the control regimen (50 Gy)
total dose in 13 fractions matching the IBTR rate in the 25- is ‘wasted’. This implies a time-corrected EQD2/3.5 of 42 Gy
fraction group, sometimes involving interpolation between for the 5-week regimen compared with 45 Gy for the 3-
test dose levels. In START-A, IBTR after 13 fractions of 3.2 Gy week schedule. The Danish-led HYPO trial [7] offers an in-
was closer than 13 fractions of 3.0 Gy to IBTR after 25 dependent test of START-B in a comparable group of pa-
fractions of 2.0 Gy, from which a direct a/b estimate of 3.5 tients, in whom the 9-year risk of locoregional recurrence
Gy (95% confidence interval 1.2e5.7) was based on the 10- was 3.3% (95% confidence interval 2.0e5.0) in the 50 Gy in
year total of 349 IBTR events in 3646 women [24]. The 8.4 25 fractions group compared with 3.0% (95% confidence
Gy reduction from 50 Gy to 41.6 Gy needed to match the interval 1.9e4.5) in the 40 Gy in 15 fractions group (risk
IBTR of 3.2 Gy fractions with 25 fractions of 2.0 Gy is a vivid difference 20.3%; 95% confidence interval 22.3e1.7), a result
measure of fraction size sensitivity at play. very similar to START-B.
To our knowledge, START-P/-A trials generated the only What have we seen in FAST-Forward? The trial generated
direct clinical estimate of a/b for a cancer, others being an a/b estimate for IBTR of 3.7 Gy (95% confidence interval
based on non-randomised or randomised comparisons that 0.3e7.1), the wide confidence interval reflecting very low
do not control for one or more variables, especially time. incidence of IBTR. The analysis plan did not incorporate a
START-B is a good example of the latter, testing 50 Gy in 25 hypothetical time correction, so the a/b estimate of 3.7 Gy
fractions over 5 weeks against 40 Gy in 15 fractions of 2.7 Gy necessarily incorporates all underlying biology, including
over 3 weeks. Applying the a/b ¼ 3.5 generated by START- fraction size sensitivity, completeness of repair and putative
P/-A, the equivalent total dose in 2.0 Gy fractions (EQD2/ time effects. Regardless of whether or not there is a time
3.5) of the 3-week schedule is only 45 Gy (Table 4), yet based effect, the clinically effective EQD2/3.7 of 26 Gy in five frac-
on 95 IBTR events in 2215 patients (4.3%), the test schedule tions is 41 Gy in 2 Gy fractions (see Table 4). The difference
was non-inferior to 50 Gy (hazard ratio 0.77; 95% confi- in estimated anti-tumour effect between this EQD2/3.7 ¼ 41
dence interval 0.51e1.16, P ¼ 0.21). In fact, the point esti- for the five-fraction schedule and EQD2/3.7 ¼ 45 Gy of 40 Gy
mate 10-year IBTR rate of the 3-week regimen was 1% lower in 15 fractions would be too small to detect at such high
than the 5-week control regimen (ns). A post-hoc analysis levels of local control. Nevertheless, a robust clinical
asked the question ‘If this difference is real, what would it conclusion can be drawn, namely that the five-fraction
tell us about the impact of treatment time?’ [24]. We know regimen has shown non-inferiority in relation to the pre-
that in laryngeal carcinomas, at least 0.5 Gy/day can be defined 1.6% excess IBTR boundary set in the protocol.
‘wasted’ compensating for accelerated repopulation from Questions have been raised whether 26 Gy in five fractions
the fourth week of treatment onwards, first described by has any anti-tumour effect at all [27]. With a 5-year inci-
Withers et al. [25] in patients treated with primary radio- dence of IBTR of 2.1% (95% confidence interval 1.4e3.1) after
therapy and confirmed by Lyhne et al. [26] in a randomised 40 Gy in 15 fractions, the incidence without any radio-
clinical trial comparing 60 Gy in 30 fractions delivered five therapy would be expected to be about 6% at 5 years and
versus six times per week. Breast cancers have relatively 10% at 10 years, according to systematic overviews of
low mitotic rates at presentation, but they might be in an radiotherapy effects [28]. The observed 5-year incidence of
accelerated phase of repopulation by the time radiotherapy IBTR after 26 Gy in five fractions is hardly consistent with an
starts several weeks or months after primary surgery and/or absence of effect.

Table 4
2 Gy equivalents (EQD2) for regimens (referenced) with relevant a/b point values from manuscript text

a/b Gy / Regimen/reference Y 3.7 3.5 3.0 2.8 2.3 2.0 1.8 1.7
50 Gy/25 fractions 50.0 50.0 50.0 50.0 50.0 50.0 50.0 50.0
43.5 Gy/15 fractions [16] 50.4 50.6 51.3 51.7 52.6 53.3 53.8 54.1
42.9 Gy/13 fractions [15] 52.7 53.0 54.0 54.5 55.9 56.8 57.6 58.0
42.5 Gy/16 fractions [12] 47.4 47.6 48.1 48.3 49.0 49.5 49.9 50.1
41.6 Gy/13 fractions [9] 50.4 50.7 51.6 52.0 53.2 54.1 54.7 55.1
40 Gy/15 fractions [4,8,10] 44.7 44.9 45.4 45.6 46.2 46.7 47.0 47.2
39 Gy/13 fractions [9,15] 45.9 46.1 46.8 47.1 48.1 48.7 49.3 49.5
30 Gy/5 fractions [5] 51.1 51.8 54.0 55.0 57.9 60.0 61.6 62.4
28.5 Gy/5 fractions [5] 47.0 47.7 49.6 50.5 53.0 54.9 56.3 57.0
27 Gy/5 fractions [4] 43.1 43.7 45.4 46.1 48.4 50.0 51.2 51.8
26 Gy/5 fractions [4] 40.6 41.1 42.6 43.3 45.3 46.8 47.9 48.5
 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439 437

Some Radiobiological Considerations: Late Reacting Normal The 95% confidence intervals of a/b point estimates for all
Tissues NTE scored in the FAST-Forward trial fall within the confi-
dence intervals of a/b estimates for all late NTE in the FAST and
The discussion of tumour responses above has a lot to say START-P/-A trials. One interpretation, and statistically
about the potential impact of time on IBTR. Turning to late speaking the likeliest, is that they are all internally consistent
NTE, meticulous data generated in human skin are consis- with each other. Alternatively, the differences in a/b estimates
tent with a minimal measurable effect of time. Turesson and is real, and late NTE are truly slightly more likely after 26 Gy in
Thames [29] reported a tiny time effect for telangiectasia five fractions. If so, we exclude repopulation for the reasons
associated with a complete absence of mitotic figures in described above, leaving slow (>24 h) repair between daily
capillary endothelium on serial skin biopsies over many fractions reported by Turesson and Thames [29] and modelled
weeks of radiotherapy, the lack of mitoses excluding repo- in the FAST-Forward trial protocol (appendix 2) as the likely
pulation as a mechanism. The effect was thought to prob- explanation [4]. Alternatively, lower rates of moist desqua-
ably represent a very slow component of repair decaying mation (high a/b) after five-fraction regimens may cause less
with a T1/2 of around 40 days. The same post-hoc investi- consequential late NTE (same high a/b), enough to reduce the
gation of a time effect in breast cancer in START-B described a/b estimate of late NTE compared with conventional frac-
above included analysing the effect of time on late NTE as a tionation. These somewhat esoteric considerations should
negative control, yielding an estimate of 0.14 Gy/day (95% not obscure the all-important clinical conclusion that 26 Gy in
confidence interval e0.09 to 0.34 Gy/day, P ¼ 0.29) for a five daily fractions offers patients comparable NTE rates and
change in photographic breast appearance [26]. non-inferior IBTR to 40 Gy in 15 fractions.
The reason for providing this level of detail is that the
selection of FAST-Forward test dose levels 27 and 26 Gy
assumed, firstly, no clinically significant time effect for late UK Consensus and Recommendations for
NTE between 1 and 3 weeks; secondly, complete sublethal Implementation
damage repair between fractions; and thirdly, an a/b of 2.8
Gy for late NTE, the last assumption based on the combined The UK consensus meeting [2] included an in-depth re-
estimates of a/b in START-A and FAST. On this basis, the view of the FAST-Forward results, including many of the
EQD2/2.8 of all FAST-Forward schedules relative to 50 Gy in clinical aspects examined here. The results of FAST-Forward
25 fractions are shown in Table 5, where negative values were planned to be taken together with those of IMPORT
indicate estimated NTE rates lower than 50 Gy in 25 LOW [30], which had the same control regimen of 40 Gy in
fractions. 15 fractions to the whole breast and, therefore, are appli-
Although the 27 Gy test dose level was predicted to be cable to partial-breast radiotherapy. There is no clinical
iso-effective for NTE with 40 Gy in 15 fractions, the rationale for excluding groups that were under-represented
observed iso-effect for NTE at 5 years was closer to 26 Gy, unless there is a logical argument for doing so. The de-
suggesting a slightly lower a/b value (see Table 4). The a/b cisions taken at the consensus meeting were to adopt 26 Gy
point estimates are all around 2 Gy, corresponding to EQD2/ in five daily fractions of 5.2 Gy for whole-breast, partial-
2 of about 47 Gy for 26 Gy in five fractions. This compares to breast and chest wall radiotherapy as the standard regimen.
EQD2/2.8 of about 46 Gy for 40 Gy in 15 fractions, the latter The coronavirus pandemic has unexpectedly given cli-
using the combined estimate of a/b ¼ 2.8 for this regimen nicians and centres all over the world experience of 26 Gy in
based on START-A and FAST. five daily fractions. Audit of that experience by centre, re-
gion or country should aid confidence in incorporating it
into national or international guidelines. The original pub-
Table 5 lication [4] and appendices include links to the trial protocol
Relative EQD in 2 Gy fractions of FAST-Forward schedules and the as a resource; the UK consensus weblink in this document is
absolute percentage difference in adverse events (DAE) expected also a resource and the FAST-Forward team have provided
compared with 50 Gy in 25 fractions assuming (i) a/b ¼ 2.8 Gy as advice both to individual centres and via webinars to in-
per START-A and FAST, (ii) complete repair of sublethal damage ternational groups over the last year. The START trials’ [8,9]
between fractions and (iii) a doseeresponse gradient correspond- 5-year outcomes were published in 2008 and the 40 Gy in
ing to g¼ 1.4 as per START-A trial (https://www.icr.ac.uk/our- 15 fractions schedule was adopted as UK standard of care in
research/centres-and-collaborations/centres-at-the-icr/clinical-
2009 (https://www.nice.org.uk/guidance/ng101) as a result,
trials-and-statistics-unit/clinical-trials/fast_forward_page/)
albeit that the 10-year outcomes [10] gave clinicians and
Fractionation regimen EQD2/2.8 (Gy) DAE (%)* patients confidence that the regimen was safe and effective
50 Gy/25 fractions/5 weeks 50.0 reference in the longer term. Similarly, the 26 Gy five-fraction
40.05 Gy/15 fractions/3 weeks 45.6 e12.3 schedule is ready for adoption globally, and indeed is
27 Gy/5 fractions/1 week 46.1 e11.1 already going through that process in some countries.
(5.4 Gy/fraction) Although, based on the START [10] and FAST [5] data, it is
26 Gy/5 fractions/1 week 43.3 e18.8 anticipated that outcomes will remain non-inferior at 10
(5.2 Gy/fraction) years, it is important to continue collecting data to the 10-
* Negative values indicate estimated normal tissue effect rates year timepoint to provide reassurance around the longer-
lower than after 50 Gy in 25 fractions. term safety and efficacy of the five daily fraction schedule.
438 A.M. Brunt et al. / Clinical Oncology 33 (2021) 430e439

Conclusions [5] Brunt AM, Haviland JS, Sydenham M, Agrawal RK, Algurafi H,
Alhasso A, et al. Ten-year results of FAST: a randomized
controlled trial of 5-fraction whole breast radiotherapy for
We conclude that 26 Gy in five daily fractions for breast
early breast cancer. J Clin Oncol 2020;38:3261e3272. https://
radiotherapy is an effective regimen for tumour control. doi.org/10.1200/JCO.19.02750.
There is no evidence or scientific rationale to argue against [6] Levy A, Rivera S. 1-week hypofractionated adjuvant whole-
it for any subgroup. With regards to adverse effects, it is as breast radiotherapy: towards a new standard? Lancet 2020;
well tolerated as moderate hypofractionation over 3 weeks 395(10237):1588e1589. https://doi.org/10.1016/S0140-
of daily radiotherapy. Furthermore, it is convenient for pa- 6736(20)30978-8.
tients and less burdensome for radiotherapy departments. [7] Offersen BV, Alsner J, Nielsen HM, Jakobsen EH, Nielsen MH,
We recommend that 26 Gy in five daily fractions for all Krause M, et al. Hypofractionated versus standard fraction-
indications of whole-breast, partial-breast and chest wall ated radiotherapy in patients with early breast cancer or
ductal carcinoma in situ in a randomized phase III trial: the
radiotherapy be adopted as the standard of care.
DBCG HYPO trial. J Clin Oncol 2020;38:3615e3625. https://
doi.org/10.1200/JCO.20.01363.
[8] Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ,
Conflicts of Interest Bliss JM, et al. The UK standardisation of breast radiotherapy
(START) trial A of radiotherapy hypofractionation for treat-
All authors were also authors of the FAST-Forward 2020 ment of early breast cancer: a randomised trial. Lancet Oncol
publication in The Lancet and have continued roles in the 2008;9:331e341. https://doi.org/10.1016/S1470-2045(08)
FAST-Forward trial. 70077-9.
[9] Bentzen SM, Agrawal RK, Aird EG, Barrett JM, Barrett-Lee PJ,
Bentzen SM, et al. The UK standardisation of breast radio-
Acknowledgements therapy (START) trial B of radiotherapy hypofractionation for
treatment of early breast cancer: a randomised trial. Lancet
We thank the patients who participated in this trial and 2008;371:1098e1107.
staff at the participating centres and at ICR-CTSU; we also [10] Haviland JS, Owen JR, Dewar JA, Agrawal RK, Barrett J, Barrett-
thank FAST-Forward Trial Management Group members Lee PJ, et al. The UK standardisation of breast radiotherapy
past and present, and the Independent Data Monitoring (START) trials of radiotherapy hypofractionation for treatment
of early breast cancer: 10-year follow-up results of two
Committee and Trial Steering Committee for overseeing the
randomised controlled trials. Lancet Oncol 2013;14:
trial. The FAST-Forward trial is funded by the National
1086e1094. https://doi.org/10.1016/S1470-2045(13)70386-3.
Institute for Health Research (NIHR) Health Technology [11] Whelan TJ, Pignol JP, Levine MN, Julian JA, MacKenzie R,
Assessment Programme - HTA (UK) (09/01/47), with Cancer Parpia S, et al. Long-term results of hypofractionated radiation
Research programme grants to support the work of ICR- therapy for breast cancer. N Engl J Med 2010;362:513e520.
CTSU (C1491/A15955; C1491/A25351). We acknowledge https://doi.org/10.1056/NEJMoa0906260.
NHS funding to the NIHR Biomedical Research Centre at the [12] Smith BD, Bentzen SM, Correa CR, Hahn CA, Hardenbergh PH,
Royal Marsden NHS Foundation Trust and The Institute of Ibbott GS, et al. Fractionation for whole breast irradiation: an
Cancer Research (London, UK). The views expressed are American Society for Radiation Oncology (ASTRO) evidence-
those of the authors and not necessarily those of the NIHR based guideline. Int J Radiat Oncol Biol Phys 2011;81:59e68.
[13] Bane AL, Whelan TJ, Pond GR, Parpia S, Gohla G, Fyles AW,
or the Department of Health and Social Care.
et al. Tumor factors predictive of response to hypofractionated
radiotherapy in a randomized trial following breast
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