The document discusses the FAST Forward study, a phase III randomized trial comparing different fractionation schedules for adjuvant radiotherapy in breast cancer. The study involved 4096 patients randomized to receive either 40 Gy in 15 fractions, 27 Gy in 5 fractions, or 26 Gy in 5 fractions. At median follow-up of 71.5 months, there was no significant difference in ipsilateral breast tumor recurrence between groups. However, 27 Gy in 5 fractions was associated with significantly increased risk of moderate or marked late normal tissue effects compared to 40 Gy, based on clinical, patient-reported, and photographic assessments. Estimated α/β ratios were 3.7 Gy for tumor control and 1.7 Gy for normal tissue toxicity.

1. Can we go forward with FAST Forward?
The Journal club
FAST Forward study
Dr Kanhu Charan Patro
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2. The article
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THE LANCET ONCOLOGY

3. It is all about
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4. Adrian Murray Brunt
• Royal Stoke University
Hospital
• Current position
– Professor of Clinical
Oncology
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5. The background
• Adjuvant radiotherapy for breast cancer is the
standard after BCS and mastectomy if indicated.
• 25 # of 2 Gy over 5 weeks-standard
– Early Breast Cancer Trialists’ Collaborative Group
• A 3-wk schedule of 15 # has been the UK
standard of care since 2009 and is now an
international standard for adjuvant local
radiotherapy
– START trials
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6. α⁄β= SENSITIVITY TO FRACTION SIZE
• If α ⁄β ratio of tumor is high (often 10 or
greater) and α⁄β ratio of normal tissue is low
(often < 5), lower dose per fraction (hyper
fractionation) is preferred
– e.g., HNSCC, Ca lung
• If α⁄β ratio of tumor is less than normal tissue
then a larger dose per fraction
(hypofractionation) is preferred
– e.g., prostate cancer, breast cancer
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7. α/β ratio breast
• Breast cancer is an exception in showing low
α/β ratio.
• Hence it should be sensitive to high dose per
fraction.
• Adjusted α/β value for tumor control was
estimated to be 3.5 Gy
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8. Why hypofraction?
• Results were consistent with hypothesis that
the breast cancer cells were sensitive to high
dose per fraction since they have low α/β
ratio
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9. The evolution
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10. The metaanalysis-START trials
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11. UK FAST TRIAL
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Weekly regimen

12. UK IMPORT LOW-IMRT
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Reduced breast Partial breast

13. UK IMPORT HIGH-IMRT SIB
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Results are awaited

14. The trial introduction
• Phase lll, randomized, non-inferiority trial
• Multicentre-97 hospitals
• UK
• Trial registration-ISRCTN19906132
• Nov 24, 2011 to June 19, 2014
• 4096 patients of breast cancer
• 5-year results
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15. Inclusions
• 18 years
• With invasive carcinoma of the breast
• (pT1–3, pN0–1, M0)
• Breast conservation surgery or mastectomy
• Reconstruction allowed
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16. Exclusions
• Aged ≥65 years, pT1, grade 1 or 2, [ER] pos.,
HER2 negative, pN0, M0
• Amendment on Feb 15, 2013
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17. Allowed and not allowed
Allowed
• Concurrent endocrine
therapy or trastuzumab, or
both
• Axillary surgery (sentinel
node biopsy or axillary
dissection
Not allowed
• Concurrent chemotherapy
• Nodal radiotherapy
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18. Enrolled/ITT/Per-protocol
Enrolled-4110
ITT-4096
Per protocol-4006
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19. Patient demography
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20. Patient demography
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21. Patient demography
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22. Patient demography
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23. Radiation details- Target
• Whole breast clinical target volume, including the soft
tissues from 5 mm below the skin surface to the deep
fascia.
• Postmastectomy chest wall clinical target volume
encompassed 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.
• PTV-1cm
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24. Radiation details-Plan
• The treatment plan was optimized with 3D
dose compensation to achieve the
• 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.
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25. Radiation details- Prescription
• A tangential opposing pair beam arrangement
encompassed the whole breast or chest wall PTV
• Minimizing the ipsilateral lung and heart
exposure.
• Following PTV dose distribution:
– > 95% of PTV received 95% of prescribed dose
– < 5% of PTV received 105% or more,
– <2% of PTV received 107% or more
– Global maximum of < 110%.
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26. Radiation details- Constraints
CONTROL
• Ipsilateral lung
–V12 < 15%
• Heart
–V2<30%
–V10<5%
EXPERIMENTAL
• Ipsilateral lung
• V8< 15%
• Heart
–V5<30%
–V7<5%
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27. Radiation details- Verification
CONTROL
• Treatment verification
was required for at least
– Three fractions in the first
week with correction for any
systematic error
– Then once weekly with a
tolerance of 5 mm
EXPERIMENTAL
• Verification imaging for
each fraction with
recommendations to
correct all measured
displacements.
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28. Issues
• Local control
• Adverse effects
– Breast tissue
– Lung
– Heart
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29. OUTCOME end points
• Primary endpoint was ipsilateral breast tumor relapse
– Defined as invasive carcinoma or ductal carcinoma 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.
• Secondary endpoints
– late normal tissue effects assessed by [PPP] physicians,
patients, and from photographs,
– Other disease-related and survival outcomes (loco regional
relapse, distant relapse, disease free survival, and overall
survival
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30. Statistical analysis
• Patients were randomly assigned (1:1:1)
• Computer-generated random permuted blocks were used
• 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 for relapse
• Because of multiple testing, a significance level of 0・005 was used
for the clinician and patient normal tissue effects assessments.
• All hypotheses for the normal tissue effects endpoints were two-
sided
• Kaplan-Meier estimates (with 95% CIs) of 5-year ipsilateral Breast
tumour relapse incidence
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31. Statistical analysis
• Death from any cause as a competing event in a
Fine–Gray competing risks regression model
• Cross-sectional 5-year analyses compared
prevalence of moderate or marked effects versus
none or mild effects between groups using risk
ratios and risk differences and Fisher’s exact test
• Longitudinal analyses of moderate or marked
effects (vs none or mild) using generalized
estimating equations including all assessments,
comparing groups across the whole follow-up
period using odds ratios (ORs) and the Wald test
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32. Statistical analysis
• No formal interim analyses were done
• All analyses were performed on an ITT basis
that included all patients
• Because the main hypothesis was non-
inferiority, the primary endpoint was also
tested in the per-protocol population,
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33. Statistical analysis
• 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
5# schedules (critical hazard ratio [HR] of 1・81)
• Normal tissue effects were assessed by[PPP]
physicians, patients, and from photographs
• The database snapshot was taken on Nov 22, 2019;
Stata, version 15 (StataCorp)
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34. Statistical analysis
• 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 effects as per
methods in the START and FAST trials.
• The α/β estimate for breast cancer was obtained from a Cox
proportional hazards regression model basing on time to first
ipsilateral breast tumor relapse, and for late normal tissue
effects from generalized estimating equations models
including all follow-up assessments (separate models for
photographic and clinician assessments).
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35. Assessment- PPP mode
• PPP mode
– Physician
– Patient
– Photography
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36. Assessment- Physician mode
• Assessed by physicians for ipsilateral breast
tumour relapse and late normal tissue effects
at annual follow-up visits. Starting 12 months
after trial entry.
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37. Late-onset normal tissue effects in
ipsilateral breast
• Late-onset normal tissue effects in ipsilateral
breast or chest wall
– Breast distortion,
– Shrinkage,
– Induration
– Telangiectasia
– Breast or chest wall oedema
– Discomfort
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38. Assessment-Graded by physician
• Four-point scale
– None
– A little,
– Quite a bit,
– Very much
• Interpreted
– None,
– Mild,
– Moderate,
– Marked
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39. Assessment- Patient mode
• EORTC of Cancer QLQ-BR23 breast cancer
module
• Before randomization at 3, 6, 12, 24, and 60
months
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40. Assessment - Scale
• Patient assessments used a four point scale (not
at all, a little, quite a bit, and very much)
• Protocol-specific questions relating to changes to
the affected breast after treatment (including
breast appearance changed, smaller, harder or
firmer, and skin appearance changed).
• Breast size and surgical deficit were assessed
from the baseline photographs on a three-point
scale (small, medium, and large)
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41. Assessment – Photographic mode
• In the photographic sub study, 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 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 photographs were scored by three observers who were
masked to patient identity and treatment allocation following
scoring procedures established in the START trials.
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42. Result –Ipsilateral tumor recurrence
• Median follow-up of 71・5 months
• 79 patients
– 31 in the 40 Gy group
– 27 in the 27 Gy group-
• HRs versus 40 Gy is 0・86 (95% CI 0・51 to 1・44)
– 21 in the 26 Gy group-
• HRs versus 40 Gy is 0・67 (95% CI 0・38 to 1・16)
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43. Ipsilateral breast tumor relapse
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44. Relapse : time-to-event analysis
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45. Mortality : time-to-event analysis
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46. Relapses, second primary cancers,
and deaths by fractionation schedule
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47. Normal tissue effects- Clinical
• At 5 years moderate or marked 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.
• OR Across all clinician assessments from 1–5 years
– 1・55 (95% CI 1・32 to 1・83, p<0・0001) for 27 Gy/ 5#
– 1・12 (95% CI 0・94 to 1・34, p=0・20) for 26 Gy / 5#
• Patient and photographic assessments showed higher
normal tissue effect risk for 27 Gy not for 26 Gy.
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48. Normal tissue effects
Photographic assessment
• 1737 patients
• At 2 years, mild or marked change in photographic breast appearance was
reported in
– 35/411 (8・5%) 40 Gy,
– 67/429 (15・6%) for 27 Gy
– 46/427 (10・8%) for 26 Gy;
• At 5 years were
– 34 (12・0%) of 283 for 40 Gy,
– 83 (26・9%) of 308 for 27 Gy
– 37 (13・0%) of 284 for 26 Gy Modeling
• 2-year and 5-year together
– 27Gy vs 40 Gy (OR 2・29 [95% CI 1・60 to 3・27], p<0・0001),
– 26Gy vs 40 Gy (OR 1・26 [0・85 to 1・86], p=0・24
– 26 Gy had a significantly lower risk of change in photographic breast
appearance than 27 Gy (p=0・0006).
– 27 Gy had a significantly increased risk of mild or marked change in breast
appearance
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49. Longitudinal analysis of moderate or marked clinician-
assessed late normal tissue effects for patients with at
least one annual clinical assessment
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50. Longitudinal analysis of moderate or marked clinician-
assessed late normal tissue effects for patients with at
least one annual clinical assessment
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51. Longitudinal analysis of moderate or marked patient-assessed
late normal tissue effects from baseline to 5 years
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52. Longitudinal analysis of moderate or marked patient-assessed
late normal tissue effects from baseline to 5 years
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53. Longitudinal analysis of moderate or marked patient-assessed
late normal tissue effects from baseline to 5 years
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54. α/β estimate- relapse
The a/ß 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
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55. α/β estimate- Normal Tissue
• Unadjusted α/β estimate for any moderate or
marked clinician-assessed normal tissue effects in
the breast or chest wall was 1・7 Gy
• EQD2 estimates
– 47・1 Gy for 40 Gy in 15 fractions
– 51・6 Gy for 27 Gy in 5 fractions
– 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
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56. α/β estimate- Photographic
• Unadjusted α/β estimate for any moderate or
marked clinician-assessed normal tissue
effects in the breast or chest wall was 1・8 Gy
• EQD2 estimates
– 46・1 Gy for 40 Gy in 15 fractions
– 48・2 Gy for 27 Gy in 5 fractions
– 45・2 Gy for 26 Gy in 5 fractions
• Adjusting for breast size and surgical deficit
assessed from the baseline photographs
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57. Worries
• BCS VS MRM
• Age
• Chemo used
• Dose distribution
• Boost
• Left vs Right
• Stage
• Nodal irradiation
• Brachial plexus
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58. Strength of the study
• Well randomized
• Late tissue reaction assessment
• ITT analysis
• Well matched pair analysis
• PPP mode assessment
• α/β estimation
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59. Pit falls of the study
• No subgroup analysis- on going
• No longer follow up
• Following recruitment into the main trial a further sub
study 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 sub study are not
reported here because follow-up is not yet mature.
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60. Summary
• 5-yr ipsilateral breast tumor relapse incidence after a
1-wk course of adj. breast radiotherapy delivered in
5# is non-inferior to the standard 3-wk 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
effects, clinician-assessed normal tissue effects, and
photographic change in breast appearance, and is
similar to normal tissue effects expected after 46–48
Gy in 2 Gy #
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61. Take home message
1. The consistency of FAST-Forward results with
earlier hypofractionation trials supports the
adoption of 26 Gy in 5 daily # as a new standard
for women with operable breast cancer requiring
adjuvant to partial and whole breast
2. 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
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In this corona situation
Think of hypofractionation
Go forward
With FAST Forward

62. IF YOU
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