EVIDENCE FROM START LIKE TRIALS

1. Evidence from START like trials
Is it ending of START era?
Dr Kanhu Charan Patro
6/4/2020 1

2. I will slow my flow
• Why hypofractionation?
• The evolution of trials.
• The Largest Metanalysis- RADIATION ONCOLOGY JOURNAL/2020
• The 10 year f/up START-10yr follow up of START trials/LANCET/2020
• Long term safety metanalysis- The Breast Journal/2019
• The Indian data and recommendation
• The ASTRO recommendations-2018/PRO
• The summary of FAST Forward
• Limitations of FIRST Forward over START in practice
• Conclusions
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3. Background
• Historically, the standard of care is 50GY/25# for MRM and BCS with
boost or with out boost.
• Recognizing the limitations of CF for convenience and cost,
randomized trials in the 1990s and 2000s investigated if moderate
hypofractionation (HF), defined as daily doses of 265 to 330 cGy,
could yield oncologic and /cosmetic outcomes similar to
conventional.
• Initial trial reports supported the safety and effectiveness and
response.
• Later the ASTRO updated guideline on hypofractionation schedule in
2018
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4. Main studies
• START PILOT
• START A
• START B
• RMH/GOC
• ONTARIO/OCOG
• Many more
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5. The radiobiology of breast
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6. α/β ratio breast and Why hypofraction?
• Breast cancer is an exception in showing low α/β ratio.
• So they are sensitive to high dose per fraction.
• Adjusted α/β value for tumor control was estimated to be 3.5 GY
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7. The evolution
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8. UK FAST TRIAL
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Weekly regimen

9. UK IMPORT LOW-IMRT
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Reduced breast Partial breast

10. UK IMPORT HIGH-IMRT SIB
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Results are awaited

11. START profile
START A
START B
Jan 20, 1999 to Dec 20, 2002
Jan 4, 1999 to Oct 12, 2001
5 fractions a week in control group
5 fractions a fortnight in experimental arms
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12. The metaanalysis-START trials
126/4/2020 Yarnold et al/BJR

13. 10 year follow up of START trials/LANCET/2020
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14. Locoregional recurrence
START A START B
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15. Survival analysis
START A START B
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16. Normal tissue effects in the breast
comparing hypofractionated regimens
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17. Late normal tissue effect
START A START B
Long-term follow-up confirms that hypofractionated radiotherapy is safe and
effective for patients with early breast cancer. The results support the continued use of 40 Gy
in 15 fractions
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18. The largest metanalysis
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19. The trial schema
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20. A-Overall Survival, B-Disease-Free Survival
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21. C- Locoregional Recurrence, D- Distant Met
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22. A-Acute Skin Toxicity, B-Acute Lung Toxicity,
C-Late Skin Toxicity
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23. A-Lymphedema, B-Shoulder Restriction,
C-late Cardiac Related Toxicity
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24. Long term safety metanalysis
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25. The trials
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26. The study characteristics
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27. The outcome table
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28. The late effect
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29. The metanalysis summary
• There is no difference in outcomes between conventional
fractionation and hypofractionated in terms of efficacy when we
evaluate local recurrence, loco-regional recurrence, distance
recurrence, disease-free survival and mortality.
• There is also no difference concerning safety when we assess the
occurrence of fibrosis, ischemia and ribs fractures.
• Hypofractionated showed better results in relation to breast edema,
telangiectasia, and acute skin radiation toxicity
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30. The INDIAN data
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31. Indian data –TMC- Retrospective- 925 patents
Conclusion: Local recurrence rates following hypofractionated radiation in our population were comparable
with those reported by the START trialists and were found to be safe in the medium term for patients
irrespective of breast conservation surgery/mastectomy or radiotherapy to the supraclavicular field.
Molecular group frequencies were comparable with Western populations but did not affect LRRFS
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32. Indian data-CMC experience-prospective-[n-136]
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Hypofractionated RT is feasible and very
relevant in Indian population in terms of
acute skin toxicity.

33. Indian data –TMH-Retrospective-520 patients
Conclusion
• Clinical outcomes of HFRT were
comparable to conventional RT in
women undergoing BCT.
• However LRC rates were statistically
inferior in patients undergoing MRM in
presence of node positive disease,
hormone receptor negative status and
high grade (IDC grade 3) tumors.
• Hypofractionation should be
cautiously used in this subgroup of
patients
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34. Indian data –SMS-,Jaipur-Prosp.- [n-100 MRM]
HF postmastectomy RT is comparable to conventional RT without evidence of higher adverse effects or
inferior locoregional tumor control and has an added advantage of increased compliance because of short
duration; hence, it can help in accommodating more breast cancer patients in a calendar year, ultimately
resulting in decreased waiting list, increased turnover, and reduced cost of treatment
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35. Indian data –SGPGI- Lucknow-Retrospective
Conclusions: The risk of local recurrence among
patients of breast cancer treated with HFRT after BCS
or MRM was not worse when compared to CFRT
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36. Indian data Oncologist pool-Recommendation
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37. TMH guidelines
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Panel qualified its initial vote in favor of hypofractionated schedules, to state that such techniques be used only
in centers with advanced simulation and planning systems

38. The ASTRO recommendations
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39. The ASTRO recommendations
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40. ASTRO recommends
Hypractionation recommended
• Any stage
• Any grade
• Any age
• Any nodal area
• Any side
• Any chemo
• Any size
• Any immobilization
• Any position[prone vs supine]
• Any concurrent status[HT/Trastazumab]
• Any receptor status
• Any boost
Individual decision
• Rare histology
• DCIS
• Collagen vascular disease
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41. Are we fast enough to start FAST Forward?
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42. The FAST Forward
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THE LANCET ONCOLOGY

43. It is all about
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44. 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)
446/4/2020 DR KANHU

45. 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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46. 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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47. Weaknesses 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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48. Worries
• BCS VS MRM
• Age
• Chemo used
• Dose distribution
• Boost
• Left vs Right
• Stage
• Nodal irradiation
• Brachial plexus
486/4/2020 DR KANHU

49. α/β estimate- Clinical FAST Forward- a caution
• Unadjusted α/β estimate for any moderate or marked clinician-
assessed normal tissue effects in the breast or chest wall was 1・7 Gy
496/4/2020 DR KANHU

50. 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.
• 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.[PPP]
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51. The comparison
Three week regimen-START like
• Many RCT
• Many metanalysis
• Long term follow up
• Subgroup analysis
• ASTRO recommendation
• Good Indian data and practice
One Week regimen-FAST Forward
• Single RCT
• No metanalysis
• No long term follow up
• No subgroup analysis
• Few centers started
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52. The hierarchy of evidence
FAST Forward
START LIKE
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53. Take home message
1. Strong evidence from 3week regimen
2. 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
3. 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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54. Thanks
•Organizers- Gujarat AROI
•Audience
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