Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.

1. Hypofractionation in breast cancer
Dr Dodul Mondal
MD, DNB
All India Institute of Medical Sciences, New Delhi
Dodul Mondal

2. Rationale
Standard radiotherapy after BCS or mastectomy for early breast cancer is 50Gy
in 25 daily fractions over 5weeks (followed by 10-16Gy boost if required)
So, Why to shift to Hypofractionation???
 Has to be at least equally effective for oncologic outcome
 Cosmesis has to be at least equally good
 Patient convenience
 Can reduce burden on treatment machine
 Can it serve better to provide care to more patients?
Dodul Mondal

3. Radiobiology-Fractionation
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
(hyperfractionation) is preferred
e.g., HNSCC, Ca lung
If α⁄β ratio of tumor is < normal tissue then a larger dose per fraction
(hypofractionation) is preferred
e.g., prostate cancer, breast cancer
α⁄β= SENSITIVITY TO FRACTION SIZE
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4. So, there is a chance that high dose per fraction may be an alternative,
as good, if not better than conventional fractionation…
SCIENCE
BUT
EVIDENCE???
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5. Hypofractionation in Breast cancer: Evidence
Hypo-fractionated with dose >2Gy was not popular because of fear of
increased late effect and impaired cosmesis.
Initial hypofractionation studies of 1970s failed to address adequate total dose
adjustment with high dose per fraction excessive late toxicity*
Schedules with lower total dose delivered in fewer, larger fractions were
popular in UK and Canada for several decades e.g. 40Gy/15#/3wk
Retrospective studies suggested similar outcome in terms of local control and
cosmesis.
* Bates TD, Br J Radiol. 1988 Jul;61(727):625-30.
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6. Case Series and Cohort Studies Evaluating
Hypofractionation for Whole-Breast Irradiation
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7. Cochrane Database Syst Rev. 2008 Jul 16;(3)Dodul Mondal

8. Local recurrence free survival
Breast appearance
Survival at five years
Late skin toxicity at five years
Late radiation toxicity in subcutaneous tissue
Unconventional fractionation regimens did not affect breast appearance or
toxicity, nor appear to affect local cancer relapse
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9. Randomized Trials of Hypofractionation for
Whole-Breast Irradiation
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10. Whelan et al JNCI 2002
I
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A
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U
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T Dodul Mondal

11. Cosmetic outcome and local control: Initial result
Arms Baseline 3 year 5 year
LRC AT 5
YEAR
SWBI 83%(604) 77%(498) 79%(423) 97.2%
AHBI 84%(616) 77%(518) 78%(448) 96.8%
Whelan et al JNCI 2002
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12. Dodul Mondal

13. Whelan et al NEJM 2010
• Median FU: 10 years
Long term follow up
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14. Dodul Mondal

15. Royal Marsden-GOC Trial… initial hypothesis
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16. Royal Marsden-GOC Trial… initial hypothesis
Arm Dose (Gy) No of
Fractions
Dose/fx
(Gy)
Duration
(weeks)
Control Arm 50 25 2 5
Test Arm1 42.9 13 3.3 5
Test Arm2 39 13 3 5
Radiotherapy and Oncology 75 (2005) 9–17
α⁄β= 3
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17. Result- Cosmesis
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18. Overall α⁄β= 3
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19. UK Standardization of Breast Radiotherapy (START) trials
Trials
Total
Dos(Gy)
No .of
Fraction
Fraction
Size (Gy)
Time
(Week)
START A 41.6 13 3.2 5
N=2235 39 13 3 5
50 25 2 5
START B
40 15 2.67 3
N=2215 50 25 2 5
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20. START A trial
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21. Lancet Oncol 2008; 9: 331–41
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22. Local-regional tumour relapse in 2236 patients
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23. Forest plot of late normal tissue effects assessed as moderate/marked by patients and mild/marked from
photographs
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24. LATE EFFECTS
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25. START B trial
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26. Dodul Mondal

27. LOCOREGIONAL RELAPSE DISTANT RELAPSE
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28. Survival analyses of relapse and mortality according to fractionation schedule
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29. LATE EFFECTS
Mild/marked change in breast appearance
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30. Forest plot of late normal tissue effects assessed as moderate/marked by patients and
mild/marked from photographs
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31. UK FAST
trial
2003-2007
No of
patients
Total dose
(Gy)
No of
fractions
Fraction size
(Gy)
Time (week)
302 50 25 2 5
308 30 5 6 5
305 28.5 5 5.7 5
Extreme hypofractionation1: UK FAST trial
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32. Dodul Mondal

33. BREAST SHRINKAGE
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34. BREAST INDURATION
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35. Extreme hypofractionation2: UK FAST Forward trial
40.05Gy/15fx/3week
CONTROL TEST1 TEST2
27 Gy/5 fx/1week
 All patients under 40 years
 40-49 years with grade 3 tumours and/or LVI.
 50-59 years with adverse prognostic factor,
grade or LVI
26 Gy/5 fx/1week
± Sequential Boost
10Gy/5Fx or 16Gy/8fx
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36. Dodul Mondal

37. Dodul Mondal

38.  367 women
 ≥70 years
 Nonmetastatic T1 or T2
 Breast-conserving surgery with or without lymph
node dissection followed by and adjuvant RT
 50 Gy (25 fractions, 5 weeks) ± boost OR
 Median follow-up 93 months
(9–140)
 The 5- and 7-year CSS, LRFS,
and MFS rates were similar in
both groups
 HYPOFRACTIONATION is
an acceptable alternative 32.5 Gy (five fractions of 6.5 Gy, once
weekly). No Boost Dodul Mondal

39. At this time, published data support the feasibility of hypofractionated RNI and the need
for a prospective randomized trial addressing clinical outcomes and toxicity of
hypofractionated RNI compared with standard fractionation RNIDodul Mondal

40. Overview of hypofractionation trials
Trials Total Dos(Gy) No .of Fraction Fraction Size (Gy) Time(Week)
Ontario
COG
50 25 2 5
42.5 16 2.65 3
RMH-GOC
50 25 2 5
42.9 13 3.3 5
39 13 3 5
START A
50 25 2 5
41.6 13 3.2 5
39 13 3 5
START B
50 25 2 5
40 15 2.67 3
UK FAST
TRIAL
50 25 2 5
30 5 6 5
28.5 5 5.7 5
SUMMARY OF PUBLISHED TRIALS
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41. ONGOING…
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42. NRG ONCOLOGY RTOG 1005
A PHASE III TRIAL OF ACCELERATED WHOLE BREAST
IRRADIATION WITH HYPOFRACTIONATION PLUS CONCURRENT
BOOST VERSUS STANDARD WHOLE BREAST IRRADIATION PLUS
SEQUENTIAL BOOST FOR EARLY-STAGE BREAST CANCER
Dodul Mondal

43. 50Gy/25fx
42.7Gy/16fx
12Gy/6fx
14Gy/7fx
25+6 or 25+7 fraction
Sequential
48Gy/15fx
40Gy/15fx
15 fractions
Concurrent
NRG ONCOLOGY RTOG 1005
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44. NRG ONCOLOGY RTOG 1005
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45. IMPORT LOW
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46. IMPORT HIGH
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47. Yat Tsang et al. Interim Analysis of Treatment Plans in the IMPORT HIGH (CR UK/06/003) Trial, 2014
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48. Hypofractionation in early breast cancer: as good
as conventional fractionation, if not better
Similar locoregional control, survival
Cosmesis is good to excellent
Multiple RCTs, Robust data
Convenient to patients
So, more cost effective
Means to provide necessary care to more patients?
Time to change practice
Dodul Mondal

49. THANK YOU
Dodul Mondal