Hypofractionation in breast cancer

Dr Dodul MondalMD, DNB

All India Institute of Medical Sciences, New Delhi

Dodul Mondal

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

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

Dodul Mondal

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???

Dodul Mondal

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.

Dodul Mondal

Case Series and Cohort Studies Evaluating Hypofractionation for Whole-Breast Irradiation

Dodul Mondal

Cochrane Database Syst Rev. 2008 Jul 16;(3)Dodul Mondal

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

Dodul Mondal

Randomized Trials of Hypofractionation for

Whole-Breast Irradiation

Dodul Mondal

Whelan et al JNCI 2002

I

N

I

T

I

A

L

R

E

S

U

L

T Dodul Mondal

Cosmetic outcome and local control: Initial result

Arms Baseline 3 year 5 yearLRC 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

Dodul Mondal

Dodul Mondal

Whelan et al NEJM 2010

• Median FU: 10 years

Long term follow up

Dodul Mondal

Dodul Mondal

Royal Marsden-GOC Trial… initial hypothesis

Dodul Mondal

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

Dodul Mondal

Result- Cosmesis

Dodul Mondal

Overall α⁄β= 3

Dodul Mondal

UK Standardization of Breast Radiotherapy (START) trials

TrialsTotal

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 B40 15 2.67 3

N=2215 50 25 2 5

Dodul Mondal

START A trial

Dodul Mondal

Lancet Oncol 2008; 9: 331–41Dodul Mondal

Local-regional tumour relapse in 2236 patientsDodul Mondal

Forest plot of late normal tissue effects assessed as moderate/marked by patients and mild/marked from

photographs

Dodul Mondal

LATE EFFECTS

Dodul Mondal

START B trial

Dodul Mondal

Dodul Mondal

LOCOREGIONAL RELAPSE DISTANT RELAPSE

Dodul Mondal

Survival analyses of relapse and mortality according to fractionation schedule

Dodul Mondal

LATE EFFECTS

Mild/marked change in breast appearance

Dodul Mondal

Forest plot of late normal tissue effects assessed as moderate/marked by patients and

mild/marked from photographs

Dodul Mondal

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

Dodul Mondal

Dodul Mondal

BREAST SHRINKAGE

Dodul Mondal

BREAST INDURATION

Dodul Mondal

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/8fxDodul Mondal

Dodul Mondal

Dodul Mondal

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 BoostDodul Mondal

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

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 B50 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

Dodul Mondal

ONGOING…

Dodul Mondal

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

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

Dodul Mondal

NRG ONCOLOGY RTOG 1005

Dodul Mondal

IMPORT LOW

Dodul Mondal

IMPORT HIGH

Dodul Mondal

Yat Tsang et al. Interim Analysis of Treatment Plans in the IMPORT HIGH (CR UK/06/003) Trial, 2014

Dodul Mondal

Hypofractionation in early breast cancer: as goodas 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

THANK YOU

Dodul Mondal