Hypofractionated Radiotherapy for breast cancer: Updated evidence

Tabassum Wadasadawala Associate Professor of Radiation Oncology

Tata Memorial Centre

Mumbai, INDIA

2rd Bangladesh Breast Cancer Conference, Dhaka, December 2017

twadasadawala@actrec.gov.in

Changing paradigms of Radiotherapy in EBC

Radiobiological

Paradigm

Technological

paradigm

Hypo-fractionated RT for whole and partial breast

irradiation

Conventional

dose and

fractionation

Impact of adjuvant radiation in breast cancer following BCS EBCTCG MA: Lancet 2011:378:1707-16

Radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer

death rate by about a sixth

Radiotherapy given in conventional fractionation over 5-6 weeks

ALL patients undergoing BCS should receive adjuvant radiation

Postmastectomy RT: EBCTCG MA 2014

• Reduction in LRR up to 15-18% and breast cancer mortality up to 8-10%

• PMRT becoming standard of care for all node positive women (indications for PMRT expanding)

Recommended by recent GUIDELINES as well

(Recht et al, Ann Surg 2017)

What is time, dose & fractionation (TDS)?

• Dose is amount of energy absorbed from the radiation beam which is required to control disease

• Time is overall time to deliver the prescribed dose

• Fractionation is division of total dose

into no of separate fractions over the total treatment time – Needed to increase tolerance – Exploit difference in repair capacity of

tumor and normal tissues – Reduction in number of tumor cells

with each dose

5

Conventional Hypofractionation

• Daily , 5-6 weeks

• 5 fractions per week

• 1.8-2.0 Gy per fraction

• Pros and cons:

– Effective (most commonly practiced)

– Evidence based

– Inconvenient (5-6 weeks)

– Significant acute/late toxicity

• Daily, 2-4 weeks

• 2-5 fractions per week

• >2 Gy per fraction

• Reduction in total dose

• Pros and cons:

– Shortening of overall treatment time

– Resource sparing

– Cost effective

– Less acute and late toxicity

Radiobiological basis • Alpha/beta ratio for breast cancer: low

similar to that of normal breast tissue

• In contrast to the conventional belief of alpha/beta 10 for tumor

• Robust data to support this: START trials

Endpoint α/β ratio (Gy)

95% CI

Loco-regional relapse (A) 4.0 0..0-8.9

Loco-regional relapse (pilot) 3.5 1.2-5.7

Breast shrinkage 3.5 0.7-6.4

Breast induration 4.0 2.3-5.6

Telengiectasia 3.8 1.8-5.7

Breast edema 4.7 2.4-7.0

When, Whom & How

• Hypofractionated radiotherapy: – Whole breast

– Partial breast

– Simultaneous integrated boost

• Accelerated partial breast irradiation: – Interstitial brachytherapy

– External beam

– Intra-operative

– Balloon brachytherapy

8

Hypofractionation: Whole breast

Safe for tumor control and late effects

Haviland et al, Lancet 2013

UK FAST Trial

Yarnold J, Radio Oncol 2011, 2012

α/β ratio estimated for breast shrinkage 2.5

Dose in-homogeneity had no greater impact on comparison of the two arms

Primary endpoint: 2 year change in photographic breast appearance

FAST-FORWARD Trial • N=4000

• Primary endpoint: Ipsilateral breast tumor control

• Sequential boost 10-16 Gy in 2.0 Gy fractions allowed in all three arms

• pT1-3N0-1MO, BCS/MRM

• Only acute toxicity data published: encouraging (mild toxicity)

Brunt M, Radio Oncol 2016

Zhou et al Surgical Oncology 2015 13

Concerns with hypo-fractionation • Recommends HFRT for ≥ 50 years, BCS, T1-2N0, not

receiving chemotherapy

• ‘Choosing Wisely’ campaign by the ASTRO • Is HFRT safe for:

– Young women – High grade tumors – Large breast size – Patients receiving systemic chemotherapy – Pure DCIS – Regional nodal irradiation – Post-mastectomy women – Lung and heart

14

Concerns with hypo-fractionation

Hypofractionation: RNI is safe (START trials)

Haviland et al, R&O 2017, article in press

Median FU 10 years

Hypofractionation: post mastectomy radiation is safe

Sun et al, ASTRO abstract 5, 2017

Phase 3 trial, median FU 52 months

50 Gy/25# 43.5 Gy/15# • Primary endpoint LRR

(8.4% vs. 6.0%, p value 0.396)

Hypofractionation: Partial breast (IMPORT LOW)

• Non inferiority trial with primary endpoint: Ipsi-lateral local tumor control

• Presumed 5 year LR rate in control arm: 2.5%

• Women ≥ 50 years with tumors up to 3 cm, N0-1 and clear margins (at least 2 mm)

Coles C, Lancet Oncol 2017 18

n-=675 n-=674 n-=669

1.1%

0.2%

0.5%

Median FU 72 months

Hypo-fractionation with SIB (IMPORT HIGH)

• Women needing a tumor bed boost dose after breast conservation surgery, appropriate adjuvant systemic therapy, and whole-breast radiotherapy.

• Dose escalated simultaneous integrated boost (SIB) with intensity-modulated radiotherapy after conservation surgery

19

Conclusions: Hypofractionation

• Hypo-fractionation is here to stay

• Safe

• Effective

• Randomized studies confirm α∕β ratios between 3-4

• However, it is also advisable to evaluate the safety of this approach in our own patient population

20

Rationale for Accelerated Partial Breast Irradiation: 15-30% drop out rate after BCT

• Lack of commitment to usual 5-6 weeks course of adjuvant RT

• Lack of access (distance, transport) (Athas et al: JNCI 92:269-271, 2000)

• Logistics (ambulatory status, social support, temporary loss of employment)

• Prolonged waiting time

• Physician bias

• Availability of expertise & facility

• Cost

• Patient age (Ballard et al: JNCI 88:716-725, 1996)

• Fear of radiation treatment

Women opt for mastectomy though eligible for BCS or never receive RT after BCS even in the west

Lazovich DA, JAMA, 1991

Strong clinico-pathological rationale

• 69-90% recurrences occur at the immediate vicinity of the primary tumor

• Incidence of elsewhere failures 0.9-3.5%

• Several studies on mastectomy specimens suggest residual disease may

extend 1 to 2.5 cm margin around excision cavity

• Potential for reduced injury to the organs at risk (heart & lung)

• Cost effective (cuts down treatment visits, absence from work)

Skowronek J, JCB 2012, Faverly DR Cancer 2001

Interstitial Implant Mammosite Multi-lumen brachytherapy

Intra-operative

techniques 3DCRT / IMRT

A range of External beam & Brachytherapy techniques for APBI

Seeds Electronic

brachytherapy

APPROPRIATE SELECTION OF TECHNIQUE AND CASE: CRITICAL

R SARIN, NATURE CLINICAL PRACTICE ONCOLOGY, 2005

Ongoing & published phase III trials of APBI

APBI: RECOMMENDATIONS

Author (ref) N Technique Median FU

(months)

Tsize

(Median)

Histology ASTRO CS group (Percent/LR) p value

Suitable Cautionary Unsuitable

Ferraro DJ,

2012

202 IBT 64 1.0 cm IDC/DCIS/

ILC

28.7% 51.5% 19.8% NS at 5 years, ASTRO

CS failed to predict LR,

LRR or DFS Overall 3.0%

Wilkinson

JB*, 2012

1813 All except

IORT

60.6 1.0 cm IDC/DCIS 36.5%

2.5%

46.9%

3.3%

16.7%

4.6%

NS at 5 years

Vicini FA

2011

199 IBT 133 NR IDC 47.7%

2.6%

31.7%

7.8%

20.6%

2.5%

NS at 10 years,

ASTRO CS did

not predict LR MacHaffie DR,

2011

136 MammoSite 60 1.0 cm IDC/DCIS

24.6%

1.6%

42.2%

4.8%

33.2%

6.6%

NS at 5 years

TMH, 2014 112 IBT 125 2.0 cm IDC 24.5%

0.0%

59.8%

7.4%

15.7%

6.2%

10 year LR not as

per ASTRO CS

group

ASTRO-CS (TMH data): Does not predict risk of LR

Radioth Oncol 2013 29

Local recurrence (primary endpoint)

5.9% vs. 5.1% at median follow up of 10.2 years

• N=1184, • Duration: 2004-2009 • GEC-ESTRO Study • Conventional WBI + TBB vs. APBI using exclusively MIB • Inclusion criteria:

– ≥40 yrs, pTis or pT1–2a (≤3 cm diameter), – pN0/pNmi, and M0 – Local excision least 2 mm margins (ILC or DCIS, at least 5 mm), – No LVSI

• Median follow-up was 6.6 yrs • Median age 62 years

Strnad Lancet 2015 & 2017

30

5 year outcome APBI WBI P value

LR 1.44% 0.92% 0.42

DFS 95.0% 94.5% 0.79

OS 95.5% 97.3% 0.11

Late grade 2-3 skin 3.2% 5.7% 0.08

Late grade 2-3 subcutaneous

7.6% 6.3% 0.53

• 4 studies 5415patients (2 RCTs and 2 non-RCTs)

• IBTR significantly higher IORT vs WBI (RR 2.83)

• Overall mortality did not differ significantly

• Prudent selection of suitable patients with low risk of LR necessary

31

• Median FU 36 months

• Grade 1/2 toxicities increased with APBI (P.001) 35% v 17%

• Telangiectasia, breast induration, breast pain increased

• Fat necrosis significantly more likely after APBI (3% v 0.9%; P .01).

• Conclusion- Cautioned against the use of 3D-CRT APBI outside the context of a controlled trial

J Clin Oncol 31:4038-4045. © 2013 32

• Increase in dose conformity with more normal tissue sparing.

• >40 yrs, ≤25 mm

• 30 Gy to tumour bed in five non consecutive #

• 520 patients 2004-2013

• Median follow-up of 5.0 years

• IBTR rate was 1.5% in both

• 5-year OS 96.6% for WBI vs 99.4% for APBI

• Better results considering acute (p = 0.0001), late (p = 0.004), and cosmetic outcome (p = 0.045)with APBI

European Journal of Cancer (2015)

33

• Increase in dose conformity with more normal tissue sparing.

• >40 yrs, ≤25 mm

• 30 Gy to tumour bed in five non consecutive #

• 520 patients 2004-2013

• Median follow-up of 5.0 years

• IBTR rate was 1.5% in both

• 5-year OS 96.6% for WBI vs 99.4% for APBI

• Better results considering acute (p = 0.0001), late (p = 0.004), and cosmetic outcome (p = 0.045)with APBI

European Journal of Cancer (2015)

34

Conclusion: APBI

• Randomized and prospective data from interstitial brachytherapy series: reassuring and can be considered standard in selected women

• A word of caution for intra-operative techniques

• IMRT better than 3DCRT for APBI

• ASTRO-CS not useful for patient selection

35

THANK YOU FOR YOUR KIND ATTENTION