Post on 19-Jul-2018
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
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
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
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
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