A brief overview of current issues in radiotherapy of breast cancer, meant mainly for post-grad trainees

1. BREAST CANCER RADIOTHERAPY:
CURRENT ISSUES
Dr Jyotirup Goswami
Department of Radiotherapy
Westbank Hospital

2.  The more things change, the more they remain the
same:
 The target, dose, fractionation and delivery
modalities are all changing in breast cancer.
 Yet, some of the key questions of yesterday still
remain!

3. NEW STANDARDS OF CARE IN
RADIOTHERAPY OF BREAST CANCER
 Whole breast RT followed by tumor bed boost
 APBI
 Conformal RT
 IMRT & VMAT
 Hypofractionated RT
 Changing indications for post-mastectomy
radiotherapy (chest wall & nodal)
 Prone breast RT

4. BCS+RT
 Mastectomy is no longer a standard of care in
breast cancer surgery
 BCS is possible in all EBC and is also practised in
LABC
 Whole breast RT is compulsory in BCT
 Results of BCS+RT and mastectomy are equivalent
 Local control rates are also significantly improved
by use of boost to tumor bed

5. BCS+RT VS MASTECTOMY: RCTS
Institute IGR Milan NSABP NCI EORTC Danish
B-06
Stage 1 1 1,2 1,2 1,2 1,2,3
Surgery 2cm gross Quad- Lump- Gross excision 1 cm gross Wide excision
margin rantectomy ectomy margin
Follow-up(y) 15 20 20 18 10 6
OS:BCS+RT(%) 73 42 46 59 65 79
M(%) 65 41 47 58 66 82
LR: BCS+RT(%) 9 9 14 22 20 3
M(%) 14 2 10 6 12 4

6. The pooled meta-analysis of 15 RCTs
shows a threefold reduction in local
failure & a small but significant
BCS+RT VS BCS improvement in OS with RT after BCS
Vinh-Hung et al. JNCI ( 2004);96:115-121

7. EBCTCG META-ANALYSIS (LANCET 2000)
 Meta-analysis of 10  Breast cancer mortality
and 20 yr results of 40 was significantly
RCTs of EBC. reduced
 N=20 000  However, mortality due
 50% node positive to other causes was
significantly increased.
 Local recurrence after
BCS was reduced by  Absolute increase in
approximately 2/3 with 20-yr survival was 2-
RT, irrespective of type 4% (except those
of RT and stage. women at very low risk
of recurrence).

8. EBCTCG META-ANALYSIS (LANCET 2005)
 78 RCTs of EBC.  15-yr breast cancer
 N= 42 000 mortality was
significantly
 7300 had BCS
reduced, from 35.9% to
 Local recurrence rate 30.5%
at 5 years, after BCS
 Overall mortality
was reduced by post-
op RT from 26% to 7%. reduction with RT was
5.3% at 15-yrs.
 Similar proportional
benefit of RT in ALL
stages. Absolute
benefit varies with the
actual risk, according
to stage.

9. BREAST CONSERVATION THERAPY:
NODE NEGATIVE DISEASE
5 yr gain 16.1% 15 yr gain 5.1%
LR OS
EBCTCG Lancet 2005,vol 366, 2093

10. BREAST CONSERVATION THERAPY:
NODE POSITIVE DISEASE
LR OS
5 yr gain 30.1% 15 yr gain 7.1%
EBCTCG Lancet 2005,vol 366, 2093

11. EBCTCG META-ANALYSIS (LANCET 2011)
 17 RCTs of BCS+RT vs  15-yr breast cancer
BCS alone mortality was
 N= 10 801 significantly
(pN0=7287, pN+=1050 reduced, from 25.2% to
) 21.4%
 ANY recurrence rate at  Similar proportional
10 years, after BCS benefit of RT in ALL
was reduced by post- stages. Absolute
op RT from 35% to benefit varies with the
19.3%. actual risk, according
to stage.

13. BOOST VS NO BOOST
EORTC 22881-10882 TRIAL
Bartelink et al

14.  Planning of boost is largely dependant on localisation
method and modality used
 Many centres practise clinical planning, especially if
electrons are to be used
 CT based planning, though preferable, is also
problematic
 Cavity location is not always clear.
 Also the shape and size of the cavity will
change, depending on when the image is taken

15. SEROMA CONTOURING GUIDELINES
 STV (Seroma Target
Volume)= tumor cavity
 CTV= STV+1cm
(EDITED from skin and
chest wall by 5mm)
 PTV=CTV+1cm
 STV to EXclude breast
tissue stranding, but
INclude surgical clips (if
present)
Wong et al

16. BOOST MODALITIES
 En-face electrons
 HDR brachytherapy
 3DCRT/IMRT/VMAT
 IMPT
 Modulated electrons (MERT)
 Electrons are still the commonest and simplest
modality. But dosimetrically the most inferior!
 HDR brachytherapy is a labour
intensive, cosmetically demanding, but
dosimetrically excellent alternative for deep-seated
tumors. (>3cm from skin)

17. BOOST DOSIMETRY
DE VS MET VS VMAT
Alexander et al

18. BREAST CONTOURING GUIDELINES
 Because more and more centres are doing
conformal CT-based planning for breast
cancer, contouring guidelines for the intact breast/
chest wall are also increasingly necessary.
 The RTOG has come up with a Breast Cancer
Atlas.

19. BREAST CANCER ATLAS
For IIB/III
after NACT
& BCS

20. REGIONAL NODAL CONTOURING

21. DURING CT SIMULATION
Post-BCS
Post-Mastectomy

22. Breast-superior
Breast-inferior

23. SCF begins

24. Axillary level III begins

25. Axillary level II begins

26. Axillary level I begins

27. Axillary level I ends

28. IMC begins

29. IMC ends

30. APBI
 Twin rationale:
(1) Most breast cancer recurrences occur in the index
quadrant.
(2) Many patients cannot come for prolonged 5-6
week adjuvant radiotherapy for logistic reasons.

31. APBI: INDICATIONS
(ASTRO RECOMMENDATIONS)
Suitable outside clinical trial Suitable only in a clinical
(ALL of) trial
 Age>60 years (ANY of)
 BRCA negative
 Age 50-59 years
 T1N0M0 (pT<2cm)
 BRCA negative
 EIC negative
 T1/2,N0,M0 (pT2-3 cm)
 Unifocal
 EIC <3cm
 IDC/ favourable histology
 Unifocal
 Margin negative (>2mm)
 ILC
 LCIS negative
 Margin close (<2mm)
 ER positive
 ER negative

32. ASTRO: “UNSUITABLE” FOR APBI
ANY OF:
 T>3cm/T4 or N+
 BRCA mutated
 High grade
 LVSI extensive
 EIC+ve (>3cm)
 Multifocal disease (contraindication to BCS per se)
 Margin positive
 Received neoadjuvant chemotherapy

33. APBI: MODALITIES
 Intra-operative electrons (ELIOT)
 Intra-operative/ peri-operative HDR interstitial
brachytherapy
 Mammosite
 Intra-operative orthovoltage X rays (TARGIT)

34. 20
16
2 34 10 12
11
5 7

35. 3D CONFORMAL BRACHYTHERAPY

36. TARGIT

37. ELIOT

38. 3DCRT AND IMRT

39. MAMMOSITE

40. COMPARISON OF APBI TECHNIQUES

41. APBI: CLINICAL RESULTS SO FAR

42. HDR INTERSTITIAL BRACHYTHERAPY:
RESULTS
Institution Dose Dose Rate Ipsilateral Cosmesis &
breast Complications
recurrence
rate
William 32-34 HDR 2.1% (5-yr) >90% achieved good
Beaumont Gy/8-10# to excellent cosmesis
Hospital,
USA 50 Gy LDR 0.9% (5-yr)
Ochsner 32-34 HDR 8% 75% achieved good to
Clinic, USA Gy/8-10# excellent cosmesis
50 Gy LDR
London 37.2 HDR 16.2% at 5 Median overall
Regional Gy/10# yrs* cosmetic score 89%.
Cancer
Centre,
Ontario,
Canada

43. HDR INTERSTITIAL BRACHYTHERAPY:
RESULTS
Institution Dose Dose Rate Ipsilateral Cosmesis &
breast Complications
recurrence
rate
National 30.3-36.4 HDR 6.7% Excellent to good
Institute of Gy/7# cosmesis in 84.4%.
Oncology,
Hungary
Tufts New 34 Gy/10# HDR 6.1% (5-yr 89% had excellent
England, actuarial) cosmesis at 5 years.
USA
Guy’s 55 Gy LDR 37%* Cosmesis good to
Hospital, excellent in 85%.
London
*= inappropriate selection of patients for APBI

44. MAMMOSITE:
RESULTS
Institution Dose Ipsilateral Cosmesis &
breast Complications
recurrence
rate
American Society of 34 Gy/10# 1.79% 3-yr Good-excellent cosmesis
Breast Surgeons actuarial LRR in >93%.
Mammosite Breast
Brachytherapy
Registry trial (97
institutions)
Rush University 34 Gy/10# 5.7% (crude) Good-excellent cosmesis
Medical Centre, in 93%.
Chicago, USA

45. IORT:
RESULTS
Institution Dose Modality Ipsilateral Cosmesis &
breast Complications
recurrence
rate
European 21 Gy Electrons 1% Mild/severe fibrosis in
Institute of 3%.
Oncology,
Milan
State 15-20 Gy 120 kV X 29% Acceptable
University of rays
Buffalo, USA
University 20 Gy 50 kV X 0% Acceptable
College, rays
London
(TARGIT)

46. EBRT (3DCRT): RESULTS

47. PROSPECTIVE RCTS OF APBI

48. IMRT BREAST: WHY?
 Dosimetric advantages include:
(1) better dose homogeneity for whole breast RT
(2) better coverage of tumor cavity
(3) feasibility of SIB
 Forward planned IMRT (field-in-field) is preferred as
it is simple and effective.

49. FORWARD PLAN IMRT
Courtesy: Budrukkar A

52. IMPORT TRIALS
(PHASE III RCTS FROM UK)
IMPORT High: (2008-ongoing) IMPORT Low: (2006-2010)
 To test dose-escalated IMRT in  To test PBI by IMRT in low-
high-risk EBC after BCS risk EBC after BCS
 High risk by v/o (ANY)  (ALL) IDC/no ILC/pN0/no
N+/grade III/T>2/NACT LVE/pT<3cm/unifocal/grade
received/margin<5mm/age 18- I,II or III/margin>2mm
49 yrs/LVE+ 3 arms:
3 arms:  WBRT (15#/3 weeks)
 WBRT followed by sequential  WBRT +PBI (each 15#/3
boost (56 Gy/23#) weeks)
 WBRT with SIB (48Gy/15#)  PBI (15#/3 weeks)
 WBRT with SIB (53Gy/15#)
Primary endpoint: Local
Primary endpoint: Breast fibrosis control (ipsilateral)

53. HYPOFRACTIONATED RT
 Started as an empirical practice in government-run
health care systems of UK and Canada
 Initially, a purely logistical exercise to reduce
treatment duration & create machine space
 Recently, 2 large trials, START-A and START-B,
have validated that clinically as well,
hypofractionated RT is safe and effective.
 In fact, even while delivering a lower BED, the
hypofractionated regimens have shown a survival
advantage over conventional fractionation!

54.  START-A: (1998-2002)  Locoregional relapse
 N=2236 rates were 3.6%, 3.5%
and 5.2%, respectively
 EBC (pT1-T3a, pN0-
N1, M0)
 BCS=1900 (85%) &  Late effects, based on
MRM=336 (15%) photographs and patient
assessments, were
3 arms:
significantly lower with 39
 50 Gy/25#/5 weeks Gy as compared to 50 Gy
 41.6 Gy/13#/5 weeks  This trial estimated α/β of
 39 Gy/13#/5 weeks breast cancer as 4.6Gy
for tumor control and
 Median FU=5.1 years 3.4Gy for late change in
photographic appearance.
Lancet Online. March 19,2008

55.  START-B: (1999-2001)  Locoregional relapse
 N=2215 rates were 3.3% and
2.2%, respectively
 EBC (pT1-T3a, pN0-N1,
M0)
 BCS=2038 (92%) &  Absolute differences in
MRM=177 (8%) locoregional relapse was -
0.7% (95%CI -1.7% to
2 arms:
0.9%), meaning that with
 50 Gy/25#/5 weeks
40Gy the relapse rate
 40 Gy/15#/3 weeks would be at most 1%
worse and at best 1.7%
 Median FU=6 years BETTER!
Lancet Online. March 19,2008

56. HYPOFRACTIONATION FROM THE
RADIOBIOLOGIC VIEWPOINT
UK-FAST: (2004-2007)  Primary end-point was 2 yr
 N=915 change in photographic
appearance of breast
 Favourable EBCs after BCS
(age>50 yrs, pT<3cm, pN0)  3-yr physician assessed
moderate to marked breast
adverse effects were 9.5%,
3 arms: 11.1% and 17.3%
 50Gy/25$/5 weeks respectively.
 28.5Gy/5#/5 weeks (once-
weekly)  Conclusion:At 3 yrs median
 30Gy/5#/5 weeks (once- FU, 28.5Gy/5# (@5.7Gy/#)
weekly) is comparable to 50Gy/25#
for breast adverse effects
and significantly milder than
 Median FU=37.3 months 30Gy/5# (@6Gy/#)
Radiotherapy & Oncology. Epub.2011

57. CHANGING INDICATIONS OF PMRT
 New indications include:
 Any AXLN +ve
 High grade tumors
 LVE
 PNI
 Age <45-50 years
 pT>2cm
 Scoring systems are often used.

58. PN1 VS PN2 FOR CHEST WALL RT
 Classically, pN2 disease (>=4 positive axillary
nodes) was the indication for postmastectomy chest
wall RT
 Subgroup analysis of the DBCG 82 b&c trials
(2007) suggested SIMILAR survival benefit of
PMRT for 1-3 vs 4+ LN.
 The St Gallen Consensus (2007) is to treat the SCF
even for pN1 (1-3 positive axillary nodes)
 The SUPREMO trial evaluated the benefit of PMRT
in 1-3 axillary lymph node positive patients.

60. SUPREMO TRIAL
(SELECTIVE USE OF POSTOPERATIVE
RADIOTHERAPY AFTER MASTECTOMY)
 Started 2006. Expected to
complete end-2012.
 N=1600 (planned); 1295  Objective: To determine the
randomised so far* overall survival of
intermediate risk patients
 pT1-T3 (+/- multifocal ds), treated with post-op RT
pN0-N1 (not more than 3
AXLN positive), M0 ,post-
MRM  Primary endpoint: OS, acute
 No bilateral breast cancer, & late morbidities
margins clear (at least 1mm),
no IMC nodes  Secondary endpoints:
 Chemotherapy as required Locoregional recurrence
rates, metastasis-free
survival, DFS, QoL, cost-
2 arms: effectiveness
 Standard RT to chest wall &
SCF
 Observation
*personal communication

61. IS THERE A ROLE OF AXILLARY NODAL RT?
 Axillary nodal RT is no longer indicated if complete
axillary dissection (>10 LN sampled) has been
performed.
 Axillary nodal RT significantly adds to the
lymphoedema morbidity
 The only possible indications today are:
 (1) incomplete/ no axillary dissection
 (2) positive axillary nodes WITH extracapsular
extension (ECE)/ perinodal extension (PNE)

62. IS SCF RT REQUIRED
AT ALL?
 Studies suggest that isolated SCF recurrences are
uncommon, for both pN1 and pN3 disease
 The main risk for pN3 disease, is not SCF
recurrence but distant metastasis

63. PRONE BREAST RT
 Suitable for pendulous
breasts, where breast-only
RT is required.
 Results in significantly better
coverage of the breast and
significant reduction of dose
to the ipsilateral lung.
 Heart dose remains
unchanged.
 BUT there is significantly
more grade 1-2 dermatitis
AND setup error.
Varga et al

64. THANK YOU