Adjuvant Radiotherapy

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
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Guidelines Breast
Version 2010.1.1
Adjuvant Radiotherapy
Adjuvant Radiotherapy (RT)
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Guidelines Breast
Version 2010.1.1
 Version 2002:
Souchon / Seegenschmiedt
 Versionen 2003 – 2009:
Blohmer / Göhring / Souchon /
Seegenschmiedt
 Version 2010:
Souchon / Janni
EBCTCG-Metaanalysis: MRM+AxD+/-RT
5th Cycle (2000/1/1 - Events to 2006/9/30; 20 Trials) updated
pN0 = 1296 (16%), pN+(1-3) = 3222(39%), pN+(4/>) = 2794(34%)
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Gains /Treatment(s)
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Guidelines Breast
Version 2010.1.1
5-y gain due to RT
Local
Relapses
Lymph
Node
Status
4.7%
pN0
15-y gain due to RT
BC
Mortality
pN0
0.3%
9.4%
pN0
26.4%
15-y: M+AxD + RT
3.2%
pN0
26.1%
5-y gain due to RT
16.1%
pN1(1-3)
0.1; ns
3222
pN1(1-3)
8.1%
15-y: M+AxD, no RT
25.9%
pN1(1-3)
51.4%
15-y: M+AxD + RT
5.7%
pN1(1-3)
43.3%
5-y gain due to RT
22.5%
pN+(4/>)
15-y gain due to RT
Logrank
2p
1296
15-y: M+AxD, no RT
15-y gain due to RT
No
Pts
0.001
2794
pN+(4/>)
7.3%
15-y: M+AxD, no RT
40.8%
pN+(4/>)
76.3%
15-y: M+AxD + RT
12.9%
pN+(4/>)
69.0%
0.0008
Darby S, on behalf of the Early Breast Cancer Trialists' Collaborative Group University of Oxford, GB.
Overview of the randomised trials of radiotherapy in early breast cancer. SABCS 2009 [MS3-1]
EBCTCG-Metaanalysis: BCS +/- RT
5th Cycle (2000/1/1 - Events to 2006/9/30; 17 Trials) updated
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Gains /Treatment(s)
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Guidelines Breast
Version 2010.1.1
5-y gain due to RT
Local
Relapses
Nodal
Status
14.3%
pN0/+
15-y gain due to RT
BC
Mortality
pN0/+
3.6%
27.8%
pN0/+
25.3%
15-y: BCS + RT
9.9%
pN0/+
21.7%
5-y gain due to RT
12.4%
pN0
0.0003
7334
pN0
3.2%
15-y: BCS, no RT
24.9%
pN0
20.6%
15-y: BCS + RT
9.4%
pN0
17.4%
5-y gain due to RT
29.2%
pN+
15-y gain due to RT
Logrank
2p
10.906
15-y: BCS, no RT
15-y gain due to RT
Pts n
0.006
1111
pN+
6.6%
15-y: BCS, no RT
46.4%
pN+
50.6%
15-y: BCS + RT
13.8%
pN+
44.0%
0.07
Darby S, on behalf of the Early Breast Cancer Trialists' Collaborative Group University of Oxford, GB.
Overview of the randomised trials of radiotherapy in early breast cancer. SABCS 2009 [MS3-1]
EBCTCG-Metaanalysis: BCT +/- RT
5th Cycle (2000/1/1 - Events to 2006/9/30; 17 Trials) updated
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Guidelines Breast
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Gains /Treatment(s)
Local
Relapses
Nodal
Status
BC
Mortality
Pts n
Logrank 2p
Patients with absolute reduction in 5-yr local recurrence rate >10%
5-y gain due to RT
22.4%
15-y gain due to RT
pN0
4812
pN0
5.4%
15-y: BCS, no RT
37.3%
pN0
29.6%
15-y: BCS + RT
13.8%
pN0
24.1%
0.02
Patients with absolute reduction in 5-yr local recurrence rate <10%
5-y gain due to RT
6.7%
15-y gain due to RT
pN0
2522
pN0
1.1%
15-y: BCS, no RT
18.6%
pN0
13.6%
15-y: BCS + RT
7.5%
pN0
12.54%
>0.1; ns
Darby S, on behalf of the Early Breast Cancer Trialists' Collaborative Group University of Oxford, GB.
Overview of the randomised trials of radiotherapy in early breast cancer. SABCS 2009 [MS3-1]
Postmastectomy Radiotherapy
(PMRT)* to the Chest Wall
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Guidelines Breast
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 >3 tumor infiltrated lymph nodes (Lnn.)
1a
A
++
 1-3 tumor infiltrated lymph nodes (Lnn.)
(depending on patients‘ age)
 T3 / T4
 pT3 pN0
 If R0 is impossible to reach
 After primary systemic treatment (PST)
based on the initial stage prior to PST
(cN+, cT3/4a-d)
 in young pts with high risk features
 RT of supra-/infraclav. region in > 3 Lnn.
1a
A
+
1a
2b
A
B
++
+/-
1a
A
++
2a
A
++
3b
1a
C
A
++
++
1a
A
++
* Indications for PMRT are independent of
adjuvant systemic treatment
Postmastectomy Radiotherapy
(PMRT)
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Guidelines Breast
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Kunkler I. EJSO 2009 Nov 23. [Epub ahead of print]
Postmastectomy Radiotherapy
(PMRT) to the Chest Wall in pN0
Patients
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Rowell NP. Radiother Oncol 2009;91:23-32
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Guidelines Breast
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Risk factors for enhanced risk of locoregional relapse (LRR)
lymphatic vessel invasion
 grading G3
 tumor >2 cm
 „close resection margin“ (Cave: different definitions!)
 premenopausal status
 age <50 yrs.
Consider effects of modern adjuvant systemic cytotoxic treatment!

Postmastectomy Radiotherapy
(PMRT) in pN0 Patients
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Locoregional relapse risk (LRR; 10 yrs) depending on the
number of risk factors
Guidelines Breast
Version 2010.1.1
 0 risk factor:
 1 risk factor:
 ≥1 risk factors:
5%
≤10%
≥15%
 Meta-analysis of 3 randomized trials:
 PMRT: decreasing LRR by 83%
 PMRT: increasing OS by 16%
Rowell NP. Radiother Oncol 2009;91:23-32
RT of the Breast
after Breast Conserving Surgery (BCS)
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Guidelines Breast
Version 2010.1.1
 Whole breast irradiation (WBI)
 consider hypofractionation for WBI in selected pts
 Partial breast irradiation (PBI)
1a
A
++
2a
B
+/-
3
C
+/-*
1b
A
+
C
+/-
- No long term follow up! Only as part of prospective trials!°
 Boost-irradiation (improves local control)
 Absolute benefit depending on patient‘s age
1b
 Dose-effect relationship independent of pts.‘ age
1b
 Boost-irradiation in node-negative tumors,
endocrine responsive, complete resection
3a
°Consider ASTRO Consensus Statement 2009
*Study participation recommended
Boost RT after BCS
in Invasive Carcinoma
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Guidelines Breast
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 Improved local tumor control
1b
A
+
 All ages: LRR reduction (12 ≥ 7%)
1b
A
+
 < 40 years: LRR reduction (29 ≥ 10%)
1b
A
++
 high grade invasive ductal cancer
2b
A
+
 Additional boost RT does not impact survival
Accelerated Partial Breast Irradiation (APBI)
after BCS in Invasive Carcinoma
Criteria for Decision Making I
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Guidelines Breast
Version 2010.1.1
Consensus Statement from the American Society for Radiation Oncology
(ASTRO) regarding APBI. Smith BD et al. IJROBP 2009;74:987-1001
Accelerated Partial Breast Irradiation (APBI)
after BCS in Invasive Carcinoma
Criteria for Decision Making II
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Guidelines Breast
Version 2010.1.1
Consensus Statement from the American Society for Radiation Oncology
(ASTRO) regarding APBI. Smith BD et al. IJROBP 2009;74:987-1001
Resection Margins: Do They Influence Effectiveness
of RT for Invasive Ductal Cancer or DCIS ?
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EORTC 22881/10882-Trials: Boost vs No Boost-RT
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Guidelines Breast
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
young age and high-grade invasive ductal cancer were the most important risk
factors for local relapse, while margin status had no significant influence

A boost dose of 16 Gy significantly reduced the negative effects of both young age
and high-grade invasive cancer
Jones HA, Antonini N, Hart AA, et al. JCO 2009;27:4939-47
Side Effects of Radiotherapy
(Analysis of EORTC 22881-10882 trial after median f/u of 10.7 yrs)
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Guidelines Breast
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
Independant prognostic factors (p< 0.01) of fibrosis with an
increase of moderate/severe fibrosis rate from 13 to 28%
 Maximum irradiation dose: increasing risk with increasing
maximum WBI dose
 Boost (26.9%) vs no boost (12.6%): HR = 2.3, CI 95%: 1.97-2.69,
p=0,0001
 Boost technique, energy of electron boost (MeV)
 Concomitant CTX: increased with concomitant CTX
 Tamoxifen vs. no tamoxifen: increased in postmenopausal
woman receiving adjuvant tamoxifen
 Postsurgery complication: increased for pts with postoperative
breast edema or haematoma
Note: Side effects of radiotherapy are
 Independent of age
 Decreased, if WBI was delivered with >6 MV photons
EORTC22881-10882 trial; Collette S et al. Eur J Cancer 2008;44:2587-99
Fraction Size in RT for Breast
Conservation in Early Breast Cancer
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Prospective randomised trials comparing different concepts of
hypofractionation versus standard fractionated adjuvant radiotherapy
following breast conserving surgery
Guidelines Breast
Version 2010.1.1
Study
n
Canadiana
Canadiana
RMH/GOCb
RMH/COGb
1234
RMH/COGb
START Ac
START Ac
START Ac
1410
2236
START Bd
START Bd
2215
Total
7095
f/u
yrs
10
10
10
10
10
5
5
5
5
5
Standard
Local
relapse %
6.7
Hypofractionation
Local relapse
p (to standard)
Local Survival
relapse
6.2
n.s.
n.s.
9.6
n.s.
n.s.
14.8
n.s.
n.s.
3.4
5.0
n.s.
n.s
n.s.
n.s.
12.1
3.5
3.5
2.3
n.s.
0.03
better
p (to standard)
Late
Dose
effects
(Gy)
50
n.s.
42.5
50
0.001
42.9
worse
n.s.
39
50
n.s.
41.6
0.01
39
better
50
n.s.
40
# of
fractions
25
16
25
13
13
25
13
13
25
15
a: Whelan T et al. J Natl Cancer Inst 2002; 94:1143-50; b: Owen JR et al. Lancet Oncol 2006;7:467-471; c: START
Trialists’ Group. Lancet Oncol 2008;9:331-41; d: START Trialists’ Group. Lancet 2008;371(9618):1098-107; James
ML et al. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003860
Kirova IJROBP 2009;75:76-81; Brunt AM et al. EJC 2009;7(3)Suppl. 1.#7LBA, Botti Cancer Radiother
2009;13:92-6; Mannino EJC 2009;45:730-1
Fraction Size in RT for Breast Conservation in Early
Breast Cancer – New Trial: the UK FAST Trial
A 5-fraction regimen of adjuvant radiotherapy for women with early breast
cancer: first analysis of the randomised UK FAST trial
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5 x 5.7 Gy to 28.5 Gy
5 x 6.0 Gy to 30 Gy
vs. 25 x 2.0 Gy to 50 Gy WBI
Guidelines Breast
Version 2010.1.1
n = 915
Median follow up was 28.3 months.
2 local tumor relapses have been recorded
Moist desquamation:
50 Gy
12
30 Gy
3
28.5 Gy
2
686 patients had 2-year photographic assessments:
50 Gy
30 Gy
RR
p
Mild changes:
18.8% 24.1% 1.39
n.s.
Marked changes: 1.7%
9.1%
5.55
<0.001
Clinically-assessed moderate/marked adverse effects:
30 Gy vs: 50 Gy HR 2.12, p = 0.001
28.5 Gy vs: 50 Gy HR 1.02, p = 0.94
28.5 Gy RR p
20.0% 1.09 n.s.
4.0%
2.33 n.s
Brunt et al. ECCO 2009; #7LBA
Radiotherapy of the Axilla
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Guidelines Breast
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 No irradiation if sentinel node is negative
1
B
++
 Clinically involved (N1, N2a), SN+ and no or
incomplete axillary clearing
3b B
++
 Postoperative tumor residuals
2b B
++
 In case of contraindication or patients
withdrawal of sufficient axillary clearing
2b C
+
 Axillary RT due to extracapsular tumor spread
(ECS)
2b
B
--
Radiotherapy (RT) of
Other Locoregional Lymph Node Areas
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Guidelines Breast
Version 2010.1.1
Supra-/infraclavicular lymph node irradiation:
Level III involved

In case of irradiation of axilla

pN1a (1–3)

pN2a (> 3) (if only clearance of level I)

(p)N3a-c
Axillary radiation

Following axillary clearing of level I + II

SNB 
In case of contraindication or patients

withdrawal of sufficient axillary clearing
 Internal mammary lymph node irradiation
3b
3b
1aa
2a
3a
B
B
B
B
B
+
+
+
+
++
3b
4
D
D
-
2b
C
+/-
2b C
+/-
Radiotherapy of
Other Locoregional Lymph Node Areas
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Guidelines Breast
Version 2010.1.1
 Internal mammary lymph node irradiation*:
 Internal
node irradiation*:
Duemammary
to the lacklymph
of sufficient
data
individual decision in case of:
due to the lack of sufficient data
 N2b,
N3b in case of:
individual
decision
2b
D
4 D
-
>pN1b
 N2b,
N3b (involvement of internal mammary

>pN1b
(involvement
of internal
lymph
node detected
bymammary
SNB)
node detected by SNB),
 lymph
pN1c–pN3

pN1c – pN3c
3b
D
3b D
* The role of RT of internal mammary lymphatics is subject of
ongoing clinical trials (French Group; EORTC 22922)
+/+/-
Key Points
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Guidelines Breast
Version 2010.1.1
 The best results for all clinical endpoints can be obtained by an optimal
combination of surgery, systemic treatment and radiotherapy. This might be
considered as a plea for dedicated breast cancer centers.
 Adjuvant systemic treatment has a positive effect on survival (LoE 1a)
 The influence of adjuvant systemic treatment on locoregional control is
existing but not large enough to obviate the use of radiation therapy (LoE 1a)
 Both, adjuvant systemic treatment and radiotherapy should be started as
soon as possible after surgery (LoE 2a)
 Combined chemotherapy and radiotherapy leads to a higher risk of
especially late toxicity: the sequential administration is therefore preferred
(LoE 2b)
 The sequence can be discussed on a patient per patient base depending on
type (especially the duration) of treatment and the individual patients‘ risk
factors
Trastuzumab in Combination with
Concurrent Radiotherapy
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Trastuzumab concurrent
with radiotherapy
2b
B
+
Trastuzumab in Combination with
Concurrent Radiotherapy
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Guidelines Breast
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Tolerability and adverse event data from the NCCTG Phase III Trial N9831
Halyard M et al. JCO 2009;27:2638-44
Remaining Questions
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Guidelines Breast
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 The most appropriate sequence of radiation
therapy, chemotherapy, endocrine treatment as
well as trastuzumab treatment in HER2 positive
breast cancers might very well remain to stay
unknown.
Poortmans P. Evidence based radiation oncology: breast cancer.
Radiother Oncol 2007;84:84-101