Transcript Document

Radiation Breast Oncology
Highlights of SABC 2006
Alison Bevan, MD PhD
UCSF Radiation Oncology
January, 2007
Topics
I. Updates
a. Evaluating the impact of adjuvant radiation in older
women with ER+ ESBC on Tamoxifen (# 11)
b. Who needs a boost? Defining radiation dose (#10)
c. MammoSite TM (ASTRO #52)
II. New
a. DCIS: Who can avoid RT (#29)
b. EBCTCG Meta-Analysis (ASTRO #4, SABC #40) )
IV. Conclusions
Radiation dose: who needs a boost
to decrease LRR?
• Whole breast radiotherapy is delivered over 5 to 6
weeks.
• Boost is delivered over the last 5-8 days to the tumor
bed
• Cost from patient’s point of view: time and toxicity
• Prior to EORTC trial, no guidelines
EORTC Boost Trial
Bartelink, H., et al. NEJM, 2001
• >5500 patients with stage I&II
• 50Gy (5 weeks) ± 16Gy boost (8 days) after complete
excision
• Systemic therapy decreased LRR (HR .75) but
disappeared in multivariate analysis
P<.0001
5y LRR
Boost
4.3%
No Boost
7.3%
EORTC Boost Trial
Bartelink, H., et al. NEJM, 2001
• Benefit was age-related, particularly important for
those younger than 50 years
• No difference in DM, OS
Boost
No Boost
p value
LRR
4%
7%
<.001
<40y
10%
19.5%
.002
>60y
2.5%
4%
.14
Randomized trial evaluating 10 Gy
boost (Lyon Trial)
Romestaing, P et al, JCO 1997
• 1024 women with tumors <3cm with negative
margins
5 years
Boost
No boost
LRR
3.6%
4.5%
Impact of boost on LRR, cosmesis & survival
10 year results
Bartelink H et al., EORTC 22881-10882 Abstract #10
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•
•
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No difference in OS (82%, p.93)
Fibrosis increased with boost 4.4% v 1.6% p<.0001
Cumulative LRR 10% v 6%
All statistically significant
age
Boost
No Boost
Absolute benefit
≤40
13.5%
24%
10.5%
41-50
9%
12.5%
4%
51-60
5%
8%
3%
>60
4%
7%
3%
Impact of boost on LRR, cosmesis & survival
10 year results
Bartelink H et al., EORTC 22881-10882 Abstract #10
• Benefit in all ages
• Despite some poor boost techniques
• Is absolute benefit of 3% critical?
Impact of boost on LRR, cosmesis & survival
10 year results
Bartelink, H et al., EORTC 22881-10882 Abstract #10
• The boost is very important for young patients <35y and less
important with increasing age
• Also incomplete excision arm consisting of 255pts
randomized to 10Gy v 26Gy with increased local control (NS)
& severe fibrosis
• New studies: microarrays to distinguish pathological features
Early Breast Cancer Trialists
Collaborative Group (EBCTCG)
Meta-analysis
1995
Post-operative radiation significantly reduced breast
cancer deaths but increased non-breast cancer deaths
resulting in no significant improvement survival.
2000
Significant reduction isolated local recurrence and breast
cancer mortality with radiation but increase in non-breast
cancer deaths with a non-significant benefit overall
survival at 20 years.
Effects of radiotherapy and differences in the
extent of surgery for early breast cancer on
local recurrence and 15 year survival: An
overview of the randomized trials
Early Breast Cancer Trialists’ Collaborative Group
(EBCTCG)
Lancet 366: 2087-2106, 2005
ASTRO abstract #4, 2006
SABC abstract #40, 2006
EBCTCG: local therapies
No. Trials
No. women
Total (by 1995)
78
42,080
CS +/- RT
10
7,311
Mastectomy +/- RT
Mastectomy vs. CS +/- RT
Nodal surgery vs. RT
Nodal surgery vs. none
RM vs. MRM
36
11
9
8
4
16,177
6,615
4,550
2,502
4,925
EBCTCG: endpoints for trial
comparison
• 5 year isolated LRR (75% occurred within 5
years)
• 15 year breast cancer mortality
• 15 year all cause mortality
EBCTCG: breast cancer specific
survival benefit at 15 years
Trials with <10% absolute difference in 5 year isolated
local-regional recurrence
15 year breast cancer mortality benefit 1%
(M±RT N-, MRM v RM, M v CS+R)
Trials with 10-20% absolute difference
15 year breast cancer mortality benefit 4.5%
(CS±R n-, M ±R n+, axillary dissection v no axillary treatment)
Trials with >20% absolute difference
15 year breast cancer mortality benefit 6%
(CS ±R n+, M without axilllary dissection ±R n+)
EBCTCG: BCS trials
• Radiotherapy After BCS, 10 trials with 7311 women
RT
5y LRR
15y breast
ca mortality
No RT absolute benefit
7%
26%
19%
30.5%
35.9%
5.4%
Overall mortality reduction 5.3%
EBCTCG: BCS & RT
LRR
N0
16%
N+
30%
15y absolute survival benefit
5%
7%
(Mastectomy N+ 5%)
EBCTCG: local therapy comparisons
For the women who received adjuvant systemic therapy:
5y isolated LRR
No Systemic therapy
Systemic therapy
15y reduction breast ca mortality
28%
8%
6%
Better local treatment adds to the effects of systemic therapy
on LR and breast cancer mortality
EBCTCG: local therapy comparisons
Decrease breast
5 yr. Isolated Loc-reg
Node Node +
cancer mortality 15 yr.
Node Node +
Mastectomy +/- RT
Mastectomy
Mastectomy + RT
6%
2%
23%
6%
+4%
- 5%
Mastectomy, CS+RT
Mastectomy
CS+RT
5%
9%
8%
5%
+1%
-2%
CS +/- RT
CS
CS + RT
23%
7%
41%
11%
-5%
- 7%
EBCTCG: toxicity & OS
Radiotherapy was associated with a significant
increase in contralateral breast cancer at 15 years
(7.5% vs. 9.3%)
Radiotherapy was associated with a significant
increase in non-breast cancer deaths at 15 years
(14.6% vs. 15.9%)
The excess mortality was primarily from heart
disease and lung cancer
EBCTCG: local therapy comparisons
Rule of 4
Proportional relationship between effects on local
control and breast cancer mortality:
“One breast cancer death (in the absence of any
other causes of death) would be avoided for every
4 local recurrences prevented.”
4:1 local recurrence benefit/breast cancer survival
benefit
EBCTCG: local therapy comparisons
Rule of 4
For example:
LRR without RT
LRR with RT
26%
10%
Absolute benefit = 16% at 5 years then survival benefit
4% at 15 years
Lumpectomy + Tamoxifen with & without XRT for
Women ≥70 years with Early Stage Breast Cancer
Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11
• 8.2 year follow-up (5yr NEJM, 2004)
• About 200pts in each group had no axillary exploration
≥70 years
≤2cm, cN0, ER+
Lumpectomy (631pts)
TamRT
Tam
Lumpectomy + Tamoxifen with & without XRT for
Women ≥70 years with Early Stage Breast Cancer
Hughes, KS et al. CALGB 9343, NEJM, 2005
5 year
TamRT
Tam
p value
LRR
1%
4%
p<0.0001
OS
87%
86%
p=0.94
FFDM
99%
98%
p=0.97
Mastectomy
Free
99%
98%
p=0.15
Lumpectomy + Tamoxifen with & without XRT for
Women ≥70 years with Early Stage Breast Cancer
Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11
8.2 years
TamRT
Tam
p value
LRR
1% (4)
7% (23)
<.001
In-breast
1% (4)
6.3% (20)
sig
Axillary rec
0
1.2%(4)
sig
Mastectomy rate
1%
3%
NS
Distant mets
3%
3%
NS
BSS
2%
2%
NS
Mortality
27%
26%
NS
Lumpectomy + Tamoxifen with & without XRT for
Women ≥70 years with Early Stage Breast Cancer
Hughes, KS et al. CALGB 9343, RTOG, ECOG Abstract #11
• Absolute LRR difference of 5-6%
• No statistical difference in mastectomy rate, distant
metastases, BSS, OS
• Cosmesis inferior in TamRT arm
• No thromboembolic events
• Conclusion: reasonable option for some patients
Lumpectomy + Tamoxifen with & without XRT for
Women ≥50 years with Early Stage Breast Cancer
Fyles, AW et al, NEJM 2004 & ASTRO abstract #8 2006 (PMH)
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•
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•
T1/T2N0 ER+
Median age 68y
No association with age
ER+ T1 had 9.9% versus 4.4% (≥60y: 7% v 3.7% p=.02)
Tumors ≤1cm, 6.7% v 3%
% at 8y
TamRT
Tam
p
IBR
4.1
12.2
<.0001
Axillary Rec
1.2
2.9
.08
DFS
82
76
.046
DM
5.6
3.8
.075
OS
89
89
.67
Comparison of Trials
author
years
characteristics
LRR
Hughes
8
≥70, T1 ER+ cN0
7% v 1%
Fyles
8
≥60, T1 ER+ cN ±
9.9% v 4.4%
Quad, ±N, ≤2.5cm
>65≤70
56-65
4.4% v 4%
12.1%v 2.4%
Veronesi
10
(low numbers n=80, 25)
Considerations
•
•
•
•
•
•
Age
Hormone Receptor +
Toxicity of Tamoxifen
Co-morbidities
Life expectancy
Patient preference
MammoSiteTM : multi-institutional 2 year
experience with ESBC
Cuttino, LW, et al ASTRO abstract #52
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•
•
•
9 institutions, 2000-2004
483 patients with stage 0, I, II
In-breast failure in 6 pts, 4 outside lumpectomy site
Closed cavity placement reduced risk of infection from
9% to 4.8%
• Infection related to overall cosmesis being fair to poor
• Cosmesis good/excellent in 91%
Lumpectomy alone for low risk DCIS
5 year results of intergroup trial E5194
Hughes, L et al., ECOG, NCCTG Abstract #29
• 711 patients with DCIS enrolled from 1997-2002 (29 ineligible)
• Median age 60 years (range 28-88)
• Median f/u was 4.96 years
• Adjuvant Tamoxifen allowed in 2000 (ER status testing routine)
• All pathology reviewed at Vanderbilt University
• 89% acceptable for study after central review (excluded size
<3mm)
Lumpectomy alone for low risk DCIS
5 year results of intergroup trial E5194
Hughes, L et al., ECOG, NCCTG Abstract #29
DCIS
Lumpectomy (711 pts)
Group I
Low/int grade <2.5cm
Group II
High grade <1cm
Post-op mammogram clear for calcifications
Margins>3mm
Observation
30% Tamoxifen
Lumpectomy alone for low risk DCIS
5 year results of intergroup trial E5194
Hughes, L et al., ECOG, NCCTG Abstract #29
Low-Int grade(580 pts)
High grade (102 pts)
•median tumor size 6mm
•18% >1cm.
•median margin 5-10mm.
•31% declared intention for TAM
•median tumor size 7mm
•Median margin 5-10mm
•30% declared intention to take
TAM
Ipsi breast events
6.8%
13.7%
50% DCIS and 50% Invasive
Contralateral events 3.5% & 4.2%
Lumpectomy alone for low risk DCIS
5 year results of intergroup trial E5194
Hughes, L et al, ECOG, NCCTG Abstract #29
1.
Observation is acceptable for rigorously evaluated and
selected patients with low to intermediate grade DCIS of the
breast
2.
For high grade lesions (Grade 3), excision is inadequate
3.
Early data, need longer f/u
4.
Who got Tam, LRR with grade, age and margins status?
Prospective Study of Wide Excision
Alone for DCIS of the Breast
Dana Farber/Brigham and Woman’s CC
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•
•
•
•
•
•
158 pts, median age 51
≥1cm margins, Grade 1/2 (50/50), ≤2.5cm by mammo
No Tamoxifen
Rate of ipsi recurrence was 2.4% per year
5 year rate of 12%
Closed early--met stopping rules
84% re-excision, 6% multiple re-excisions
?younger, larger tumors, no Tamoxifen?
Wong, J et al. JCO, 2005
Conclusions
• Boost: benefit in all age groups
• Tamoxifen without radiation after local excision for some ≥ 70
years women with ER+ ESBC may be acceptable
• EBCTCG: local control benefits breast cancer survival at 15
years
• Low-risk DCIS: no adjuvant radiation may be needed for
small tumors with wide margins
• MammoSiteTM trials are immature; closed technique superior
in reducing infection
DCIS Collaborative Group
CS+RT in 1003 pts
LRR
5y
10y
15y
Solin
5%
10%
19%