Transcript Document

Refining Radiotherapy for
Early Breast Cancer: The
Challenges.
David Dodwell
Radiotherapy in Practice
Sheffield Hallam University
October 2010
Refining Radiotherapy for
Early Breast Cancer
Current practice
Toxicity
Prediction of benefit
Partial breast radiotherapy
Ongoing trials
Choices
Radiotherapy for early breast
cancer – plenty of demand
Increased incidence
Increased breast screening
Changing surgical techniques
Increasing indications
Better risk-benefit ratio
Radiotherapy for early breast
cancer – plenty of demand
Following lumpectomy – almost always
For DCIS - commonly
Following mastectomy - often
After neo-adjuvant chemotherapy usually
Following lumpectomy
BCS ± RT in N-ve disease
Prognostic factors and 5-year local recurrence risk
Characteristic
Radiotherapy
vs control
Absolute
reduction
(SE)
p for trend
(each factor
separately)
Age (years)
< 50
50 – 59
60 – 69
70+
11 vs 33
6 vs 22
4 vs 15
2 vs 9
22 (2)
15 (2)
11 (1)
7 (1)
<0.001
0.001
Tumour grade
Well differentiated
Moderately differentiated
Poorly differentiated
3 vs 11
7 vs 22
10 vs 33
8 (2)
15 (2)
22 (3)
<0.001
<0.001
Tumour size (T category)
1-20 mm (T1)
21-50 mm (T2)
>50 mm (T3) or T4
4 vs 17
13 vs 33
-
13 (1)
21 (3)
-
0.005
0.8
ER status
ER-poor
ER-positive
12 vs 29
5 vs 21
17 (3)
16 (1)
0.6
0.6
All women
6 vs 20
14 (1)
Preliminary results. Not for publication or citation
p for trend
(all factors
simultaneously)
7EBCTCG Fifth Cycle
Tamoxifen alone in older patients?
• 636 patients >70years
• Tam vs Tam + RT
• Node negative, ER+
Hughes et al SABCS 2006
Following lumpectomy for
DCIS
Radiotherapy after breast conserving
surgery in women with carcinoma in situ
(CIS±RT)
• 4100 women in 5 trials, started 1985-1990
- median follow-up 8.7 years, 295 deaths
• Surgery: BCS
- Clear margins not always required
• Radiotherapy: Whole breast
Preliminary results. Not for publication or citation
20EBCTCG Fifth Cycle
CIS±RT
RECURRENCE (CIS and invasive)
BREAST CANCER MORTALITY
Preliminary results. Not for publication or citation
21EBCTCG Fifth Cycle
Radiotherapy after carcinoma in situ (CIS±RT)
Conclusions
• In these trials, radiotherapy reduced recurrence by
about 10%
• Radiotherapy had no effect on mortality from breast
cancer
Preliminary results. Not for publication or citation
22EBCTCG Fifth Cycle
Variation in radiotherapy given to DCIS cases
treated with breast-conserving surgery
% of conservatively treated Sloane Project
cases being given radiotherapy
100
90
80
70
60
50
40
30
20
10
0
UK Breast Screening Unit
Radiotherapy given
Radiotherapy not given
After mastectomy
Radiotherapy after Mastectomy
with Axillary Clearance
(Mast+AC+RT vs. Mast+AC)
• 11 000 women in 26 trials, started 1961-84
– Years 0-9: 5000 deaths in 70 000 woman-years
– Years 10+: 2000 deaths in 40 000 woman-years
• Radiotherapy
– All trials: axilla and/or supraclavicular fossa
– Most trials: chest wall and internal mammary chain
Preliminary results. Not for publication or citation
25EBCTCG Fifth Cycle
Mast+AC+RT vs. Mast+AC
Year 2000 NIH consensus conference:
RT recommendations after mastectomy, axillary
clearance and pathology (p) of nodes (N):
• pN0 : no RT
• pN4+ : RT
• pN1-3: more uncertainty
Preliminary results. Not for publication or citation
26EBCTCG Fifth Cycle
Mast+AC+RT
vs.
Mast+AC
Isolated local recurrence by pathological nodal status (pN)
pN0
49 events in 1277 women
pN1-3
399 events in 3316 women
Preliminary results. Not for publication or citation
pN4+
487 events in 2813 women
27EBCTCG Fifth Cycle
Mast+AC+RT
vs.
Mast+AC
Breast cancer mortality by pathological nodal status (pN)
pN0
414 events in 1354 women
pN1-3
pN4+
1552 events in 3344 women 1986 events in 2876 women
Preliminary results. Not for publication or citation
28EBCTCG Fifth Cycle
Mast+AC+RT
vs.
Mast+AC
Any death by pathological nodal status (pN)
pN0
903 events in 1354 women
pN1-3
pN4+
1934 events in 3344 women 2134 events in 2876 women
Preliminary results. Not for publication or citation
29EBCTCG Fifth Cycle
Mast+AC+RT vs. Mast+AC
Conclusions
• In N0 disease, RT did not reduce mortality from breast
cancer in these trials and 15-year overall survival was
poorer with RT than without it.
• On average in these old RT trials, 15-year breast
cancer mortality was reduced, and 15-year overall
survival was improved both for N1-3 and N4+ disease
Preliminary results. Not for publication or citation
30EBCTCG Fifth Cycle
Radiotherapy after neoadjuvant
chemotherapy?
• To the breast post BCS
• If positive nodes post remaining post
Mx/ANC
• If pre-chemotherapy staging (+SLNB)
suggests nodal involvement (irrespective of
response) post Mx/ANC
Buchholz 2008
Remarks on benefits of RT
•With better RT regimens the proportional reduction in
breast cancer mortality may be more than in these trials
•If absolute recurrence risks are lower nowadays, absolute
gains from RT may be correspondingly lower
•More study still needed of RT benefits at 10 years, 20
years, and beyond
•General RT recommendations and individual RT choices
should depend not only on these old trials but also on
many other considerations
Preliminary results. Not for publication or citation
32EBCTCG Fifth Cycle
Toxicity
EBCTCG 2006 Overview,
PROVISIONAL RESULTS
RT given vs. no RT given
NON-BREAST-CANCER MORTALITY
15-yr mortality
Absolute
Age
RT
Control
15-yr loss
(se)
<50
5.3 %
4.6%
0.7 % (0.6)
0.0008
50-59
13.2 %
11.6 %
1.7 % (1.0)
0.006
60-69
29.4 %
26.4 %
3.0 % (1.5)
0.004
70+
60.6 %
55.0 %
5.7% (5.0)
>0.1
EBCTCG 2006: PROVISIONAL RESULTS
Logrank p
Variability in heart dose
30
20
Heart dose
(Gy)
10
0
Right 6 MV
breast tangential pair
Left 6 MV
breast tangential pair
Right 6 MV direct
IMC field
Left 6 MV direct
IMC field
Target and field arrangement
Taylor et al. Int J Radiat Oncol Biol Phys (in press)
Reduction in dose to cardiac structures from
left tangential radiotherapy
Mean dose (Gy)
Year
Heart
Left anterior
descending
artery
Right
coronary
artery
Circumflex
coronary
artery
Sweden 1970s*
13.3
31.8
9.1
6.9
Sweden 1990s*
4.7
21.9
2.0
2.8
UK 2006
2.3
7.6
2.0
1.2
* Taylor et al. Int J Radiat Oncol Biol Phys (in press)
EBCTCG 2006: PROVISIONAL RESULTS
Summary
• Breast radiotherapy prevents breast cancer deaths
• Radiotherapy can cause death from heart disease
• Current regimens still deliver some heart doses
• Dose-response relationships may predict cardiac
hazard
• Improve understanding of radiation-induced heart
disease
Effect of radiotherapy (in trials of RT vs not, or RT vs more surgery)
on second primary cancers
Total
events
Contralateral breast cancerb
Cancer of other sitec
Lung cancer
Oesophagus cancer
Leukaemia
Soft-tissue sarcoma
Other specified sites
a
Excess
events
Ratio of
rates (se)a
1316
122.4
1.22 (0.06)
0.0005
1534
139.2
1.22 (0.06)
0.0002
255
32
59
26
1020
57.0
10.0
15.0
10.8
31.6
1.60 (0.16)
1.89 (0.50)
1.71 (0.36)
2.34 (0.62)
1.07 (0.07)
0.0002
0.08
0.04
0.03
NS
Ratio of annual event rates irradiated vs unirradiated
Contralateral breast cancer as the first or only site of recurrence.
c
Other than breast or non-melanoma skin cancer.
b
2p
Prediction of benefit
.........................
.........................
.........................
.........................
Genomic profiling
Cheng 2008
Outcome after PMRT by ER/PR/HER-2
Kyndi et al 2008
Can we improve patient selection?
• At present by avoiding RT (or modifying
RT) at a ‘low’ level of recurrence risk +/high competing mortality risks
• In future my improved understanding of
recurrence risk + better predictive ability
Radiotherapy for early breast
cancer – a success story
After breast conservation
95-98% local control
1% serious morbidity
60-80% ‘good’ cosmesis
Radiotherapy for pharyngeal
cancer
35% local control
15% serious morbidity
20-40% 5 year survival
Partial Breast Radiotherapy
Rationale For APBI
•
•
•
•
•
 Time and Inconvenience of BCT
Improve Documented Underutilization of BCT
Potentially Reduce Acute and Chronic Toxicity
Improve Quality of Life of Patients
Eliminate Scheduling Problems With Systemic
Chemotherapy
Scientific Rationale
- APBI • Two types of local failure can develop after standard
breast conserving therapy (BCT):
– Recurrence of index lesion (True Recurrence/Marginal Miss)
– Development of a new cancer (Elsewhere Failure)
• Major effect of post-lumpectomy RT:
– Reduce risk of recurrence in tumor bed region (TR/MM)
• Recurrences away from tumor bed (‘Elsewhere’ Failures):
– It is not clear if the development of these new cancers is impacted by
whole breast RT
Rationale for Whole Breast
Irradiation
• Pathologic Justification:
– Older pathologic data from mastectomy specimens
– 30-40% of cases with occult areas of disease
elsewhere in the breast
– Whole breast RT theoretically given in an attempt
to ‘treat’ these additional sites of disease
• In addition to the index lesion
Catheter Based Brachytherapy
Traditional Free-Hand
Multi-catheter
Technique
Kuske template
Published Interstitial APBI Data
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Guy’s Hospital (n=27)
1987
Florence, Italy (n=115)
Oschner Clinic (n=300)
London Regional Cancer Center (n=39)
William Beaumont Hospital (n=199)
Orebro Medical Center (n=45)
Virginia Commonwealth University (n=59)
National Institute of Oncology – Hungary (n=245)
University of Kansas (n=24)
RTOG 95-17 (n=99)
Massachusetts General Hospital (n=48)
Tufts/Brown University (n=79)
German/Austrian Trial (n=156)
William Beaumont Hospital (199)
2008
Interstitial Experience
- Selected APBI Studies • RTOG 95-17:
–
–
–
–
–
–
Phase I/II PBI Trial
12 institutions
99 patients enrolled
Median f/u: 6.14 yrs
5-yr actuarial local recurrence rate: 4%
Int J Radiat Oncol Biol Phys
• William Beaumont Hospital:
–
–
–
–
199 patients (LDR/HDR brachytherapy)
Median follow-up: 8.6 yrs
10-yr actuarial local recurrence: 3.8%
Int J Radiat Oncol Biol Phys 68 (2): 341-6, 2007
WBH Data: Matched:Pair Analysis
- 12 Year Actuarial Outcome APBI vs. WBRT
12 Year Outcome Measure
APBI (n=199)
WBRT (n=199)
p
5%
4%
0.5
Clonally Distinct / Elsewhere
2%
2%
0.6
Clonally Related / TRMM
3%
2%
0.6
Contralateral Failure
6%
8%
0.2
Regional Nodal Failure
2%
0.5 %
0.3
Distant Metastases Free Survival
95 %
90 %
0.08
Freedom From Failure
91 %
87 %
0.4
Cause-Specific Survival
95 %
93 %
0.3
Cosmesis (excellent/good)
99%
96%
0.1
5 yr DFS after IBTR
75 %
67 %
0.1
IBTR
Published APBI Results
- Catheter Based Brachytherapy Institution
NIO-Hungary (phase II)
WBH
Orebro University
MGH
Tufts/Brown University
NIO-Hungary (phase III)
Oschner Clinic
RTOG 95-17
Tufts-Brown University
VCU
University of Wisconsin
Joe Arrington Cancer Center
German-Austrian MC Trial
University Kansas
Florence Italy
Totals
*12-year rate, += 7-year rate
** High-risk patients
#
Patients
45
199
50
48
33
128
51
99
33
59
247
136
274
24
90
1463
Follow-Up
(Months)
136
113
86
84
84
81
75
74
58
50
48
48
38
37
27
27-136
% Local
Recurrence
9.3*
5*
4+
2
9
4.7
2.0
4.0
6
5.1
3**
3.7
0.4
0
4.4
0-9%
Balloon Catheter
‘MammoSite’
• MammoSite device
(Cytyc Surgical
Products)
• Inflatable Balloon Placed
In Lumpectomy Cavity
At Surgery
• HDR brachytherapy
• 34 Gy in 10 fractions
• FDA clearance May 2002
• Since 2002, > 40,000
cases treated
TARGIT trial very early
results suggest equivalence to
conventional WBRT
3D Conformal External Beam Radiotherapy
- APBI -
Radiotherapy for early breast
cancer – ongoing trials
To identify benefits in intermediate risk
groups – SUPREMO
To optimise dose/volume according to
risk – IMPORT
To minimize inconvenience - TARGIT
High volume
Already very successful
Statistically challenging
Is it a funding priority?
Technical developments?
or
A better biological
understanding?
Or improving service
delivery – addressing unequal
access & variability in
practice?