Indications for Radiation Therapy and Selection of ... · PDF fileIndications for Radiation...
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Indications for Radiation Therapy and Selection of
Treatment Fields After Preoperative Therapy
Thomas A. Buchholz, M.D.
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Radiation and Preoperative Chemotherapy
Radiation Overview• Important role in breast conservation therapy• New questions with preoperative chemotherapy
– indications for postmastectomy radiation– indications for lymph node irradiation– should decisions be effected by response?– what is the efficacy of radiation treatment?
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Radiation After Mastectomy
Known facts about postmastectomy radiation• Some patients are at risk for local recurrence• In such patients, radiation
– reduces the risk of local-regional recurrence– decreases the risk of subsequent metastases– improves cause-specific and overall survival– adds to the benefits of systemic therapy
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Oxford Overview: Mastectomy +/-Postmastectomy Radiation Trials
29% vs. 8%
60%vs. 55%
Local Recurrence• 72% reduction
Breast Ca Survival• none in LN-• 5% for LN+
Lancet 366:2087, 2005
Lymph Node-Positive DiseaseLocal Recurrence Breast Ca Deaths
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None of These TrialsIncluded Patients Treated
With PreoperativeChemotherapy
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Preoperative Chemotherapy Affects Radiation Decisions
Historical indications for postmastectomy radiation• Pathology based• Consensus statements
– tumor size > 5 cm– >4 positive lymph nodes
• Stage II w/ 1-3 +LN – unclear• Not indicated for lymph node-negative disease
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Neoadjuvant ChemotherapyChanges Pathological ExtentOf Disease In Most Patients
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Local-Regional Recurrence and Pathological Extent of Disease
Correlated pathology and local-regional recurrence
150 patients: preoperative chemotherapy
MastectomyChemotherapyNo Radiation
1,031 patients: postoperative chemotherapy
Buchholz et al., Int J Radiat Oncol Biol Phys, 2003
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Pathological Size of the Primary Tumor
Adjuvant Preop Adjuvant Preop Adjuvant Preop0%
10%
20%
30%
40%
50%p =0.014 p =0.0002 p =0.028
5-Y
ear
LR
R
0 -2.0 cm 2.1-5.0 cm >5.0 cm
28%
46%
9%
18%
36%
15%
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Pathological Nodal Status
0%
10%
20%
30%
40%
50%
60%p =0.143 p =0.087 p <0.0001
5-Y
ear
LR
R
0 +LN 1-3+LN >4+LNAdjuvant Preop Adjuvant Preop Adjuvant Preop
12%
23%
53%
7%10%
18%
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The Risk of Local-Regional Recurrence According to a
Pathological Extent of Diseaseis Different in Patients Treated
with Preoperative ChemotherapyCompared to the Risk in Patients
Treated with Initial Surgery
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Local-Regional Recurrence Risk After Preoperative Chemotherapy + Mastectomy
150 patients, 1974-1998 at MDACC• treated on prospective clinical trials • preoperative chemotherapy • modified radical mastectomy• no radiation therapy
Buchholz et al., JCO, 2002
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Factors Associated with Local-Regional Recurrence
Postoperative Factors• number of positive lymph nodes
• primary tumor size• tamoxifen use
Pretreatment Factors• clinical stage• clinical T stage• clinical N stage
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Multivariate Analysis: Both Pre- and Post-Chemotherapy Factors are Important
Factors p value hazard ratio• pretreatment stage III <0.001 4.5• >4 positive lymph nodes 0.008 2.7• no tamoxifen use 0.027 3.9
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Take Home Message
Risk for local-regional recurrence depends in part on the pretreatment stage of disease• Stage III has relevant risk• What about stage II?
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Recurrences in Clinical Stage I/II
n=46
n=67
n=19(LRR 29%)
(LRR 11%)
(LRR 2%)
P=0.0057
Garg et al., Int J Radiat Oncol Biol Phys, 2004
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Recurrences in Stage II
n = 6
n = 84
n = 42
P = < 0.0001
(LRR 67%)
(LRR 8%)
(LRR 6%)
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NSABP B-18 (Mamounas, SABCS, 2003)
B-18 Study• Mastectomy patients did not receive radiation • 87% of pts in the trial had T1, T2 tumors• 239 patients were treated with preoperativechemotherapy + mastectomy
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Local-Regional Recurrence According to Response
10-yr LRR by Pathological Response • breast pCR w/ LN- or LN+ (n=13) 0%• residual disease w/ LN- 10.5%• residual disease w/ LN+ 20.3%
Patients with 1-3+LN had similar risk as those with >4 +LN
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Is PostmastectomyRadiation Therapy
Effective?
(In the Setting of Neoadjuvant Chemotherapy)
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Limited Available Data
136 patientsNo XRT
713 patientsNeoadjuvant Doxorubicin
Mastectomy
579 patients+ XRT
XRT: Non-randomized6 consecutive prospective MDACC trials1974-1998
Huang et al., JCO, 2005
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Comparisons Between Groups
3
22
11
20
56
12
39
24
44
85
0 20 40 60 80 100
Close/pos. margins
4 or more pos. nodes
Minimal response
Clinical N2-3
Clinical T3-4
Percentage of Patients
RT
No RT
Irradiated patients had significantly worse::
P < .01 for all factors
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Local-Regional Recurrence
Years
151050
Rat
e of
LR
R1.0
.8
.6
.4
.2
0.0
P < .0001
22%
12%
No Radiation
Radiation
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Local-Regional RecurrenceBy Extent of Disease
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Local-Regional Recurrence
Stage I-II
Years
151050
Rat
e of
LR
R
1.00
.80
.60
.40
.20
0.00
P = 0.82
Clinical Stage I-II
Stage III-IV
Years
151050R
ate
of L
RR
1.0
.8
.6
.4
.2
0.0
20% (no RT)
P = 0.009
Clinical Stage III
9% (RT)
Good pathologic response to chemotherapy
(0-5cm tumor, 0-3 nodes)
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Local-Regional Recurrence
Multivariate analysis Hazard P-valueNo radiationNo radiation 4.14.1 ..00010001≥≥20% pos. nodes20% pos. nodes 2.92.9 .0001.0001Stage Stage ≥≥ IIIBIIIB 2.32.3 ..001001Nodes sampled < 10Nodes sampled < 10 2.02.0 ..005005No tamoxifenNo tamoxifen 1.91.9 ..034034ER negativeER negative 1.81.8 ..014014Path size >2cmPath size >2cm 1.71.7 ..026026
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Cause-Specific Survival
Univariate subset analysis P-value• clinical stage IIIB/C 0.002• clinical T4 tumors 0.015• 4 or more positive nodes 0.011
Radiation improved CSS ~ 20%
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Cause-Specific Survival
151050
1.0
.8
.6
.4
.2
0.0
44% (RT)
24% (no RT)P=.015
Clinical T4Univariate Subset Analyses
Radiation improved CSS ~ 20%
151050
1.0
.8
.6
.4
.2
0.0
P=.011
39% (RT)
18% (no RT)
≥ 4 nodes
151050
1.0
.8
.6
.4
.2
0.0
44% (RT)
22% (no RT)P=.002
Stage IIIB/C
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Cause-Specific Survival
Multivariate analysis Hazard P-valueStage ≥ IIIB 2.4 .0001Path. tumor size >0 cm 2.3 .001≥4 positive nodes 2.1 .0001No radiation 1.8 .001Nodes sampled <10 1.5 .004ER negative 1.5 .003
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Local-Regional Recurrencesin Patients with a pCR
Clinical Stage II Disease• no radiation: 0/20• radiation: 0/10• no LRR events
Clinical Stage III Disease
P = 0.040
93%
67%
n=62
n=12
McGuire et al., Int J Radiat Oncol Biol Phys, in press
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Patients with Stage IIIDisease and a pCR
41%
88%77%
33%
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SelectingRadiation Treatment
Fields
(There is no data to guide clinicians in patientstreated with neoadjuvant chemotherapy)
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Postmastectomy Radiation and Treatment Field Selection
Postmastectomy Radiation and Lymphatic Radiation• preoperative stage III disease - yes• higher risk preoperative stage II disease – yes
cofactors to consider: >2 cm residual primary, LVSI, extracapsular extension, close margins, >20% + LN
• lower risk preoperative stage II – risks/benefits • stage II with pCR – most likely no
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Possible Clinical Trial
Postmastectomy Radiation
Eligibility Pretreatment Stage II/IIIPostoperative• >4 cm primary• -LN
Observation
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Conclusions
After preoperative chemo and mastectomy:•• reduces localreduces local--regional recurrenceregional recurrence•• deaths from breast cancer for selected patientsdeaths from breast cancer for selected patients
Radiation is indicated for:•• pretreatment stage III or clinical T3 tumorpretreatment stage III or clinical T3 tumor•• >>4 positive nodes before or after chemotherapy4 positive nodes before or after chemotherapy•• selected patients with pretreatment stage II diseaseselected patients with pretreatment stage II disease