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ISIORT Europe
IOERT to the tumor bed, followed by whole breast irradiation:Update of the Pooled Analysis on the
BIO-Boost
Sedlmayer F, Fastner G, Merz F, Reitsamer R, Menzel C Salzburg / ACiabattoni A, Petrucci A Rom SGF Neri / IHagen E Klagenfurt / A Willich N, Schuck A, Brinkmann M Münster / DOrecchia R Mailand /IValentini V Rom UC Gemelli/I
BIO-Boost: Linac-based IORT with Electrons
9-10 Gy IORT Boost +
50 Gy Whole-Breast
Patients ISIORT BIO-Boost Pooled Analysis
„Best Selection“: T1-2 N0 G1-2, >50a: 331 Patients (30%)N-positive and/or G3 and/or T3 and/or Age<45a. 716 Pat. (60%)
T N Grading
Dcis 8 N0 611 T0 5 N1 343 G1 143T1 695 N2 32 G2 538T2 295 N3 7 G3 284T3 7 Nx 9 Gx 3
n.st. 21 29 62
Age: 57,3 a (22,5 – 89,9)
Methods
• Energies 4-12 MeV (6/8 MeV);
• IOERT prescription dose: med. 9,7 Gy (5-17)
• Postoperative WBRT: 50/51Gy (998 pts.)
• Time gap to XRT : 5 wks. (HT) – 28 wks. (ChT)
ISIORT BIO-Boost PA
Analysis 5/08 ISIORT BIO-Boost PA
• 1200 Pat; IORT 10/98 – 12/05
– 60 Pats.: secondary mastectomy– 9 Pat. : refused WBRT– 10 pats. lost to FU– Remaining: 1121 Patients
• Med FU: 59,6 mths. (1 – 114)
Analysis 5/08 ISIORT BIO-Boost PA
• 8 In-Breast Recurrences
• In-Breast Tumor Control Rate: 99,3 %• 93 patients developed metastases • DFS (7a): 87,7 %• DSS 94,5 %• OS 90,2 %
In-Breast Recurrences NN age T/N Stage Grade
HR-Status Location Margins DCIS
GAP IORT/RT (weeks)
Time to Recurr. (mths)
MA 59 pT1c/N0 G3 neg true LR inv.: min. 1,5 mm pos 31,6 12is.: 3,5 mm
JG 54 pT1c(m)/pN0 G3 postrue LR ( DCIS ) R1 neg 3,2 25
TM 68 pT2/N0(i+) G3 neg true LR inv.: min 1 mm pos 6,1 29,3is.: min 1 mm
AS 77 pT2 (m) pN0 G2 pos Out
Quadr. R1 (in situ) pos 4 83
SA 46 G2 pos Out
Quadr. inv.: 4 mm pos 6,7 34
36715 50 pT2/pN0 G1/2 neg Out
Quadr. R0 neg 7 n.s.
PB 52 pT1c/N0/L1 G3 neg Out
Quadr. inv.: R1 pektoral pos 5 30is.: min. 3,5 mm
RR 72 pT2(m)/N0/L1 G2 pos Out
Quadr. Inv.: min. 5 mm pos 8,6 17is.: n.s.
pT1c(m)pN0(sn) L1
In-Breast Recurrences NN age T/N Stage Grade
HR-Status Location Margins DCIS
GAP IORT/RT (weeks)
Time to Recurr. (mths)
MA 59 pT1c/N0 G3 neg true LR inv.: min. 1,5 mm pos 31,6 12is.: 3,5 mm
JG 54 pT1c(m)/pN0 G3 postrue LR ( DCIS ) R1 neg 3,2 25
TM 68 pT2/N0(i+) G3 neg true LR inv.: min 1 mm pos 6,1 29,3is.: min 1 mm
AS 77 pT2 (m) pN0 G2 pos Out
Quadr. R1 (in situ) pos 4 83
SA 46 G2 pos Out
Quadr. inv.: 4 mm pos 6,7 34
36715 50 pT2/pN0 G1/2 neg Out
Quadr. R0 neg 7 n.s.
PB 52 pT1c/N0/L1 G3 neg Out
Quadr. inv.: R1 pektoral pos 5 30is.: min. 3,5 mm
RR 72 pT2(m)/N0/L1 G2 pos Out
Quadr. Inv.: min. 5 mm pos 8,6 17is.: n.s.
pT1c(m)pN0(sn) L1
In-Breast Recurrences NN age T/N Stage Grade
HR-Status Location Margins DCIS
GAP IORT/RT (weeks)
Time to Recurr. (mths)
MA 59 pT1c/N0 G3 neg true LR inv.: min. 1,5 mm pos 31,6 12is.: 3,5 mm
JG 54 pT1c(m)/pN0 G3 postrue LR ( DCIS ) R1 neg 3,2 25
TM 68 pT2/N0(i+) G3 neg true LR inv.: min 1 mm pos 6,1 29,3is.: min 1 mm
AS 77 pT2 (m) pN0 G2 pos Out
Quadr. R1 (in situ) pos 4 83
SA 46 G2 pos Out
Quadr. inv.: 4 mm pos 6,7 34
36715 50 pT2/pN0 G1/2 neg Out
Quadr. R0 neg 7 n.s.
PB 52 pT1c/N0/L1 G3 neg Out
Quadr. inv.: R1 pektoral pos 5 30is.: min. 3,5 mm
RR 72 pT2(m)/N0/L1 G2 pos Out
Quadr. Inv.: min. 5 mm pos 8,6 17is.: n.s.
pT1c(m)pN0(sn) L1
In-Breast Recurrences NN age T/N Stage Grade
HR-Status Location Margins DCIS
GAP IORT/RT (weeks)
Time to Recurr. (mths)
MA 59 pT1c/N0 G3 neg true LR inv.: min. 1,5 mm pos 31,6 12is.: 3,5 mm
JG 54 pT1c(m)/pN0 G3 postrue LR ( DCIS ) R1 neg 3,2 25
TM 68 pT2/N0(i+) G3 neg true LR inv.: min 1 mm pos 6,1 29,3is.: min 1 mm
AS 77 pT2 (m) pN0 G2 pos Out
Quadr. R1 (in situ) pos 4 83
SA 46 G2 pos Out
Quadr. inv.: 4 mm pos 6,7 34
36715 50 pT2/pN0 G1/2 neg Out
Quadr. R0 neg 7 n.s.
PB 52 pT1c/N0/L1 G3 neg Out
Quadr. inv.: R1 pektoral pos 5 30is.: min. 3,5 mm
RR 72 pT2(m)/N0/L1 G2 pos Out
Quadr. Inv.: min. 5 mm pos 8,6 17is.: n.s.
pT1c(m)pN0(sn) L1
In-Breast Recurrences NN age T/N Stage Grade
HR-Status Location Margins DCIS
GAP IORT/RT (weeks)
Time to Recurr. (mths)
MA 59 pT1c/N0 G3 neg true LR inv.: min. 1,5 mm pos 31,6 12is.: 3,5 mm
JG 54 pT1c(m)/pN0 G3 postrue LR ( DCIS ) R1 neg 3,2 25
TM 68 pT2/N0(i+) G3 neg true LR inv.: min 1 mm pos 6,1 29,3is.: min 1 mm
AS 77 pT2 (m) pN0 G2 pos Out
Quadr. R1 (in situ) pos 4 83
SA 46 G2 pos Out
Quadr. inv.: 4 mm pos 6,7 34
36715 50 pT2/pN0 G1/2 neg Out
Quadr. R0 neg 7 n.s.
PB 52 pT1c/N0/L1 G3 neg Out
Quadr. inv.: R1 pektoral pos 5 30is.: min. 3,5 mm
RR 72 pT2(m)/N0/L1 G2 pos Out
Quadr. Inv.: min. 5 mm pos 8,6 17is.: n.s.
pT1c(m)pN0(sn) L1
In-Breast Recurrences - Summary
• 3 True Local Recurrences– All G3, – close margin status / R1,– time to recurrence: 12 – 29,3 months (med 22)
• 5 Out-Quadrant Recurences– 3/5 multicentric– time to recurrence: 17 – 83 months (med. 41)
• All NO• Prominent DCIS in 6/8• No time gap Influence IORT/XRT
ISIORT Europe BIO-Boost Analysis 5/08:
Disease Free Survival (7a):
N0: 93,2 %N1: 82,9 % N2: 69,1%
T1 : 91,7 %T2 : 85 %
Kaplan-Meier - disease free survival (all data)
65,0
70,0
75,0
80,0
85,0
90,0
95,0
100,0
0 20 40 60 80 100 120
Survival time [months]Pe
rcen
tage
sur
viva
l rat
e
N0
N1
N2
Kaplan-Meier - disease free survival (all data)
84,5
86,5
88,5
90,5
92,5
94,5
96,5
98,5
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
T1
T2
Follow-up 2/08: Disease Specific Survival (7a)
Kaplan-Meier - disease specific survival (all data)
88,0
90,0
92,0
94,0
96,0
98,0
100,0
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
N0
N1
N2
Kaplan-Meier - Disease-specific survival (all data)
94
95
96
97
98
99
100
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
Kaplan-Meier - disease specific survival (all data)
93,0
94,0
95,0
96,0
97,0
98,0
99,0
100,0
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
T1
T2
7 a: 94,8% (all)
Follow-up 4/07: Overall Survival (7a) 5 a: 95,6%
Kaplan-Meier - overall survival (all data)
89
91
93
95
97
99
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
7 a: 91,5% (all)
Kaplan-Meier - overall survival (all data)
73,0
78,0
83,0
88,0
93,0
98,0
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
N0
N1
N2
Kaplan-Meier - overall survival (all data)
85,0
87,0
89,0
91,0
93,0
95,0
97,0
99,0
0 20 40 60 80 100 120
Survival time [months]
Perc
enta
ge s
urvi
val r
ate
T1
T2
Boost-RT for everybody ?
Effect of age and radiation dose on local control after breast conserving treatment: EORTC trial 22881-10882Antonini N, …. Bartelink HRadiotherapy and Oncology 82 (2007) 265–271
Boost (16 Gy) versus No-Boost following WBRT with 50 Gy
n = 5.318 Pat.
Re-Analysis at 77,5 Mo med FU:Boost-advantage for all age groups
Spline Kurve for age and risk for developement of a local recurrenceLN-Transformation function in terms of Hazard Risk ratios (5-a-steps)
1. Age-independent boost effect: halfened LR-Rates2. Reduced absolute LR-Risk with growing age3. Highest absolute gain at ages < 45 a
IOERT with 10 Gy has an iso-effect of at least 17 Gy in standard fractionation
IOERT vs. postop. Boost Int J Cancer 2006
In-Breast Tumor Recurrence
after 5 a:
4,3 vs. 0 % P < 0,01
Why BIO-Boost 10 Gy and not Single Modality (ELIOT) 22 Gy ?
• No “low risk” selection, normal case mix• LQ model not tested for doses > 20 Gy for
equal tumor effects, but predicts significant more normal tissue reaction (fibrosis / necrosis).
• Different Surgical techniques : Tumorectomy ≠ (modified) Quadrantectomy
Bio-Boost Milano/ELIOT
Veronesi, Orecchia et al Ann Surg 2005
Why Boost and not Single Modality?
• Incidence of out-quadrant tumor foci ?– unclear, 30- 80% in pathologic series,
MRI,– 50 Gy WB-RT usually controls out-
quadrant low tumor burden – Distant quadrant IBTR occur later than
true LRs !
In-Breast Recurrence : changing topography with time I
• Freedman et al, IJROBP 2005: 1190 Pat. following WBRT • „True“ Local Recurrence 2%, 5%, and 7% after 5, 10, and 15 a,• Recurrence „elsewhere“ :
1%, 2%, and 6 % nach 5, 10, and 15 a
• Krauss et al. IJROBP 2004 : – 1448 Pat. > 60 Gy, med. FU 8.5 a
• 79 In-Breast Recurrences :– 59 IBR (74.7%) “true” LR / Marginal misses,– 20 (25.3%) Out-Quadrant
• Occurence of “distant-quadrant” recurrences: 39% (5-10 y), und 27% (10-15 y)
In-Breast Recurrence : changing topography with time II
Statement 24a of the S3 guidelines of the German Cancer Society
“ Accelerated partial breast irradiation as a sole intraoperative or postoperative radiotherapy instead of whole breast radiotherapy is an experimental method and should not be performed except in studies (LoE 3, GR A)”