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13th Annual CTOS Meeting. EARLY PROGRESSION IN PATIENTS WITH HIGH-RISK SOFT TISSUE SARCOMAS AN ANALYSIS FROM A PHASE III RANDOMIZED PROSPECTIVE TRIAL (EORTC 62961/ESHO) OF NEOADJUVANT CHEMOTHERAPY WITH OR WITHOUT REGIONAL HYPERTHERMIA (RHT). - PowerPoint PPT Presentation
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EARLY PROGRESSION IN PATIENTS WITH HIGH-RISK SOFT TISSUE SARCOMAS
AN ANALYSIS FROM A PHASE III RANDOMIZED PROSPECTIVE
TRIAL (EORTC 62961/ESHO) OF NEOADJUVANT CHEMOTHERAPY WITH OR WITHOUT REGIONAL HYPERTHERMIA (RHT)
R. D. Issels, L.Lindner, Munich, GermanyP. Hohenberger, Berlin/Mannheim, Germany
13th Annual CTOS Meeting
Treatment options for locally advanced sarcoma
High grade: multimodal therapy
• Chemotherapy (systemic)
• TNF limb perfusion
• Preop. Radio-(+C) therapy
• Chemotherapy + RHTdeep-wave hyperthermia
Application of EIA with RHT
Etoposide
125 [mg/m²]
Ifosfamide
1500 [mg/m²]
Adriamycin
50 [mg/m²]
Hyperthermia (RHT)60 min [40°C-43°C]
Day
1 2 3 4
RADIATION
Arm A
Arm B
EIA
EIA
RHT
R
RADIATION
Arm A
Arm B
EIA
EIA
RHT
R
Study design
Riskgroups
Stratification: Center, Risk Group, Extremity, Non-Extremity
SURGERY
SURGERY
S1 = primary tumor ≥5 cm, G2/G3
S2 = local recurrence of S1 tumor
S3 = inadequate surgery of S1 or S2 tumor
Regional Hyperthermia (RHT) Technology
Courtesy of BSD Medical Corporation model BSD 2000 3D
ESHO quality assurance guidelines for regional hyperthermia Lagendijk et al. Int J Hyperthermia 1998
a b
ab
Study objectives
Primary Endpoint• Local Progression Free Survival (LPFS)
Secondary Endpoints • Tumor response (WHO)
• Disease Free Survival (DFS)
• Overall Survival
Patient characteristics (1)
n=341 EIA + RHT (n=169) EIA (n=172) p
Sex Male 95 (56%) 94 (55%) NS
Female 74 (44%) 78 (45%)
Age 18 – 39 years 41 (24%) 43 (25%) NS
40 – 70 years 128 (76%) 129 (75%)
Performance (WHO) 0 108 (65%) 115 (67%) NS
1 51 (31%) 50 (29%)
2 8 (4%) 7 (4%)
Patient characteristics (2)
n=341 EIA + RHT (n=169) EIA (n=172) p
Site of tumor
Extremity 73 (43%) 76 (44%) NS
Non-Extremity 96 (57%) 96 (56%)
Risk groups
S1 (primary) 78 (46%) 84 (49%) NS
S2 (recurrence) 19 (11%) 18 (10%)
S3 (inadequate surgery) 72 (43%) 70 (41%)
Patient characteristics (3)
n=341 EIA + RHT (n=169) EIA (n=172) p
Size of tumor (cm) 5-8 59 (35%) 60 (35%) NS
9-12 38 (22%) 48 (28%)
> 12 72 (43%) 64 (37%)
Median 11 11 NS
Grading G2 84 (50%) 77 (45%) NS
G3 84 (50%) 94 (55%)
Preoperative chemotherapy
n=341 EIA + RHT (n=169) EIA (n=172) p
Cycles 1-4
Received 4 cycles 150 (89%) 140 (82%) NS
Received ≤ 3 cycles 15 (9%) 23 (13%)
Received 0 cycles 4 (2%) 9 (5%)
Local treatment after chemotherapy
n=341 EIA + RHT (n=169) EIA (n=172) p
Surgery Yes 100 (59%) 101 (59%) NS
No 67 (40%) 67 (39%) NS
Not operated/ S3 group 55 53
No data 2 (1%) 4 (2%) NS
Radiotherapy Yes 103 (61%) 100 (58%) NS
No 64 (38%) 66 (38%)
No data 2 (1%) 6 (4%)
WHO objective response evaluation (96% response review)
• 117 pts notevaluable for response (61 pts with EIA+ RHT / 56 pts with EIA)
Responder EIA + RHT
(n=108)
EIA
(n=116)
Total
(n=224)
CR/PR 37 (34.3%)* 18 (15.5%)* 55 (24,6%)
SD 63 (58.3%) 71 (61,2%) 134 (59,8%)
PD 8 (7,4%) 27 (23,3%) 35 (15,6%)
* p<0.001
EORTC 62961/ESHO RHT 95-Study
% N=341Disease Free Survival (All Progressions or Death)
rhtsur2.sas IBE 20SEP2007:12:11:53
0
10
20
30
40
50
60
70
80
90
100
months
0 12 24 36 48 60 72 84 96 108 120
Fig. 1 Log-Rank: p=0.0034
Patients at Risk Events Median172 88 50 35 27 24 13 7 4 2 0 110 16.2169 114 68 44 34 20 17 13 3 1 0 88 29.9
Treatment Arm
EIAn=172 50.4%
EIA+RHTn=169 49.6%
Disease Free Survival (Any Progression or Death)
Cox hazard ratio = 0.66CI95 = 0.50-0.88, p = 0.004After 3 months: 94.0% vs. 83.2%
Diff. 10.8%, CI95=4.1-17.5%, p=0.002
After 6 months: 87.9% vs. 74.1% Diff. 13.8%, CI95=5.5-22.1%, p<0.001
EORTC 62961/ESHO RHT 95-Study
% N=341Local Progression Free Survival (Local Progression or Death)
rhtsur2.sas IBE 20SEP2007:12:11:53
0
10
20
30
40
50
60
70
80
90
100
months
0 12 24 36 48 60 72 84 96 108 120
Fig. 2 Log-Rank: p=0.0226
Patients at Risk Events Median172 99 63 45 34 29 17 8 4 2 0 95 26.2169 125 82 54 41 24 20 14 4 1 0 79 37.7
Treatment Arm
EIAn=172 50.4%
EIA+RHTn=169 49.6%
Local Progression Free Survival (Local Progression or Death)
Cox hazard ratio = 0.68CI95 = 0.50-0.93, p=0.014After 3 months: 94.6% vs. 86.2%
Diff. 8.4%, CI95=2.2-14.7%, p=0.008
After 6 months: 91.6% vs. 78.2% Diff. 13.4%, CI95=5.7-20.9%, p<0.001
Early Progression*Treatment Time Point S1 + S2 S3
EIA + RHT at 3 months 9/97 (9%) 0/72 (0%)
at 6 months 14/97 (14%) 0/72 (0%)
EIA at 3 months 18/102 (18%) 5/70 (7%)
at 6 months 25/102 (25%) 11/70 (16%)
N = 199 N = 142
* local progression or death of any reason
S1 = primary tumor ≥5 cm, GII/GIIIS2 = local recurrence of S1 tumor S3 = inadequate surgery of S1 or S2 tumor
EORTC 62961/ESHO RHT 95-StudySubgroup S1/S2
% N=199Local Progression Free Survival (Local Progression or Death)
rhtsur2.sas IBE 20SEP2007:12:11:53
0
10
20
30
40
50
60
70
80
90
100
months
0 12 24 36 48 60 72 84 96 108 120
Fig. 4 Log-Rank: p=0.4333
Patients at Risk Events Median102 57 34 26 20 17 9 4 2 1 0 57 19.597 69 42 28 19 10 9 9 2 1 0 55 29.3
Treatment Arm
EIAn=102 51.3%
EIA+RHTn=97 48.7%
Local Progression Free Survival (Local Progression or Death)
After 3 months: 90.6% vs. 81.5%Diff. 9.1%, CI95=0.5-18.7%, p=0.065
After 6 months: 85.4% vs. 74.2% Diff. 11.3%, CI95=0,0-22.5%, p=0.049
S1 + S2 - Subgroup
EORTC 62961/ESHO RHT 95-StudySubgroup S3
% N=142Local Progression Free Survival (Local Progression or Death)
rhtsur2.sas IBE 20SEP2007:12:11:53
0
10
20
30
40
50
60
70
80
90
100
months
0 12 24 36 48 60 72 84 96 108 120
Fig. 5 Log-Rank: p=0.0053
Patients at Risk Events Median70 42 29 19 14 12 8 4 2 1 0 38 30.072 56 40 26 22 14 11 5 2 0 24 -
Treatment Arm
EIAn=70 49.3%
EIA+RHTn=72 50.7%
Local Progression Free Survival (Local Progression or Death)
After 3 months: 100% vs. 92.8%Diff. 7.2%, CI95=1.1-13.4%
After 6 months: 100% vs. 84.0% Diff. 16.0%, CI95=7.3-24.6%
S3-Subgroup
Cumulative Incidence Analysis
P=0.03
NSEIA + RHT
EIADeath
Local Progression
EIA
EIA+RHT
DistantProgressionEIA + RHT
EIANS
Influence on Progression* (Cox model)
P-Value Hazard-Ratio
Non-Extremity <0.01 2.0
Tumor Size <0.01 1.8
Tumor Grade <0.01 1.5
Age NS
Sex NS
*local progression or death
ConclusionsFor patients with locally advanced high-grade STSregional hyperthermia + chemotherapy leads to a statistically significant improvement in:
Tumor response rate Disease-free survival (DFS) Local progression-free survival (LPFS)
Chemotherapy combined with hyperthermia lowers the risk of early PD for all patients
- irrespective of the time point of surgery
Patients receiving chemotherapy + hyperthermia after inadequate surgery seem to profit most
National Research Center for Environment and Health ESH
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