r. d. issels, l.lindner, munich, germany p. hohenberger, berlin/mannheim, germany
DESCRIPTION
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 PresentationTRANSCRIPT
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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
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Treatment options for locally advanced sarcoma
High grade: multimodal therapy
• Chemotherapy (systemic)
• TNF limb perfusion
• Preop. Radio-(+C) therapy
• Chemotherapy + RHTdeep-wave hyperthermia
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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
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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
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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
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a b
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ab
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Study objectives
Primary Endpoint• Local Progression Free Survival (LPFS)
Secondary Endpoints • Tumor response (WHO)
• Disease Free Survival (DFS)
• Overall Survival
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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%)
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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%)
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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%)
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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%)
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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%)
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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
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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
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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
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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
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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
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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
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Cumulative Incidence Analysis
P=0.03
NSEIA + RHT
EIADeath
Local Progression
EIA
EIA+RHT
DistantProgressionEIA + RHT
EIANS
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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
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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
O