early progression in patients with high-risk soft tissue sarcomas an analysis from a phase iii...

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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