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La chemioterapia neoadiuvante e adiuvante nei
sarcomi delle parti molli
Padova, 30 Maggio, 2008
A.Buonadonna, CRO-Aviano
Adjuvant chemotherapy in STS
Topics
- Review
-1st Italian randomized study
- National Survey
- 2nd Italian, neo-adjuvant, randomized trial
- EORTC Trial
- Conclusions
Adjuvant chemotherapy in STS
For adult soft tissue sarcomas , stage III encompasses
tumors larger than 5 cm, high grade (3-4), located deep
to the superficial fascia, that have no evidence of distant
metastasis.
After definitive loco-regional
treatment only, approximately
50% of these patients will
develop a recurrence, and
45% will die of sarcoma within
5 years.
Greene FL, Page DL, Fleming ID, et al. (2002) AJCC cancer
staging handbook, 6th edn. Berlin, Heidelberg, New York:
Chemioterapia adiuvante: Studi di Ia
generazione(1)
Institution
Stages
Years of accrual
No. of Scheme
pts
DFC/MGH, 1978/83
IIB –
ECOG, ISSG, 1985/87
IVA
RIZZOLI 1981 – 1986
III –
168
ADM
Med. F.U.
DFS %
(months)
F.U.
52
53
OS %
Last analysis
CT
P
F.U.
CT
66
NS
65
68 NS ANTMAN
1990
77
ADM
106
29
56
0.1 49
63 .06 GHERLINZONI
IVA
UCLA 1981 - 1984
III
P
1993
119
ADM
28
54
58
NS 80
85 NS EILBER
1987
SSG 1981 - 1986
III –
240
ADM
40
56
62
NS 70
75
IVA
GOG 1973 - 1982
FIGO
I/II
ALVEGARD
NS 1989
136
ADM
24
47
59
NS 42
45
OMURA
NS 1985
Chemioterapia adiuvante: Studi di Ia
generazione(2)
Institution
Stage
Pts Scheme
Med F.U.
Years of accrual
MDAH 1973 - 1976
Extremities
DFS %
p
F.U. CT
OS %
F.U.
CT
p
Author
IIB –
43 ACVAd
120
83
76
NS
n.d.
n.d
IIIB
47
120
35
54
0.05
36
65
0.06 1987
61 AVDAd
64
68
65
n.a
70
70
NS EDMONSON
MAYO
I–
1975 – 1981
IVB
NCI Extremities
II-III
BENJAMIN
1984
67 ACD
85
75
51
0.04
60
58
NS CHANG
1988
EORTC
IA –
1977 – 1988
IIIB
F. BERGONIE
IIB –
1980 – 1988
IVA
468 ACVD
80
43
56
NS
55
63
q 4w
59 ACVD
q 3w
NS BRAMWELL
1994
52
16
57
0.0003 53
87
.002 RAVAUD
1990
Trials included in the meta-analysis: 14
• Single patient data records analyzed: 1568
• Reliability: evaluated 98% of included patients
• ADM total dose: 200-500 mg/m2
• ADM per cycle: 50-90 mg/m2 either as single agent or in combination
Sarcoma Meta-analysis Collaboration
(Lancet, 350:1647-54, 1997)
Survival
Local RFS
P value
10 years results
%
Treated Controls
abs. benefit
0.016
75
81
6
Sarcoma Meta-analysis Collaboration
(Lancet, 350:1647-54, 1997)
Survival
P value
Distant
RFS
0.70
10 years results
%
Treated Controls
abs. benefit
60
70
10
Sarcoma Meta-analysis Collaboration
(Lancet, 350:1647-54, 1997)
Survival
Overall
RFS
P value
0.0001
10 years results
%
Treated Controls
abs. benefit
45
55
10
Sarcoma Meta-analysis Collaboration
(Lancet, 350:1647-54, 1997)
Survival
P value
Overall
Survival
0.12
10 years results
%
Treated Controls
abs. benefit
50
54
4
Chemioterapia adiuvante: Meta-analisi
Sarcoma Metanalysis Collaboration III
(Lancet, 350:1647-54, 1997)
Subgroups
OS
Absolute benefit at 10 years
Extremity (886pts)
Age(<30;30-60; >60
0.029
0.31
7%
/
Sex (m vsF)
Status (prim. vs rel.)
Histology(4 vs others)
Grade (low vs high)
Dimension(<5; 5-10; >10)
Marginality
Radiotherapy
0.49
0.24
0.75
0.97
0.40
0.88
0.40
/
/
/
/
/
/
/
SECOND GENERATION TRIALS II
Institution Date
Site
Selection
NCI
92-CO21
6 / 92
Extremities
High-grade
> 3 cm
EORTC
62931
4 / 92
All sites
High grade
Any dimension
RTOG
95-14
6 / 95
All sites
High-grade
> 5 cm
CNR
ITALY
6 /92
Extremities
High-grade
> 5 cm; subfascial
SECOND GENERATION TRIALS IV
Institution Schedule
Time
D.I. mg/m2/w)
mg/m2
NCI
92-CO21
ADM 70; d 1
IFO 4; d 1-5
vs
control
EORTC
62931
ADM 75; d 1
IFO 5; 24 h inf.
vs
control
ADM 20; d1-3 c.i.
IFO 2500; d1-3c.i.
DTIC 225; d1-3c.i.
vs
control
EPI 60; d 1-2
IFO 1800; d1-5
vs
control
RTOG
95-14
CNR
ITALY
Every 4 w
x5
+ G-CSF
ADM 17.5
IFO 1000
Every 3 w
x 5
+ GM-CSF
ADM 25
IFO 1667
Every 3 w
x2+4
+G-CSF
ADM 20
IFO 2500
DTIC 225
Every 3 w
x5
+ G-CSF
EPI 40
IFO 3000
SECOND GENERATION TRIALS
Similarities
• More homogeneous selection criteria
• Use of Ifosphamide
• 2 drugs combinations
• Use of Growth factors
Differences
• Dose intensity
• Sequence of approaches( S/RT/CT)
Controversy: Adjuvant chemotherapy in STS
Topics
- Review
-1st Italian randomized study
- National Survey
- 2nd Italian, neo-adjuvant, randomized trial
-EORTC Trial
- Conclusions
ADJUVANT CHEMOTHERAPY IN STS
1st Italian Sarcoma Group Trial: Study design
B
I
O
P
S
Y
S
T
A
G
I
N
G
L T
OR
OE
CA
AT
LM
E
N
T
- RAD
SURG.
- SURG.+
POSTOP-RT
- PREOP-RT
+ SURG.
S. Frustaci et al. JCO; 19: 1238-1247, 2001
S
T
R
A
T
I
F
Y
-PRIMARY
< 10 CM
-PRIMARY
> 10 CM
-RELAPSE
< 10 CM
-RELAPSE
> 10 CM
R
A
N
D
O
M
I
Z
A
T
I
O
N
C
T
F
U
ADJUVANT CHEMOTHERAPY IN STS
INCLUSION CRITERIA
•Age >16 <65 years
•PS <2 ECOG
•High grade (G3-G4 Broder), subfascial spindle cell
and polymorphous locally controlled sarcomas
•Extremities and/or girdles
•No previous radio/chemotherapeutic treatment
•Primary >5 cm; relapse of any dimension
•Written informed consent
4/97
1ST ITALIAN ADJUVANT STUDY
Chemotherapy
(one cycle every 21 days)
• Epirubicine 60mg/m2/die, days 1 and 2
• Ifosfamide 3g/m2/die, days 1, 2, 3
• Mesna 1000mg/m2 x 3/die, days 1, 2, 3
• Hydration with  2000 cc/die during days 1, 2, 3
• Anti-HT3 and corticosteroids
• G-CSF from day +7 to complete haematological recovery
• Adequate dose modifications according to the nadirs
ADJUVANT CHEMOTHERAPY IN STS
1st Italian Sarcoma Group Trial: Dose intensity
MEDIAN RELATIVE DOSE-INTENSITY (%)
EPI
I Cycle
II Cycle
III Cycle
IV Cycle
Average
88
83.1
75.7
73.2
80.0
(37.5-107.0)
(36.6-103.4)
(25-104.3)
89.5
86.2
120/m2 (47.2-106)
IFO
89.1
9g/m2 (49.8-101.6)
Average
90.9
(55.5-107.0)
85.2
(60-104.5)
80.9
82.1
(30.6-103.4)
77.7
R.D.I.
Range (49.9-104.6)
(55.5-107.1)
(52.2-103.4)
86.7
(37.4-103.8)
83.7
ADJUVANT CHEMOTHERAPY IN STS
1st Italian Trial: Disease free survival
JCO, 2001, Vol. 19, N° 5,
P=0.04
Median F.U.=59 m
Minimum F.U.=36 m
ADJUVANT CHEMOTHERAPY IN STS
1st Italian Trial: Overall survival
JCO, 2001, Vol. 19, N° 5,
JCO, 2001, Vol 19, N° 5,
P = 0.03
Median F.U.=59 m
Minimum F.U.=36 m
The First Adjuvant I.S.G. Trial; 06/92- 11/96
Summary of performed analyses
Date of OS DFS l-DFS d-DFS FU Comments
analysis
Stop of pts accrual due to the
11/96 0.007 0.001 0.009 0.002
foreseen stopping rules
11/97
11/98
11/99
11/00
0.002
0.01
0.03
0.04
0.009
0.02
0.04
0.06
09/02
0.07 0.08
0.02
0.05
0.09
n.v.
0.03
0.05
0.48
n.v.
24
36
59
74
n.v.
n.v.
89
5 years OS: 66 vs 46% (p=0.04)
ASCO 1997; oral pres.
n.r.
JCO, 2001, Vol 19, N° 5,
n.r.
Classic Paper & Current
Comments 2002, Vol 7N°4
Oncology 2003,Suppl.2:80-84
Adjuvant therapy in soft tissue sarcomas
ISG Study:06/’92-11/’96
Analysis of 09/02
Disease free survival
1.00
Median follow-up: 89.4m
0.75
Treatment
0.50
0.25
Control
0.00
0 12 24 36 48 60 72 84 96 108 120
Treat F.U.
N°pts 53
51
Cens 24
19
Events 29
32
m.DFS 48.8 16.2
p=0.08
Adjuvant therapy in soft tissue sarcomas
ISG Study:06/’92-11/’96
Analysis of 09/02
Overall survival
100
75
Median follow-up: 89.4m
Treatment
50
25
Control
5 years OS: 66 vs 46% (p=0.04)
0
0
12 24 36 48 60 72 84 96 108 120
Treat F.U.
N°pts 53
51
Cens 31
23
Events 22
28
m. OS n.r.
50.4
p=0.07
1st ISG
Study: 06/’92-11/’96; Analysis of 09/02
Subgroup analysis: Efficacy of chemotherapy
7 pts never started CT because of early relapse or refusal
100
Median follow-up: 89.4m
Treatment
Percent surviving
75
p = 0.038
50
Control
25
0
0
Overall Survival
12
24
36
48
60
72
time (months)
84
96 108 120
N°pts
Cens
Events
m.Surv
Treat F.U.
46
51
28
23
18
28
n.r.
54.3
p=0.038
1st ISG
Study: 06/’92-11/’96 Analysis of 09/02
Subgroup analysis: Dose intensity of chemotherapy
percent surviving
100
Median follow-up: 89.4m
75
50
Treatment
Control
>/=85%
<85%
25
0
0
12
24
36
48
Overall Survival
60 72
months
84
96 108 120
1st ISG
Study: 06/’92-11/’96 Analysis of 09/02
Subgroup analysis: Dose intensity of chemotherapy
percent surviving
100
Median follow-up: 89.4m
75
MEDIAN RELATIVE D.I. %
50
Cycle 1st 2nd 3rd 4th Average
Treatment
Control
>/=85%
<85%
25
0
0
12
24
36
48
EPI
Overall Survival
IFO
%
60 72
months
84
88 83.1 75.7 73.2
80.0
89.1 89.5 86.2 82.1 86.7
90.9 85.2 80.9 77.7
96 108 120
83.7
Adjuvant therapy in soft tissue sarcomas
1st ISG Study: 06/’92-11/’96 Analysis of 09/02
Post relapse survival
100
75
N°pts
Cens
Events
m.Surv
Treatment
50
Control
25
0
0
25
50
75
100
Treat F.U.
29
32
7
4
29
32
21.8 17.8
p=0.37
Controversy: Adjuvant chemotherapy in STS
Topics
- Review
-1st Italian randomized study
- National Survey
- 2nd Italian, neo-adjuvant, randomized trial
-EORTC Trial
- Conclusions
Survey dell’Italian Sarcoma Group.
- Aims: to verify the reproducibility, efficacy,
reliability of the prospective trial when applied
spontaneously outside the protocol.
- Period: 11/’96 to 06/’99
- Methods:
1) Call for data launched in June ‘99
2) Prospective data collection, spontaneous
referral of unregistered patients, homogeneous
selection criteria and treatment modality.
UPDATED RESULTS OF THE ITALIAN SURVEY
Chemotherapy
(one cycle every 21 days)
• Epirubicine 60mg/m2/die, days 1 and 2
• Ifosfamide 3g/m2/die, days 1, 2, 3
• Mesna 1000mg/m2 x 3/die, days 1, 2, 3
• Hydration with  2000 cc/die during days 1, 2, 3
• Anti-HT3 and corticosteroids
• G-CSF from day +7 to complete hematologic recovery
• Adequate dose modifications according to the nadirs
UPDATED RESULTS OF THE ITALIAN SURVEY
Evaluation of the “post-trial” treatment
TREATMENT
- Completed CT (5 cycles)
43/55 (78.2%)
- Interrupted
- for toxicity G3 - G4
- for other reasons
8/55
4/55
UPDATED RESULTS OF THE ITALIAN SURVEY
Dose Intensity
Cycles
I
II
III
EPI
96.4
94.2
Range (38.1-116) (48.3-111)
86.6
(43.5-106)
IFO
99.3
Range (38.1-117)
91.1
(26.6-105)
95.8
(41.6-111)
IV
Average
77.7
(24-109)
88.7
74.4
90.1
(23-105)
Median 97.9
94.8
88.2
75.0
Range (38.1-116.5) (52-111) (35.5-105.5) (23.5-105)
89.4
(52 - 116)
UPDATED RESULTS OF THE ITALIAN SURVEY
Survival: comparison with CNR study(11/98)
100
90
80
70
60
50
40
30
20
10
0
% OS
TREATMENT
CONTROL
SURVEY
0
12
24
36
48
60
MONTHS
72
84
96
Controversy: Adjuvant chemotherapy in STS
Topics
- Review
-1st Italian randomized study
- National Survey
- 2nd Italian, neo-adjuvant, randomized trial
-EORTC Trial
- Conclusions
Controversy: Adjuvant chemotherapy in STS
Italian Sarcoma Group
Localized adult soft tissue sarcoma of the extremities and trunk:
Integrated approach of 3 neodjuvant cycles or 3 neoadjuvant and
2 adjuvant cycles.
Controlled prospective randomized study
Clinical coordinators
Coordinating and Data Center
S.Frustaci, Aviano
P.Valagussa, Milano
A.Gronchi, Milano
M.Mercuri, Bologna
Statistical analysis
P.Verderio, Milano
Activation September 2001
Controversy: Adjuvant chemotherapy in STS
Italian Sarcoma Group
Localized adult soft tissue sarcoma of the
extremities and trunk:
Local Treatments (multiple options)
 RADICAL SURGERY
 SEQUENTIAL APPROACH
Surgery and Radiation therapy:
- Post-op radiation therapy
- Peri-op brachyther.& post-op RT
- Pre-op radiation therapy
Chemo-ipertermic perfusion and Surgery
INTEGRATED APPROACH
Synchronous chemo & pre-op RT
Controversy: Adjuvant chemotherapy in STS
Localized adult soft tissue sarcoma of the extremities and
trunk:
Inclusion Criteria
•Adult STS, primary or relapsed or considered inadequately locally treated.
•Spindle or polimorphous (Fibrosarcoma, MFH, Lipos.,
Leiomios.,
Synovial s., m. Schwannoma, A
ngiosarcoma, Rabdomios.)
• Diagnosys in accordance with Enzinger e Weiss criteria(10).
• High grade (2-3/3, according to Coindre et al.) (11).
• Deep seated
• SITE: limbs, girdles, sup. Trunk.
• SIZE: primary >5 cm (Clinical evalutaion:CT, RM)
relapse of any size.
• Age: > 18, < 65 years.
• Performance status <1 secondo ECOG (12).
STAGE III
only
Controversy: Adjuvant chemotherapy in STS
Italian Trials
1st Trial
Random
Survey
Neo-adj.
Random
Controversy: Adjuvant chemotherapy in STS
1st Trial
Random
Survey
Neo-adj.
Random
Controversy: Adjuvant chemotherapy in STS
Italian Sarcoma Group
1st Trial
Random
Survey
Neo-adj.
Random
Localized adult soft tissue sarcoma
of the extremities and trunk:
Integrated approach of 3 neodjuvant cycles
or 3 neoadjuvant and 2 adjuvant cycles.
Controlled prospective randomized study
Clinical coordinators
S.Frustaci, Aviano
A.Gronchi, Milano
M.Mercuri, Bologna
Coordinating and Data Center
P.Valagussa, Milano
Statistical analysis
P.Verderio, Milano
Activation September 2001
Controversy: Adjuvant chemotherapy in STS
Italian Sarcoma Group
1st Trial
Random
Survey
Neo-adj.
Random
Localized adult soft tissue sarcoma
Local of
Treatments
(multiple
options)
the extremities
and trunk:
Integrated
approach of 3 neodjuvant cycles
RADICAL SURGERY
or 3 neoadjuvant and 2 adjuvant cycles.
SEQUENTIAL
APPROACH
Controlled prospective
randomized study
Clinical
coordinators
Coordinating
Surgery
and Radiation
therapy: and Data Center
S.Frustaci,
Aviano radiation therapy
P.Valagussa, Milano
- Post-op
A.Gronchi, Milano
- Peri-op brachyther.& post-op RT
M.Mercuri, Bologna
Statistical analysis
- Pre-op radiation therapy
P.Verderio, Milano
Chemo-ipertermic
perfusion
and Surgery
Activation September 2001
INTEGRATED APPROACH
Synchronous chemo & pre-op RT
Controversy: Adjuvant chemotherapy in STS
Study period
1st Trial 06/’92
Random 11/’96
11/’96
Survey
06/’99
Neo-adj. 09/’01
Random 03/’07
Controversy: Adjuvant chemotherapy in STS
Study period
Pts
1st Trial 06/’92
CT: 53
Random 11/’96
FU: 51
11/’96
Survey
CT: 55
06/’99
Neo-adj. 09/’01
CT: 150
Random 03/’07
CT: 150
Controversy: Adjuvant chemotherapy in STS
Study period
Pts
1st Trial 06/’92
CT: 53
Random 11/’96
FU: 51
Survey
11/’96
06/’99
Neo-adj. 09/’01
Random 03/’07
CT: 55
CT: 150
CT: 150
Selection
High grade
Deep
>5cm
Limbs/girdle
High grade
Deep
>5cm
Limbs/girdle
Trunk
High grade
Deep
>5cm
Limbs/girdle
Trunk
Controversy: Adjuvant chemotherapy in STS
Study
period
1st Trial 06/’92
Random 11/’96
Pts
CT: 53
FU: 51
Survey
11/’96
06/’99
Neo-adj. 09/’01
Random 03/’07
Selection
Treatment
/m2
High grade
Deep
>5cm
Limbs/girdle
EPI 60mg x2d
IFO3g x3d
X 5 cycles
CT: 55
High grade
Deep
>5cm
Limbs/girdle
Trunk
CT: 150
CT: 150
emended
High grade
Deep
>5cm
Limbs/girdle
Trunk
//
id
id
3pre-op
+2 post
3pre-op
Controversy: Adjuvant chemotherapy in STS
Study
period
1st Trial 06/’92
Random 11/’96
Pts
CT: 53
FU: 51
Survey
11/’96
06/’99
CT: 55
Neo-adj. 10/’01
CT: 150
Random Ongoing CT: 150
emended
Selection
High grade
Deep
>5cm
Limbs/girdle
Treatment
/m2
EPI 60mg x2d
IFO3g x3d
X 5 cycles
High grade
Deep
>5cm
Limbs/girdle
Trunk
High grade
Deep
>5cm
Limbs/girdle
Trunk
id
5-y-OS
//
64%
P=0.004
46%
id
66%
3pre-op
+2 post
3pre-op
End point:
No diff.
Controversy: Adjuvant chemotherapy in STS
Topics
- Review
-1st Italian randomized study
- National Survey
- 2nd Italian, neo-adjuvant, randomized trial
- EORTC Trial
- Conclusions
A systematic meta-analysis of
randomized controlled trials for adjuvant
chemotherapy for localized resectable
soft-tissue sarcoma
Nabeel Pervaiz
Nigel Colterjohn
Forough Farrokhyar
Richard Tozer
Alvaro Figueredo
Michelle Ghert
Ten years later…
• Further published RCTs
• Intensification of doxorubicin dosage and addition of
ifosfamide to regimens
Objective
• To update the 1997 meta-analysis with data from
subsequent published randomized controlled trials
• Increase statistical power and narrow confidence
intervals
Methods: Study Identification
• Databases: Medline, EMBASE, Cochrane
• Search criteria: sarcoma, chemotherapy, randomized controlled trial
• Over 700 results
• Inclusion criteria: soft-tissue, localized, resectable, control arm: no
chemotherapy, adult
• Exclusion criteria: bone sarcoma, advanced disease, no control arm,
pediatric (rhabdomyoscaromca), non-randomized
Study Evaluation
• Studies evaluated by 2 independent reviewers
• Modified Detsky Quality Scale for Randomized trials
• Interobserver reliability
Outcome measures
• Local recurrence
• Distant recurrence
• Overall recurrence
• Overall survival
Background
• Sarcoma Meta-analysis Collaboration (SMAC)---originated
at Hamilton Regional Cancer Centre
• Landmark publication, Lancet 1997
• 14 RCTs
• Results:
– Hazard ratio 0.75 (95% CI .64-0.87) for overall recurrence
– Hazard radio 0.89 (95% CI 0.76-1.03)* for survival (absolute
benefit of 4%)
– *not statistically significant
Statistical Methods
•
•
•
•
•
Funnel plot for publication bias
Test for heterogeneity between studies
Pooled odds ratio
95% confidence intervals
Fixed effect method (statistical control for nonanalzyed variables)
Results
• 4 studies met inclusion and exclusion criteria, 385
patients
• Total 18 studies and 1953 patients
• One study: neo-adjuvant vs control (analysis
performed with and without data)
• Mean follow-up 4.9 years (3.4-7.8 years)
1. Brodowicz et al, Sarcoma
2000
2. Frustaci et al, JCO 2001
3. Gortzak et al, EJC 2001
4. Petrioli et al, AJCO 2002
Local Recurrence
•
•
•
•
17 trials
1700 patients
296 events
Overall hazard ratio of 0.73 (95% CI: 0.56- 0.94)
in favor of chemotherapy
• Absolute risk reduction of 4% (15% vs. 19%)
Odds ratio for local recurrence
Citation
Bergonie et al
Brodowicz et al
DFCI/MGH
EORTC
Frustaci et al
GOG
Gortzaket al
IGSC
Mayo
MDA
NCI4
NCI5
NCI6
Petrioli et al
Rizzoli et al
SAKK
SSG
Fixed Combined (17)
NTotal Treated
54
59
46
381
104
221
134
86
45
35
25
79
41
88
38
24
240
6 / 28
2 / 31
3 / 21
30 / 193
9 / 53
20 / 112
11 / 67
6 / 40
4 / 22
2 / 18
2 / 17
8 / 38
0 / 21
6 / 45
1 / 16
0 / 12
19 / 121
Control
PValue
8 / 26
6 / 28
3 / 25
51 / 188
11 / 51
16 / 109
13 / 67
8 / 46
5 / 23
5 / 17
4/ 8
9 / 41
0 / 20
9 / 43
6 / 22
0 / 12
13 / 119
.43
.09
.82
.01
.55
.52
.65
.76
.77
.18
.04
.92
.98
.34
.10
1.00
.28
.61
.25
1.22
.49
.74
1.26
.82
.84
.80
.30
.13
.95
.95
.58
.18
1.00
1.52
.18
.05
.22
.30
.28
.62
.34
.26
.18
.05
.02
.32
.02
.19
.02
.02
.71
2.10
1.38
6.81
.82
1.98
2.59
1.98
2.66
3.47
1.82
1.01
2.78
50.34
1.80
1.66
54.46
3.23
.02
.73
.56
.94
1700 129 / 855 167 / 845
0.01
0.1
Chemotherapy
Test for heterogeneity Q=15.81, df=16, p=0.4664
1
10
Control
100
Effect Lower Upper
Distant Recurrence
•
•
•
•
17 trials
1700 patients
553 events
overall hazard ratio of 0.65 (95% CI: 0.53-0.80) in
favor of chemotherapy
• Absolute risk reduction 9% (28% vs 37%)
Odds ratio for distant recurrence
Citation
Bergonie et al
Brodowicz et al
DFCI/MGH
EORTC
Frustaci et al
GOG
Gortzaket al
IGSC
Mayo
MDA
NCI4
NCI5
NCI6
Petrioli et al
Rizzoli et al
SAKK
SSG
Fixed Combined (17)
NTotal Treated
54
59
46
381
104
221
134
86
45
35
25
79
41
88
38
24
240
8 / 28
6 / 31
6 / 21
51 / 193
23 / 53
21 / 112
26 / 67
4 / 40
6 / 22
8 / 18
4 / 17
12 / 38
7 / 21
7 / 45
6 / 16
3 / 12
41 / 121
Control
PValue
14 / 26
10 / 28
7 / 25
56 / 188
26 / 51
36 / 109
31 / 67
13 / 46
6 / 23
8 / 17
3/ 8
16 / 41
10 / 20
11 / 43
10 / 22
4 / 12
53 / 119
.06
.16
.97
.47
.44
.02
.38
.03
.93
.88
.47
.49
.28
.24
.62
.65
.09
.34
.43
1.03
.85
.74
.47
.74
.28
1.06
.90
.51
.72
.50
.54
.72
.67
.64
.11
.13
.28
.54
.34
.25
.37
.08
.28
.24
.08
.29
.14
.19
.19
.11
.38
1.06
1.41
3.73
1.32
1.60
.87
1.46
.95
3.98
3.41
3.16
1.82
1.77
1.54
2.68
3.93
1.08
.00
.65
.53
.80
1700 239 / 855 314 / 845
0.01
0.1
Chemotherapy
Test for heterogeneity Q=7.8451, df=16, p=0.9533
1
10
Control
100
Effect Lower Upper
Overall Recurrence
•
•
•
•
18 trials
1747 patients
884 events
Overall hazard ratio of 0.67 (95% CI: 0.56-0.82)
in favor of chemotherapy
• Absolute risk reduction 10% (46% vs 56%)
Odds ratio for overall recurrence
Citation
Bergonie et al
Brodowicz et al
DFCI/MGH
ECOG
EORTC
Frustaci et al
GOG
Gortzaket al
IGSC
Mayo
MDA
NCI4
NCI5
NCI6
Petrioli et al
Rizzoli et al
SAKK
SSG
Fixed Combined (18)
NTotal Treated
54
59
46
47
381
104
221
134
86
45
35
25
79
41
88
38
24
240
11 / 28
7 / 31
7 / 21
9 / 24
92 / 193
28 / 53
52 / 112
30 / 67
14 / 40
12 / 22
12 / 18
9 / 17
22 / 38
9 / 21
13 / 45
7 / 16
4 / 12
65 / 121
Control
PValue
19 / 26
12 / 28
8 / 25
11 / 23
105 / 188
32 / 51
62 / 109
35 / 67
25 / 46
11 / 23
15 / 17
5/ 8
24 / 41
11 / 20
20 / 43
13 / 22
4 / 12
69 / 119
.01
.10
.92
.47
.11
.31
.12
.39
.07
.65
.13
.65
.95
.44
.09
.35
1.00
.51
.24
.39
1.06
.65
.72
.66
.66
.74
.45
1.31
.27
.67
.97
.61
.47
.54
1.00
.84
.08
.13
.31
.20
.48
.30
.39
.38
.19
.41
.05
.12
.40
.18
.19
.15
.18
.51
.75
1.20
3.66
2.09
1.08
1.46
1.12
1.46
1.08
4.23
1.57
3.77
2.38
2.11
1.13
1.98
5.46
1.40
.00
.67
.56
.82
1747 403 / 879 481 / 868
0.01
0.1
1
Chemotherapy
Test for heterogeneity Q=10.2308, df=17, p=0.8937
10
Control
100
Effect Lower Upper
Overall Survival
•
•
•
•
18 trials
1953 patients
829 deaths
overall hazard ratio of 0.77 (95% CI: 0.64-0.93) in
favor of chemotherapy
• Absolute risk reduction of 6% (40% vs 46%)
Odds ratio for overall survival
Citation
Bergonie et al
Brodowicz et al
DFCI/MGH
ECOG
EORTC
Frustaci et al
GOG
Gortzaket al
IGSC
Mayo
MDA
NCI4
NCI5
NCI6
Petrioli et al
Rizzoli et al
SAKK
SSG
Fixed Combined (18)
NTotal Treated
65
59
46
47
467
104
225
134
92
57
54
25
79
41
88
77
29
240
10 / 33
1 / 31
6 / 21
9 / 24
94 / 234
20 / 53
51 / 113
22 / 67
16 / 43
14 / 28
15 / 26
9 / 17
22 / 38
8 / 21
13 / 45
12 / 34
5 / 14
57 / 121
Control
PValue
18 / 32
3 / 28
7 / 25
10 / 23
96 / 233
28 / 51
55 / 112
28 / 67
23 / 49
12 / 29
20 / 28
5/ 8
23 / 41
9 / 20
23 / 43
25 / 43
3 / 15
57 / 119
.03
.25
.97
.68
.82
.08
.55
.28
.35
.51
.29
.65
.87
.65
.02
.05
.34
.90
.34
.28
1.03
.78
.96
.50
.85
.68
.67
1.42
.55
.67
1.08
.75
.35
.39
2.22
.97
.12
.03
.28
.24
.66
.23
.50
.34
.29
.50
.18
.12
.44
.22
.15
.16
.42
.58
.94
2.84
3.73
2.51
1.39
1.09
1.44
1.38
1.54
4.03
1.69
3.77
2.62
2.61
.85
.99
11.83
1.61
.01
.77
.64
.93
1929 384 / 963 445 / 966
0.01
0.1
1
Chemotherapy
Test for heterogeneity Q=15.9325, df=17, p=0.5286
10
Control
100
Effect Lower Upper
Discussion
• Additional 385 patients narrowed confidence
intervals
• Overall survival became statistically significant
• Definite but minimal benefit of chemotherapy in
reducing LR, DR, OR and overall survival (6%
risk reduction, 40% vs 46%)
EORTC 62931
• Presented at ASCO meeting June 2007 RCT adjuvant
chemo (Dox and Ifos) vs. control in resectable STS
• 351 patients recruited 1995-2003
• 5 yr RFS 52% in both groups, OS 64% (control) and
69% (chemo)
• Conclusion: “The hypotheses that adjuvant CT
improves RFS and OS…can both be rejected”
EORTC 62931
• Data not available for inclusion in this analysis
(authors felt that release of information would be
premature)
Conclusions
• Absolute risk reductions:
–
–
–
–
Local recurrence 4%
Distant recurrence 9%
Overall recurrence 10%
Overall survival 6% (40% vs. 46%)
• Individual patient care: These real but small
benefits must be weighed against the toxicities
associated with intensive chemotherapy