Transcript Prezentacja programu PowerPoint

M. Sklodowska-Curie Memorial Cancer Center-Institute of Oncology
Medical University of Warsaw; Warsaw, POLAND
Medical University of Gdansk; Gdansk, Poland
The updated outcomes of metastatic and/or
unresectable gastrointestinal stromal tumor (GIST)
patients treated surgically after the response to
targeted therapy with imatinib (IM)
P. Rutkowski, Z. Nowecki, P. Nyckowski, W. Dziewirski,
U. Grzesiakowska, A. Nasierowska-Guttmejer, W. Michej,
A. Woźniak, Z. Żurawski, M.Krawczyk, W. Ruka
[email protected]
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AIM
Analyze the outcomes of treatment of
inoperable/metastatic GIST CD 117(+)
patients, who initially responded to
imatinib (IM) therapy in terms of the
results of post-IM surgery.
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MATERIAL AND METHODS
• 170 advanced CD117 (+) GIST patients (inoperable
and/or metastatic) [from total number 228 pts we
excluded 27 with primary resistance; 17 with SD – <10%
tumor shrinkage and 14 with too short follow-up time)]
• September 2001 – June 2006
• 98 male (58%) and 72 female (42%);
• Median age: 56 years (range: 17-83)
• Imatinib therapy in the dose of 400-800 mg/d
• At least minor response (>10% according to RECIST)
• Median follow-up time: 25 months (range: 3 - 58)
• Last evaluation date: 29th September 2006
• Primary tumor location: 59 - gastric (35%); small intestine
– 78 (46%); large intestine – 14 (8%); others – 19 (11%).
• Mutational status known in 65 cases (70% c-KIT exon 11
mutations)
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Results
Group I:
41 patients (24%) - resections of residual disease as adjuvant
treatment due to initially inoperable and/or metastatic GIST
CD117(+) after radiological complete/partial/minor response
(according to RECIST) and lack of further response to imatinib
therapy
[17 M, 24 F; median age 55]
median duration of IM treatment before surgery - 13 months (4-32)
Imatinib continued postoperatively in all cases
36 (88%) R0/R1 resections; no major complications (prolonged
ileus in 3 cases)
5 PD (12%) & 1 DoD (2.4%) after 52 months from the IM start
Mutational status: exon 11 Kit mutations 17/19 cases
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Results
Group II:
129 patients (76%) without resections of residual during imatinib
therapy due to inoperable and/or metastatic GIST CD117(+) after
complete/partial/minor response (according to RECIST)
[81 M, 48 F; median age 56]
47 PD (36%) & 27 DoD (20.9%)
Mutational status: exon 11 Kit mutations 28/46 cases
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RESULTS: Overall Survival and Progression-Free
Survival (from the date of start of imatinib therapy) in all patients
1,0
0,9
79%
0,8
0,7
65%
0,6
0,5
0,4
Estimated probability of survival
0,3
0,2
OS
DFS
0,1
0,0
0
365
730
1095
1460
Time [days]
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RESULTS: Overall Survival (from the date of
start of imatinib therapy) in relation to surgery during IM treatment
1,0
100%
0,9
p=0.001
0,8
71%
0,7
0,6
0,5
0,4
Estimated probability of survival
0,3
0,2
no adjuvant surgery during IM
adjuvant surgery during IM
0,1
0,0
0
365
730
Time [days]
1095
1460
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Progression-Free Survival (from the date of start
of imatinib therapy) in relation to surgery during IM treatment
(median: group I- 49 m; group II – 39 months)
1,0
97%
p=0.0003
0,9
0,8
0,7
0,6
53%
0,5
0,4
Estimated probability of surv
0,3
0,2
no adjuvant surgery during IM therapy
adjuvant surgery during IM therapy
0,1
0,0
0
365
730
Time [days]
1095
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Progression-free survival (from date of surgery) of GIST
patients operated during imatinib treatment: after CR/PR
and continued imatinib therapy
1,0
0,9
84%
0,8
0,7
0,6
0,5
0,4
Estimated probability of surv
0,3
0,2
0,1
0,0
0
365
Time [days]
730
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Viable GIST cells were not detected histologically in
resection specimens in 5 patients (12%) only
Immunohistochemistry positive staining for CD 117 of gastric GIST
before imatinib treatment (diffuse staining) and of the specimen after
partial gastrectomy after IM therapy (single cells)
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Multivariate analysis of prognostic factors for PFS
---------------------------------------------------------------------------------------------------------Negative factor
Risk ratio
Wald
P-value
---------------------------------------------------------------------------------------------------------Baseline WHO performance status ≥2
No surgical resection of residual disease
Baseline high NE count
5.3
3.98
1.88
20.1
8.1
4.5
0.00001
0.004
0.03
Baseline low ALB level
Low baseline HGB level
Initially overtly malignant disease
1.11
0.77
1.15
0.07
0.39
0.95
0.8
0.52
0.32
High risk primary tumor
MI > 10/50HPF
Genetic alterations vs. exon 11 KIT mutations
GIST type other than spindle-cell
Primary tumor size >10 cm
CD34 positivity
Male gender
Primary location outside the stomach
Age < 45
Liver metastases
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
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PFS according to baseline WHO performance status
1,0
p<0.0001
0,8
70%
0,6
0,4
Estimated probability of survival
18%
0,2
WHO 0 -1
WHO > 1
0,0
0
365
730
1095
1460
Time [days]
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PFS according to baseline neutrocyte count
1,0
p<0.0001
0,9
0,8
73%
0,7
0,6
0,5
0,4
Estimated probability of survival
0,3
26%
0,2
0,1
Normal
High
0,0
0
365
730
1095
1460
Time [days]
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Multivariate analysis of prognostic factors for OS
---------------------------------------------------------------------------------------------------------Negative factor
Risk ratio
Wald
P-value
---------------------------------------------------------------------------------------------------------No surgical resection of residual disease
Baseline WHO performance status ≥2
15.5
5.03
6.6
10.6
0.01
0.001
Baseline high NE count
Baseline low ALB level
Low baseline HGB level
Initially overtly malignant disease
1.29
1.7
1.44
0.99
0.33
0.86
0.38
0.001
0.56
0.35
0.53
0.97
High risk primary tumor
MI > 10/50HPF
Genetic alterations vs. exon 11 KIT mutations
GIST type other than spindle-cell
Primary tumor size >10 cm
CD34 positivity
Male gender
Primary location outside the stomach
Age < 45
Liver metastases
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
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Discussion
Timing for operation?
The plot of the response to imatinib therapy in time (years from the
date of the first IM administration) in group of 72 patients responding
to IM therapy
After maximal
response;
Before secondary
resistance;
Usually 6 – 18 months
from imatinib start
(estimation of GEE model with gamma distribution and link function ln with empirical confidence interval)
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Discussion
Other published studies
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Hohenberger et al. ASCO 2003; ASCO 2006
Gronchi A et al. ASCO 2005
Antbacka et al. SSO 2005
Bauer et al. Int J Cancer 2005
Scaife et al. Am J Surg 2003
Bonvalot et al. Ann Surg Oncol
Raut S.C. et al. J Clin Oncol 2006
Rutkowski et. al J Surg Oncol 2006
Conclusions: maintenance of imatinib therapy after
surgery is crucial; final impact on survival and time
of implementation of surgery is controversial
Bias of this study? super-selection of the cases?
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Conclusions:
1. Surgical removal of residual disease during imatinib
treatment may allow for complete remission (approx. 20%)
in selected GIST patients after response to therapy,
probably prolonging durable remission. We are convinced
that surgical downstaging of GIST patients during imatinib
therapy is beneficial. The time of the implementation of
surgical treatment warrants further studies.
2. For group of GIST patients responding to imatinib therapy
besides lack of surgical treatment we found two additional
independent negative predictive factors for PFS: baseline
poor performance status and baseline high neutrocyte
count.
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ACKNOWLEDGEMENTS
All doctors participating of Polish Clinical GIST Registry
and our patients; colleagues from EORTC STBSG for
stimulating discussion
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Cancer Center – Institute, Warsaw, Poland
Thank you for your attention!
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