co-i kntm/k i czs m. sklodowska-curie memorial cancer center-institute of oncology medical...
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CO-I KNTM/K i CzS
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
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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
0 365 730 1095 1460
Tim e [day s ]
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Estim
ated probability of survival
O S DFS
65%
79%
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RESULTS: Overall Survival (from the date of start of imatinib therapy) in relation to surgery during IM treatment
0 365 730 1095 1460
Tim e [day s ]
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Estim
ated probability of survival
100%
71%
p=0.001
no adjuvant s urgery during IM adjuvant s urgery during IM
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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)
0 365 730 1095
Tim e [day s ]
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Estim
ated probability of survival
no adjuvant s urgery during IM therapy adjuvant s urgery during IM therapy
97%
53%
p=0.0003
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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
0 365 730
Tim e [day s ]
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Estim
ated probability of survival
84%
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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 5.3 20.1 0.00001No surgical resection of residual disease 3.98 8.1 0.004Baseline high NE count 1.88 4.5 0.03
Baseline low ALB level 1.11 0.07 0.8Low baseline HGB level 0.77 0.39 0.52Initially overtly malignant disease 1.15 0.95 0.32
High risk primary tumor n.s.MI > 10/50HPF n.s.Genetic alterations vs. exon 11 KIT mutations n.s.GIST type other than spindle-cell n.s.Primary tumor size >10 cm n.s.CD34 positivity n.s.Male gender n.s.Primary location outside the stomach n.s.Age < 45 n.s.Liver metastases n.s.
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PFS according to baseline WHO performance status
0 365 730 1095 1460
Tim e [day s ]
0,0
0,2
0,4
0,6
0,8
1,0
Estim
ated probability of survival
W HO 0 -1 W HO > 1
18%
70%
p< 0.0001
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PFS according to baseline neutrocyte count
0 365 730 1095 1460
Tim e [day s ]
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Estim
ated probability of survival
Norm al High
26%
73%
p< 0.0001
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Multivariate analysis of prognostic factors for OS----------------------------------------------------------------------------------------------------------Negative factor Risk ratio Wald P-value----------------------------------------------------------------------------------------------------------No surgical resection of residual disease 15.5 6.6 0.01 Baseline WHO performance status ≥2 5.03 10.6 0.001
Baseline high NE count 1.29 0.33 0.56Baseline low ALB level 1.7 0.86 0.35Low baseline HGB level 1.44 0.38 0.53Initially overtly malignant disease 0.99 0.001 0.97
High risk primary tumor n.s.MI > 10/50HPF n.s.Genetic alterations vs. exon 11 KIT mutations n.s.GIST type other than spindle-cell n.s.Primary tumor size >10 cm n.s.CD34 positivity n.s.Male gender n.s.Primary location outside the stomach n.s.Age < 45 n.s.Liver metastases n.s.
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DiscussionTiming 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
(estimation of GEE model with gamma distribution and link function ln with empirical confidence interval)
After maximal response;Before secondary resistance;Usually 6 – 18 months from imatinib start
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DiscussionOther published studies• 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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All doctors participating of Polish Clinical GIST Registry and our patients; colleagues from EORTC STBSG for
stimulating discussion
ACKNOWLEDGEMENTS
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Cancer Center – Institute, Warsaw, Poland
Thank you for your attention!