Transcript Predicting toxicity for patients with advanced Gastrointestinal Stromal Tumors (GIST)

EORTC
STBSG
Predicting toxicity
for patients with advanced
Gastrointestinal Stromal Tumors (GIST)
treated with imatinib mesylate :
an EORTC/ISG/AGITG randomized trial
M. Van Glabbeke, J. Verweij, P.G. Casali, J. Simes,
A. Le Cesne, P. Reichardt, R. Issels, J.R. Judson,
A.T. van Oosterom, J.-Y. Blay
Material
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Randomized phase III study comparing
daily doses of imatinib (400 mg od vs 400 mg bid)
for the treatment of patients with advanced GIST
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946 patients randomized
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942 patients started therapy
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310 patients still under therapy
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Follow-up
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Median: 42 months (3.5 years)
At 1, 2, 3 and 4 years: 99%, 90%, 81% and 4%
Methods
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Prognostic factors analyses
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End-points (binary) : occurrence of
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Investigated co-factors
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Grade 3-4 anemia, neutropenia
Grade 2-4 edema, fatigue, nausea, diarrhea, skin rash
Imatinib dose
Age, sex, PS, baseline laboratory parameters
Time since GIST diagnosis, site of origin, lesion size
Prior therapies
Logistic univariate / multivariate regression models
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Univariate model: select variables if P < 0.05
Multivariate model: keep variable if P < 0.01
Cumulative incidence of toxicities
(non hemato.grade 2+, hemato. grade 3+)
0.5
0.5
0.4
0.4
400 mg o.d.
400 mg b.i.d.
0.3
0.3
0.2
0.2
0.1
0.1
0
0
0
1
2
Years
3
4
0
1
2
3
Years
Edema - Skin rash - Fatigue - Nausea - Diarrhea
Anemia - Neutropenia
4
Multivariate models :
non hematological grade 2+ toxicities
Edema
Fatigue
Rash
Nausea
Diarrh.
Dose
++++
++++
++++
++++
++
Age
++
++
++++
Sex (F)
++++
++++
++
Perform.status
+++
++++
Identified GI origin
++
Tumor size
Prior chemo.
--+++
++ : P < 0.01, --- : P < 0.001, +++ : P < 0.001, ++++ : P < 0.0001
Multivariate models :
hematological grade 3+ toxicities
Anemia
Dose
++++
Initial hemoglobin level
----
Initial neutrophils count
Neutropenia
-----
-- : P < 0.01, ---- : P < 0.0001 , ++++ : P < 0.0001
Interactive risk calculator
www.eortc.be / tools / imatinibtoxicity
Interactive
version
Downloads
(Excel)
- For PC
- For PDA
Interactive risk calculator for predicting
imatinib toxicities in GIST patients
Interactive risk calculator for predicting toxicities
in GIST patients treated with imatinib mesylate
Patient's characteristics
▼
Imatinib dose (/day)
400
Age (years)
60
Sex (1=M, 2=F)
1
PS (WHO)
1
Pr.chem. (0=N, 1=Y)
0
Largest diam. (m m )
80
GI origin (0=N, 1=Y)
1
HGB (m m ol/l)
8
ANC (10**9/l)
9
Probability of
Edema (g2+)
18 %
Lethargy (g2+) 24 %
Rash (g2+)
9%
Nausea (g2+)
9%
Diarrhea (g2+) 14 %
Anemia (g3+)
6%
Neutrop.(g3+)
2%
Validation
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Validation data set
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Patients classified in “risk group” according to
probability of each toxicity estimated with the model
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EORTC phase I-II trial of imatinib
91 patients with advanced or metastatic sarcoma
Daily doses: 400 mg, 600 mg, 800 mg, 1000 mg
< 20%, 20-40%, > 40% or < 20%, > 20%
Comparison with the observed proportion of events
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Within the expected range for 10/13 risk groups (> 10 pts)
Overlap with the 95% confidence interval in all groups
Underestimation of edema & nausea (low risk groups)
Underestimation in male patients ?
Conclusion (I)
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All toxicities are highly dose dependent, except
neutropenia
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Anemia and neutropenia only depend on
baseline hematological factors
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Risk of non hematological toxicity increase with
age, poor PS and in female
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Confirmation of other series
Other factors
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Prior chemotherapy (fatigue)
Small lesions (rash)
Identified GI origin (diarrhea)
Conclusions (II)
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Interactive risk calculator to estimate the risk of
toxicity for individual patients
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May be used in the clinic
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Available on the internet (Excel spreadsheet)
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May be used to customized treatment ?
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Validation
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Based on a limited data set
Underestimate of edema and nausea in male patients ?
Should be validated on larger data series