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

EORTCEORTCSTBSGSTBSG

Material

Randomized phase III study comparing daily doses of imatinib (400 mg od vs 400 mg bid) for the treatment of patients with advanced GIST

946 patients randomized

942 patients started therapy

310 patients still under therapy

Follow-up Median: 42 months (3.5 years) At 1, 2, 3 and 4 years: 99%, 90%, 81% and 4%

Methods

Prognostic factors analyses

End-points (binary) : occurrence of Grade 3-4 anemia, neutropenia Grade 2-4 edema, fatigue, nausea, diarrhea, skin rash

Investigated co-factors Imatinib dose Age, sex, PS, baseline laboratory parameters Time since GIST diagnosis, site of origin, lesion size Prior therapies

Logistic univariate / multivariate regression models 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

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4

Years

0

0.1

0.2

0.3

0.4

0.5

0 1 2 3 4

Years

Edema - Skin rash - Fatigue - Nausea - DiarrheaAnemia - Neutropenia

400 mg o.d. 400 mg b.i.d.

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 Neutropenia

Dose ++++

Initial hemoglobin level ---- --

Initial neutrophils count ----

-- : 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 predictingimatinib toxicities in GIST patients

▼Imatinib dose (/day) 400 Edema (g2+) 18 %Age (years) 60 Lethargy (g2+) 24 %Sex (1=M, 2=F) 1 Rash (g2+) 9 %PS (WHO) 1 Nausea (g2+) 9 %Pr.chem. (0=N, 1=Y) 0 Diarrhea (g2+) 14 %Largest diam.(mm) 80 Anemia (g3+) 6 %GI origin (0=N, 1=Y) 1 Neutrop.(g3+) 2 %HGB (mmol/l) 8ANC (10**9/l) 9

Interactive risk calculator for predicting toxicitiesin GIST patients treated with imatinib mesylate

Patient's characteristics Probability of

Validation

Validation data set EORTC phase I-II trial of imatinib 91 patients with advanced or metastatic sarcoma Daily doses: 400 mg, 600 mg, 800 mg, 1000 mg

Patients classified in “risk group” according to probability of each toxicity estimated with the model < 20%, 20-40%, > 40% or < 20%, > 20%

Comparison with the observed proportion of events 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)

All toxicities are highly dose dependent, except neutropenia

Anemia and neutropenia only depend on baseline hematological factors

Risk of non hematological toxicity increase with age, poor PS and in female Confirmation of other series

Other factors Prior chemotherapy (fatigue) Small lesions (rash) Identified GI origin (diarrhea)

Conclusions (II)

Interactive risk calculator to estimate the risk of toxicity for individual patients

May be used in the clinic

Available on the internet (Excel spreadsheet)

May be used to customized treatment ?

Validation Based on a limited data set Underestimate of edema and nausea in male patients ? Should be validated on larger data series