External validation of the diffuse intrinsic pontine ... - Springer Link

J Neurooncol DOI 10.1007/s11060-017-2514-9

CLINICAL STUDY

External validation of the diffuse intrinsic pontine glioma survival prediction model: a collaborative report from the International DIPG Registry and the SIOPE DIPG Registry Sophie E. M. Veldhuijzen van Zanten1,9   · Adam Lane2,3 · Martijn W. Heymans4 · Joshua Baugh3 · Brooklyn Chaney3 · Lindsey M. Hoffman3 · Renee Doughman3 · Marc H. A. Jansen1 · Esther Sanchez5 · William P. Vandertop6 · Gertjan J. L. Kaspers1,7 · Dannis G. van Vuurden1 · Maryam Fouladi4 · Blaise V. Jones8 · James Leach8  Received: 21 December 2016 / Accepted: 23 May 2017 © The Author(s) 2017. This article is an open access publication

Abstract  We aimed to perform external validation of the recently developed survival prediction model for diffuse intrinsic pontine glioma (DIPG), and discuss its utility. The DIPG survival prediction model was developed in a cohort of patients from the Netherlands, United Kingdom and Germany, registered in the SIOPE DIPG Registry, and includes age 67% of the pons (96 vs. 90%) and a higher prevalence of tumors that extend towards the mesencephalon and medulla oblongata (12 and 36% higher, respectively). The validation cohort also contains a higher percentage of patients who have been treated with either radiotherapy (97 vs. 91%) and/or chemotherapy at any time during the disease course (77 vs. 60%). The 5-years’ OS of the validation cohort was 0% (vs. 2% in the derivation cohort), however, with a median OS of 10.7 (±0.35) versus 10 (±0.38). Table 2 shows the comparison of hazard ratios for each variable investigated in the original study, resulting from univariate analysis. The variables included in the DIPG survival prediction model are indicated with an arrow. The hazard ratios for these variables, i.e. age ≥3 years, symptom duration, presence of ring enhancement, and chemotherapy, point in the same direction in both cohorts. In the validation cohort, significance is only found for the use of chemotherapy. Table 3 shows the comparison of hazard ratios resulting from multivariable analyses. Again, all predictor variables point in the same direction, but in the validation cohort significance is only found for the use of chemotherapy. External validation steps Method 1: regression on the Prognostic Index The slope in the Cox proportional hazards model on the PI in the validation cohort was 0.72 and different from 1 (p = 0.01). This suggests a suboptimal discrimination and some mis-calibration of the model. Method 2: model misspecification/fit The agreement, or rather the above suggested difference (i.e. a slope of 0.72), in one or more regression coefficients between the derivation and validation cohort was tested by creating and ‘offset’ Cox proportional hazards

J Neurooncol Table 1  Baseline characteristics of children with a diffuse intrinsic pontine glioma

Category Total Sex Age

Signs and symptoms

Histology

MRI characteristics

Treatment

Outcome

Baseline variable

Female Male Mean age [years (range)] Age 67%  Ring enhancement  Encasement basilar artery   >180°;