Abstract
BACKGROUND: Window-of-opportunity (WOO) and Phase 0 trials, where drugs are administered shortly before surgery to assess pharmacokinetics and biological effects in the tumor without therapeutic intent, are rapidly gaining traction in glioblastoma drug development. A critical matter of debate in the design of these trials is whether biopsy is required for definitive histopathological diagnosis before patient inclusion. This study explores whether MRI-based radiological diagnosis of glioblastoma is sufficiently accurate to justify patient inclusion in WOO/Phase 0 trials without biopsy confirmation. MATERIAL AND METHODS: MRI scans (T1w with and without gadolinium, T2w, FLAIR, DWI and PWI) of patients referred to the neurosurgery outpatient clinic at Erasmus MC, Rotterdam, the Netherlands, because of suspected adult-type glioma, were prospectively evaluated by an expert neuroradiologist for the likelihood of glioblastoma. Patients with a history of cancer were excluded if they had multiple or infratentorial enhancing lesions, but not if they had a solitary supratentorial enhancing lesion. The neuroradiologist’s assessment was based on a 5-point Likert scale (1: definitely glioma to 5: definitely not glioma) and an estimation of the glioma’s WHO grade (1-4). The neuroradiologist’s predictions were compared to the final integrated WHO CNS5 tissue diagnosis, as concluded by a neuropathologist, and sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: A total of 90 patients were included (median age: 62 years, range 21-85 years). 52 patients were radiologically diagnosed with glioblastoma (Likert scale 1-3 and estimation of WHO grade 4). MRI-based imaging demonstrated a sensitivity of 80.4% (95% CI: 67.5-89.0%), specificity of 72.0% (95% CI: 56.2-83.5%), PPV of 78.8% (95% CI: 66.0-87.8%) and NPV of 73.6% (95% CI: 58.0-85.0%). The 11 false positives (21.2% (11/52)) included astrocytoma, IDH-mutant grade 4 (n=4), metastasis (n=5), H3K27M-mutant diffuse midline glioma (n=1) and giant cell glioma (n=1)). Age (OR 1.00, 95% CI 0.96-1.03, p = 0.84) and gender (OR 0.73, 95% CI 0.25-2.01, p = 0.56) were no predictive factors of diagnostic accuracy of radiological imaging. CONCLUSION: We consider a PPV of 78.8% for MRI-based diagnosis of glioblastoma sufficiently accurate to justify patient inclusion before definitive tissue diagnosis in WOO/phase 0 studies without the need for biopsy confirmation. False positives could potentially be reduced by incorporating CT scans of the thorax/abdomen. Further research using advanced MRI techniques or nuclear imaging may enhance diagnostic accuracy. We recommend including replacement of false positive patients in the study protocol of future WOO/phase 0 studies.