Assessment of Karnofsky (KPS) and WHO (WHO-PS) performance scores in brain tumour patients: the role of clinician bias

PURPOSE:. Inclusion of brain tumour patients in oncological protocols may be hampered by their neurological impairment. The goal of this study was to assess the reliability of Karnofsky Performance Scale (KPS) and WHO Performance Scale (WHO-PS) scores in this population. METHODS: A cross-sectional survey was conducted through the Association des Neuro-Oncologues d'Expression Française (ANOCEF) and European Neuro-Oncology Association (EANO) networks. Clinicians were asked to write a text defining their operative definition of a patient with ≥ 70 KPS and to assess KPS and WHO-PS in six different clinical case vignettes. RESULTS: Two hundred seventy-six clinicians sent a response. The operative definition mentioned a normal life (89%), what patients were able (26%) or unable (29%) to do, normal cognitive processing (8%) and caregivers (6%). Older physicians mentioned more often what patients were unable to do (p = 0.005). The two scales were homogeneous in less severely handicapped patients only. More patients were excluded for hemiplegia than for expressive aphasia. Older physicians significantly excluded more patients for KPS and WHO-PS. Speciality of the physician significantly influenced scoring. On multivariable analysis, age and speciality of the physicians were correlated with KPS and WHO-PS rating even if adjusted on cases. Discordant scoring increased with severity of the deficit: in nearly all cases, the KPS would have denied, while WHO-PS would have allowed, access to a trial. CONCLUSION: Performance scores assigned to brain tumour patients are clinician and score dependant. WHO-PS would allow more access to a trial. Specific criteria should be developed for patients with neurological deficits to facilitate their access to trials

MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation.

Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma. TMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon's 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I. A total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD. The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements