Prognostic Potential of Olfactory Function in Glioblastoma: a Prospective Observational Study

Background: Olfactory impairment is frequent in glioblastoma and is associated with poor overall survival. However, earlier studies were limited by confounding of important predictive factors and the lack of long-term olfactory assessments to evaluate treatment-related neurotoxicity.

Aim: To determine whether olfactory function is an independent prognostic marker for survival, quality of life and neurocognitive outcome in glioblastoma.

Design: Prospective, multicenter cohort study with 64 glioblastoma patients and 64 comparable controls without tumor disease. Patients were stratified by baseline olfactory status, extent of resection, radiologic involvement of olfactory regions,O6-methylguanine DNA methyltransferase (MGMT) promoter methylation, age, and Karnofsky performance status.

Methods: Olfactory function will be serially assessed from diagnosis to treatment using Sniffin' Sticks (identification and threshold tests). Psychosocial assessments, neurocognitive testing and quality of life assessments will be performed at intervals. Coronal T2- and T1-weighted MRI scans will be evaluated independently by blinded neuroradiologists to identify olfactory involvement.

Next-generation sequencing will be used to investigate molecular correlates of hyposmia. As part of a parallel translational study, blood samples will be taken to analyze extracellular vesicles.

Olfactory testing:

In the identification test, 12 sniffin sticks are presented, which the patient has to name using a selection card with four terms each. Both nostrils are tested individually at each visit during the identification test. A correct answer scores one point. A maximum of 12 points is possible.

The threshold test consists of 16 dilution levels. Each level contains one sniffin stick with odor and two blanks. All three sniffin sticks of a dilution level are presented to the patient one after the other with eyes closed. The patient must indicate which of the three sticks contains an odor. Depending on whether the patient gives the correct answer, the three sniffin sticks in the next higher or next lower level are presented next. A maximum of 16 points is possible.

Inclusion criteria

• At least 18 years of age
• Newly-diagnosed glioblastoma (IDH wild-type)
• Never received prior chemotherapy
• Never received radiotherapy to the head or neck before
• KPS ≥ 70
• No history of severe head or brain trauma requiring ICU admission or classified as Glasgow Coma Scale grade 3
• No respiratory infection at the time of inclusion
• No significant aphasia

Exclusion criteria

• Presence of Neurodegenerative diseases (e.g. Parkinson's disease, Alzheimer's disease, Huntington's disease, Korsakoff's syndrome, Pick's disease, Shy-Drager syndrome)
• History of invasive tumors or surgery in the head or neck area, except for surgeries for non-invasive skin tumors (e.g. basal cell carcinomas)
• Permanent olfactory impairment following infections (e.g., influenza, coronavirus)
• Conditions that, in the examiner's judgment, could interfere with the participant's study compliance (e.g., schizophrenia)
• Language barriers likely to interfere with participation or comprehension of study procedures.