Most Proposed Topic :
Clinical Safety and Quality Service I (projects aiming to improve efficiency and effectiveness of care delivery to meet international standards)
Proposed Topic (Second preferred): :
Research and Innovations (new projects / technology / innovations / service models)
Authors: (including presenting author): :
Peter YM WOO 1, Joyce SW CHOW 2, LI Lai FUNG 3, Natalie KO 4, Tony KT CHAN 5, Sui-to WONG 6, Michael WY LEE 7, Jenny KS PU 3, Fung Ching CHEUNG 2, Danny TM CHAN 1
Affiliation: :
1 Department of Neurosurgery, Prince of Wale Hospital
2 Department of Neurosurgery, Queen Elizabeth Hospital
3 Department of Neurosurgery, Queen Mary Hospital
4 Department of Neurosurgery, Kwong Wah Hospital
5 Department of Neurosurgery, Princess Margaret Hospital
6 Department of Neurosurgery, Tuen Mun Hospital
7 Department of Neurosurgery, Pamela Youde Nethersole Eastern Hospital
Introduction: :
Glioblastoma is the commonest primary malignant tumor in adults with a prevalence of 1-5 per 100 000 population. In spite of standard-of-care multimodality treatment, comprising of surgical resection and temozolomide chemoradiotherapy, the median overall survival (mOS) remains only 11 months. Until recently, in the last 15 years there has been no breakthrough treatment that has resulted in a significant and consistent improvement in OS. Tumor-treating fields (TTF), is a novel therapy that involves the non-invasive local administration of low intensity (1-3V/cm) alternating electric fields of intermediate frequency (200kHz) to the post-resection cavity of a glioblastoma patient by placing transducer arrays on the scalp. Preclinical studies observed that the application of electric fields resulted in mitotic arrest by disrupting spindle formation in the tumor cell metaphase thereby leading to cell death. Subsequent phase 3 randomised-clinical trials confirmed the clinical effectiveness of this treatment for newly-diagnosed glioblastoma patients. Since 2021, the Hospital Authority introduced a pilot scheme to fully subsidise TTF for selected patients in addition to conventional first-line therapy.
Objectives: :
1. To assess the clinical effectiveness of TTF in improving overall survival.
2. To assess the quality of life of patients receiving TTF.
3. To determine the adverse effects associated with TTF.
Methodology: :
This was an investigator initiated quasi experimental multicenter study that reviewed prospectively collected data from WHO grade 4 astrocytoma patients that received TMZ chemoradiotherapy and TTF. A propensity score matched comparison with historical control patients that only received TMZ chemoradiotherapy was performed to determine differences in OS. Consecutive adult patients (>/= 18 years old) from all seven HA neurosurgery centers with newly diagnosed, histologically confirmed WHO grade 4 astrocytoma from 1 January 2009 to 30 June 2022 were reviewed. All subjects completed TMZ chemoradiotherapy. Patients that only underwent a tumor biopsy, had the tumor located in the cerebellum, prior radiotherapy, had unknown tumor IDH 1 mutation status, unknown pMGMT methylation status, a prior histopathological diagnosis of a lower grade glioma or had an concomitant disabling condition that precluded attaining a Karnofsky Performance Score (KPS) of >/= 80 were excluded. Patients were not considered candidates for TTF if they experienced an active scalp or CNS infection, medically refractory seizures, radiotherapy induced skin toxicity of Radiation Therapy Oncology Group (RTOG) grade 4, had an electronically active CNS implant or had inadequate caregiver support. All TTF subjects or their legal representatives provided written informed consent. Clinical data was retrieved from the Hong Kong Glioblastoma Registry, a population level database of adult Chinese patients. This was broadly categorized into patient , tumor and treatment related factors. Patient related data included age, gender and pretreatment KPS. Tumor related data included its location, isocitrate dehydrodegenase 1 (IDH 1) mutation status and promoter O6 methylguanine methyltransferase (pMGMT) methylation status. The former was determined by immunohistochemistry or by DNA sequencing when the results were equivocal or if the patient was younger than 55 years old. pMGMT methylation analysis was performed by methylation specific polymerase chain reaction. Extent of resection (EOR) was defined according to the neurosurgeon’s description from operation records and was categorized into subtotal resection (STR) or gross total resection (GTR). The primary endpoint was OS, defined as the date of the first surgery that confirmed the diagnosis of glioblastoma until death. The secondary endpoints was the health-related quality of life (HR-QoL) at 3 months and TTF-associated adverse effects. All cases were censored by 30 September 2023. Patients in the TTF and TMZ chemoradiotherapy group (TTF + CRT) were matched (1:2) with patients from the TMZ chemoradiotherapy group (CRT).
Result & Outcome: :
A total of 144 patients were reviewed and 48 (33%) received TTF + CRT with the remaining being propensity-score matched controls that received CRT. The mean age of the TTF + CRT group was 54 (SD: 13) years and for the control group 52 (SD: 13) years. 60% (n=29) of TTF + CRT patients were male and was comparable to the control group with 53% (n=51) of patients being male (p-value 0.41). Similarly, the proportions of patients with a preoperative KPS >/= 80 (TTF + CRT: 73% vs CRT: 62%; p-value 0.36), tumor IDH-1 mutant status (TTF + CRT: 10% vs CRT: 18%; p-value 0.44), pMGMT methylation status (TTF + CRT: 40% vs CRT: 55%; p-value 0.12) and GTR (TTF + CRT: 44% vs CRT: 45%; p-value 0.91) were similar. After adjusting for these significant independent predictors for OS, the mOS of patients that had TTF + CRT was 22.4 months (IQR : 18.6-26.5) and was significantly longer than those that only underwent CRT (17.2 months; IQR: 12.1-22.3) (log-rank test: p-value < 0.01). HR-QoL of TTF patients in terms of the EORTC Functional (p-value: 0.45) and Symptom (p-value 0.42) at 3 months were comparable to control patients. 32 (67%) TTF patients experienced associated contact scalp dermatitis of RTOG grade I that was completely reversible after the application of topical hydrocortisone cream. No other TTF adverse effects were reported.
The administration of TTF as first-line treatment of patients with newly diagnosed WHO grade 4 astrocytoma is an independent predictor for OS in addition to standard-of-care CRT. Although the occurrence of adverse effects was relatively high, all involved patients only had mild reversible contact dermatitis, but QoL was not affected. TTF is a novel, safe and effective outpatient treatment for patients with an otherwise incurable tumor.
