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OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma.

ABSTRACT: Background:Preclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents toward the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase I setting. Methods:Fifteen adult patients with the first recurrence of GBM were treated with personalized SR-surgery, TTFields, and physician's choice oncological therapy. The primary endpoint was toxicity and secondary endpoints included standard efficacy outcomes. Results:SR-surgery resulted in a mean skull defect area of 10.6 cm2 producing a median TTFields enhancement of 32% (range 25-59%). The median TTFields treatment duration was 6.8 months and the median compliance rate 90%. Patients received either bevacizumab, bevacizumab/irinotecan, or temozolomide rechallenge. We observed 71 adverse events (AEs) of grades 1 (52%), 2 (35%), and 3 (13%). There were no grade 4 or 5 AEs or intervention-related serious AEs. Six patients experienced minor TTFields-induced skin rash. The median progression-free survival (PFS) was 4.6 months and the PFS rate at 6 months was 36%. The median overall survival (OS) was 15.5 months and the OS rate at 12 months was 55%. Conclusions:TTFields therapy combined with SR-surgery and medical oncological treatment is safe and nontoxic and holds the potential to improve the outcome for GBM patients through focal dose enhancement in the tumor.

SUBMITTER: Korshoej AR

PROVIDER: S-EPMC7660275 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma.

Korshoej Anders Rosendal AR Lukacova Slavka S Lassen-Ramshad Yasmin Y Rahbek Christian C Severinsen Kåre Eg KE Guldberg Trine Lignell TL Mikic Nikola N Jensen Mette Haldrup MH Cortnum Søren Ole Stigaard SOS von Oettingen Gorm G Sørensen Jens Christian Hedemann JCH

Neuro-oncology advances 20200101 1

<h4>Background</h4>Preclinical studies suggest that skull remodeling surgery (SR-surgery) increases the dose of tumor treating fields (TTFields) in glioblastoma (GBM) and prevents wasteful current shunting through the skin. SR-surgery introduces minor skull defects to focus the cancer-inhibiting currents toward the tumor and increase the treatment dose. This study aimed to test the safety and feasibility of this concept in a phase I setting.<h4>Methods</h4>Fifteen adult patients with the first r ...[more]

PMID: 33215088

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Project description:Abstract Background We present a pre-specified interim analysis of an ongoing open-label, investigator-sponsored phase 1 trial (NCT02893137) testing safety/efficacy of a new rGBM treatment. The intervention combines personalized skull-remodeling (SR) surgery with TTFields and best-choice chemotherapy. SR-surgery involves minor craniectomy, burr-holes, and/or skull thinning personalized to enhance TTFields intensity focally in the tumor. Material and Methods Accrual began Dec 2016 (planned total 15 patients). Eligibility: Age > 18 years, first recurrence focal supratentorial GBM (RANO), and KPS ? 70. Personalized electric field calculations were conducted to validate TTFields enhancement > 25% by SR-surgery. Patients were right-censored for OS and PFS at the time of analysis and excluded upon progression, death, SUSARs, or unacceptable AEs. Primary endpoints: Toxicity (CTCAEv4.0). Secondary endpoints: OS, PFS, PFS6, objective response rate (iRANO), quality of life, KPS, and steroid dose. Results The interim analysis was based on data prior to April 1, 2018. Safety data were analyzed for all enrolled patients and efficacy for all patients treated with TTFields. 16 patients were screened, 1 declined, and 2 had KPS < 70. Of the 13 enrolled patients, 3 were excluded prior to TTFields treatment (1 female due to radionecrosis/non-recurrence, 1 male due to post-op infection, and 1 female due to neurodeficit). All included patients (9 male and 1 female) had GBM IDH-wt tumors (4 MGMT-methylated). Median KPS was 90 (range 70–100) and median age 55 years (range 49 to 67). All patients received maximum safe resection at recurrence (4 had no residual tumor (RANO), 4 had non-measurable disease, and 2 had measurable disease). 8 patients received adjuvant bevacizumab monotherapy (10 mg/kg every 2 weeks, median number of cycles 9.5, range 4 to 23) and 2 received temozolomide rechallenge (200 mg/m2 every 4 weeks, 3 and 4 cycles, respectively). The mean skull-defect area was 10.5 cm2 (range 7 to 24 cm2), the median field enhancement 37 % (range 25 to 61%), and the median TTFields compliance 91% (range 61 to 95%). Within the observation period 5 patients had progression, 3 died, 5 were censored for PFS, and 7 for OS. We observed no SUSARs or grade 4/5 SAEs, but 5 grade 3 SAEs (2 generalized seizures in patients with known epilepsy, 1 post-op infection, 1 diarrhea, and 1 DVT). 2 patients had grade 1–2 skin rash, and 1 had grade 1–2 headaches. Median OS was 15.5 months, 95%-CI: 5.9-NA, median PFS 9.5 months, 95%-CI: 3.7-NA, and PFS6 58%, 95%-CI: 0.27–0.90. 1 patient had complete response during TTFields treatment. Conclusion SR-surgery including craniectomy is not associated with additional toxicity in combination with TTFields and holds promising potential for improving TTFields outcome by focally enhancing the field intensity in the tumor. A future phase 2/3 trial is being planned for efficacy assessment.

Project description:Abstract Prognosis of relapsed glioblastoma (GBM) is dismal and current treatment fails to provide prolonged survival. Small subsets of patients respond well to some novel therapeutics probably due to the genetic variations of tumors and patients. In the Phase 3 EF-11 recurrent GBM trial, a small subset of patients derived significant benefit from TTFields alone. This proof-of-concept trial [NCT01954576] will study adult patients with relapsed GBM treated with TTFields by genetic analysis of primary and recurrent tumors. Post-hoc correlations will be used between clinical response, mutational analyses and quantitative gene expression to define genomic signatures of response. Whole exome and RNA sequencing will be used to identify genomic signature of responders to TTFields. Fifteen patients with bevacizumab-naïve recurrent GBM and 15 patients with bevacizumab-refractory GBM will be treated with TTFields for 6 and 4 months respectively. Patients will undergo standard brain MRI scans without and with gadolinium contrast and perfusion imaging every 8 weeks. Tissue from the primary tumor at recurrence will be genetically analyzed. Genomic DNA (gDNA) will be extracted from patients tumor and blood samples. Purified gDNA fragments will be used for Illumina sequencing library construction. Certain germ-line variants may contribute to gliomagenesis and be associated with somatic mutations within the tumor and subtypes of GBM more or less sensitive to TTFields. Analyses will be conducted on all patients: bevacizumab-naïve and bevacizumab-refractory GBM separately, and patients with objective radiographic response (complete response + partial response (CR + PR) and stable disease (SD) separately. With 50% bevacizumab-refractory GBM patients, response rate will be significantly higher than the baseline rate of 14%. Using an Exact test with type I error of 0.05 and 80% power, the estimated sample sizes will detect a statistical difference on response rate in the TTFields group compared to historical controls. To-date 4 patients have been enrolled.

Project description:ObjectiveThe present work proposes a new clinical approach to TTFields therapy of glioblastoma. The approach combines targeted surgical skull removal (craniectomy) with TTFields therapy to enhance the induced electrical field in the underlying tumor tissue. Using computer simulations, we explore the potential of the intervention to improve the clinical efficacy of TTFields therapy of brain cancer.MethodsWe used finite element analysis to calculate the electrical field distribution in realistic head models based on MRI data from two patients: One with left cortical/subcortical glioblastoma and one with deeply seated right thalamic anaplastic astrocytoma. Field strength was assessed in the tumor regions before and after virtual removal of bone areas of varying shape and size (10 to 100 mm) immediately above the tumor. Field strength was evaluated before and after tumor resection to assess realistic clinical scenarios.ResultsFor the superficial tumor, removal of a standard craniotomy bone flap increased the electrical field strength by 60-70% in the tumor. The percentage of tissue in expected growth arrest or regression was increased from negligible values to 30-50%. The observed effects were highly focal and targeted at the regions of pathology underlying the craniectomy. No significant changes were observed in surrounding healthy tissues. Median field strengths in tumor tissue increased with increasing craniectomy diameter up to 50-70 mm. Multiple smaller burr holes were more efficient than single craniectomies of equivalent area. Craniectomy caused no significant field enhancement in the deeply seated tumor, but rather a focal enhancement in the brain tissue underlying the skull defect.ConclusionsOur results provide theoretical evidence that small and clinically feasible craniectomies may provide significant enhancement of TTFields intensity in cerebral hemispheric tumors without severely compromising brain protection or causing unacceptable heating in healthy tissues. A clinical trial is being planned to validate safety and efficacy.

Project description:Glioblastoma is the most common yet most lethal of primary brain cancers with a one-year post-diagnosis survival rate of 65% and a five-year survival rate of barely 5%. Recently the U.S. Food and Drug Administration approved a novel fourth approach (in addition to surgery, radiation therapy, and chemotherapy) to treating glioblastoma; namely, tumor treating fields (TTFields). TTFields involves the delivery of alternating electric fields to the tumor but its mechanisms of action are not fully understood. Current theories involve TTFields disrupting mitosis due to interference with proper mitotic spindle assembly. We show that TTFields also alters cellular membrane structure thus rendering it more permeant to chemotherapeutics. Increased membrane permeability through the imposition of TTFields was shown by several approaches. For example, increased permeability was indicated through increased bioluminescence with TTFields exposure or with the increased binding and ingress of membrane-associating reagents such as Dextran-FITC or ethidium D or with the demonstration by scanning electron microscopy of augmented number and sizes of holes on the cellular membrane. Further investigations showed that increases in bioluminescence and membrane hole production with TTFields exposure disappeared by 24?h after cessation of alternating electric fields thus demonstrating that this phenomenom is reversible. Preliminary investigations showed that TTFields did not induce membrane holes in normal human fibroblasts thus suggesting that the phenomenom was specific to cancer cells. With TTFields, we present evidence showing augmented membrane accessibility by compounds such as 5-aminolevulinic acid, a reagent used intraoperatively to delineate tumor from normal tissue in glioblastoma patients. In addition, this mechanism helps to explain previous reports of additive and synergistic effects between TTFields and other chemotherapies. These findings have implications for the design of combination therapies in glioblastoma and other cancers and may significantly alter standard of care strategies for these diseases.

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OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma.

Publications

OptimalTTF-1: Enhancing tumor treating fields therapy with skull remodeling surgery. A clinical phase I trial in adult recurrent glioblastoma.

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