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Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging.

ABSTRACT: Alternating electric fields have been successfully applied to cancer cells in-vitro to disrupt malignant progression and this antimitotic therapy has now been proven to be efficacious in Phase II and Phase III randomized clinical trials of patients with glioblastoma. With additional clinical trials ongoing in a number of other malignancies, there is a crucial need for a better understanding of the radiographic predictors of response and standardization of surveillance imaging interpretation. However, many radiologists have yet to become familiarized with this emerging cancer therapy and there is little active investigation to develop prognostic or predictive imaging biomarkers. This article provides an overview of the pre-clinical data that elucidate the biologic mechanisms of alternating electric fields as a cancer therapy. Results from clinical trials in patients with glioblastoma are then reviewed while elaborating on the several limitations to adoption of this promising line of treatment. Finally, a proposal for the development of imaging markers as a means of overcoming some of these limitations is made, which may improve treatment utilization by augmenting patient selection not only in glioblastoma, but also other malignant conditions for which this therapy is currently being evaluated.

SUBMITTER: Soni VS

PROVIDER: S-EPMC6884888 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging.

Soni Vikram S VS Yanagihara Ted K TK

Cancer imaging : the official publication of the International Cancer Imaging Society 20191129 1

Alternating electric fields have been successfully applied to cancer cells in-vitro to disrupt malignant progression and this antimitotic therapy has now been proven to be efficacious in Phase II and Phase III randomized clinical trials of patients with glioblastoma. With additional clinical trials ongoing in a number of other malignancies, there is a crucial need for a better understanding of the radiographic predictors of response and standardization of surveillance imaging interpretation. How ...[more]

PMID: 31783910

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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.

Project description:BackgroundTo date, there has been no large-scale, real-world study of the health-related quality of life outcomes for patients using tumor treating fields (TTFields) therapy for glioblastoma (GBM) treatment.MethodsA survey was mailed to 2,815 patients actively using TTFields for treatment of GBM in the USA (n = 2,182) and Europe (n = 633). The survey included patient-reported demographic and clinical information, as well as EuroQol's EQ-5D-5L and visual analogue scale (EQ-VAS) overall health score.ResultsA total of 1,106 applicable patients responded to the survey (USA = 782 and Europe = 324), with a mean age of 58.6 years (SD = 12.3). The average time since diagnosis and time using TTFields were 21.5 months (SD = 25.1) and 13.5 months (SD = 13.2), respectively. Over 61% of patients had been diagnosed at least 1 year prior and 28.4% at least 2 years prior; 45 patients (4.2%) had been diagnosed at least 5 years prior. Progressed disease was reported in 307 patients, while 690 reported non-progressed disease. Regression analyses showed that GBM disease progression and older age had predictable negative associations (p < 0.001) with most EQ-5D-5L dimensions and the EQ-VAS. However, longer time since diagnosis was associated with improved self-care (p < 0.05), usual activities (p < 0.01), and EQ-VAS (p < 0.05) overall and in patients with progressed disease (p < 0.01, p < 0.05, and p < 0.01, respectively). Additionally, longer time using TTFields was associated with improved mobility (p < 0.05), self-care (p < 0.001), usual activities (p < 0.01), and EQ-VAS (p < 0.01) overall; with improved EQ-VAS in progression-free patients (p < 0.05); and with improved mobility (p < 0.05), self-care (p < 0.01), usual activities (p < 0.05), and EQ-VAS (p < 0.05) in patients with progressed disease.ConclusionThis is the largest real-world study of patient-reported quality of life in GBM and TTFields treatment to date. It shows unsurprising negative associations between quality of life and disease progression and older age, as well as more novel, positive associations between quality of life and longer time since diagnosis and time using TTFields therapy.

Project description:BackgroundGlioblastoma, one of the common tumors of the central nervous system (CNS), is prone to recurrence even after standard treatment protocols. As an innovative physiotherapy method emerging in recent years, the tumor treating fields (TTFields) technique has been approved for the treatment of glioblastoma due to its non-invasive and portable features. The purpose of this study is to visualize and analyze the scientific results and research trends in TTFields therapy for glioblastoma.MethodsPublications related to TTFields therapy for glioblastoma were searched in the Web of Science Core Collection (WoSCC) database in September 2022. A bibliometric and visual analysis of publications in this field was performed mainly using CiteSpace and R software for country/region, author, journal, reference and keyword.ResultsA total of 618 publications in this field were retrieved, and 248 were finally obtained according to the search criteria, including 159 articles (64.11%) and 89 reviews (37.89%). The cumulative number of publications increased year by year, with an average growth rate (AGR) of 28.50%. The test results of Pearson correlation coefficient showed a high positive correlation between publications and citations (r=0.937, p<0.001). The USA had the largest number of publications (123, 49.60%), followed by Germany (32, 12.90%) and China (30, 12.10%). As for the country/region collaborations, the USA cooperated most closely with other countries/regions, followed by Germany and China. The degree of collaboration (DC) between countries/regions was 25.81%. The institutions with the largest number of publications were Tel Aviv Univ (10), Harvard Med Sch (10) and Novocure Ltd (10). Moreover, Wong E (18) possessed the greatest number of publications, followed by Weinberg U (11) and Kirson E (10). The DC between authors was 97.58%. STUPP R (236) was the most cited author followed by KIRSON ED (164) and GILADI M (104). JOURNAL OF NEURO-ONCOLOGY (22) was the journal with the largest number of published publications (75), followed by FRONTIERS IN ONCOLOGY (15) and CANCERS (13). The top 10 keywords that occurred frequently included glioblastoma (156), tumor treating field (152), temozolomide (134), randomized phase III (48), brain (46), survivor (46), cancer (44), trial (42), alternating electric field (42) and radiotherapy (36). Furthermore, cluster analysis was performed on the basis of keyword co-occurrence, and finally 15 clusters were formed to determine the current research status and future development trend of TTFields therapy for glioblastoma.ConclusionTTFields has been increasingly known as the fourth novel physical anti-tumor therapy in addition to surgery, radiotherapy and anti-tumor drugs. Cooperation and communication between countries/regions need to be enhanced in future research. Several studies have demonstrated the therapeutic potential of TTFields in glioma, and its application alone or in combination with other treatments has become a current research hotspot.

Dataset Information

Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging.

Publications

Tumor treating fields in the management of Glioblastoma: opportunities for advanced imaging.

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