Tumor-treating fields dosimetry in glioblastoma: Insights into treatment planning, optimization, and dose–response relationships
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PROVIDER: S-EPMC10981464 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Tumor treating fields (TTFields) is an anti-cancer technology increasingly used for the treatment of glioblastoma. Recently, cranial burr holes have been used experimentally to enhance the intensity (dose) of TTFields in the underlying tumor region. In the present study, we used computational finite element methods to systematically characterize the impact of the burr hole position and the TTFields transducer array layout on the TTFields distribution calculated in a realistic human head model. We investigated a multitude of burr hole positions and layouts to illustrate the basic principles of optimal treatment planning. The goal of the paper was to provide simple rules of thumb for physicians to use when planning the TTFields in combination with skull remodeling surgery. Our study suggests a number of key findings, namely that (1) burr holes should be placed directly above the region of interest, (2) field enhancement occurs mainly underneath the holes, (3) the ipsilateral array should directly overlap the holes and the contralateral array should be placed directly opposite, (4) arrays in a pair should be placed at far distance and not close to each other to avoid current shunting, and finally (5) rotation arrays around their central normal axis can be done without diminishing the enhancing effect of the burr holes. Minor deviations and adjustments (<3 cm) of arrays reduces the enhancement to some extent although the procedure is still effective in these settings. In conclusion, our study provides simple guiding principles for implementation of dose-enhanced TTFields in combination with burr-holes. Future studies are required to validate our findings in additional models at the patient specific level.
| S-EPMC9245346 | biostudies-literature
Project description:BackgroundTumor Treating Fields (TTF) have entered clinical practice for newly diagnosed and recurrent glioblastoma (GGM). However, controversies remain unresolved with regard to appropriate usage. We sought to determine TTF usage in major academic neuro-oncology programs in New York City, USA and Heidelberg, Germany and understand current attitudes toward TTF usage among providers.MethodsWe retrospectively determined TTF usage among patients with GGM, before and since the publication of key clinical trial results and regulatory approvals. We also surveyed attendees of an educational session related to TTF during the 2019 American Society of Clinical Oncology annual meeting.ResultsTTF usage remains infrequent (3-12% of patients with newly diagnosed GBM, and 0-16% of patients with recurrent disease) in our practices, although it has increased over time. Among 30 survey respondents (77% of whom self-identified as neuro- or medical oncologists), 60% were convinced that TTF prolongs survival for newly diagnosed GGM despite published phase III data and regulatory approval, and only 30% viewed TTF as definitively part of the standard of care treatment. A majority (87%) opposed mandating TTF incorporation into the design of clinical trials.ConclusionsProviders continue to view TTF with some level of skepticism, with a lack of additional supportive data and logistical concerns representing continued barriers to uptake.
| S-EPMC7345837 | biostudies-literature
Project description:Glioblastoma (GBM) is one of the most common tumors of the central nervous system, which is the most lethal brain cancer. GBM treatment is based primarily on surgical resection, combined with radiotherapy and chemotherapy. Despite the positive treatment, progression free survival and overall survival were not significantly prolonged because GBM almost always recurs. We are always looking forward to some new and effective treatments. In recent years, a novel treatment method called tumor treating fields (TTFields) for cancer treatment has been proposed. TTFields devices were approved by the Food and Drug Administration (FDA) for adjuvant treatment of recurrent and newly diagnosed GBMs in 2011 and 2015, respectively. This became the first breakthrough treatment for GBM in the past 10 years after the FDA approved bevacizumab for patients with relapsed GBM in 2009. This paper summarized the research results of TTFields in recent years and elaborated the mechanism of action of TTFields on GBM, including cell and animal experimental research, clinical application and social benefits.
| S-EPMC7671789 | biostudies-literature
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.
| S-EPMC6281619 | biostudies-literature
Project description:Glioblastoma (GBM) is one of the most aggressive forms of brain cancer that presents with a median survival rate of 14-30 months and along with a discouraging five-year survival rate of 4-5%. Standard treatment of newly diagnosed GBM, also known as the Stupp protocol, includes a maximally safe surgical resection followed by radiation and chemotherapy. Despite these treatment regimens, recurrence is almost inevitable, emphasizing the need for new therapies to combat the aggressive nature of GBMs. Tumor Treating Fields (TTFs) are a relatively new application to the treatment of GBMs, and results have been promising with both progression-free survival and overall survival when TTFs have been used in combination with temozolomide. This article critically reviews the biophysical and biological mechanisms of TTFs, their clinical efficacy, and discusses the results in clinical trials, including EF-11 and EF-14. Both trials have demonstrated that TTFs can enhance progression free survival and overall survival without compromising quality of life or causing severe adverse effects. Despite the high cost associated with TTFs and the need for further analysis to determine the most effective ways to integrate TTFs into GBM treatments, TTFs represent a significant advancement in GBM therapy and offer hope for improved patient prognosis.
| S-EPMC11448370 | biostudies-literature
Project description:Glioblastoma (GBM) represents a significant therapeutic challenge due to its aggressive nature. Tumor Treating Fields (TTFields) present a promising approach to GBM therapy. The primary mechanism of TTFields, an antimitotic effect, alongside numerous indirect effects including increased cell membrane permeability, signifies their potential in combination with other treatment modalities. Current combinations often include chemotherapy, particularly with temozolomide (TMZ), however, emerging data suggests potential synergy with targeted therapies, radiotherapy, and immunotherapy as well. TTFields display minimal side effects, predominantly skin-related, posing no significant barrier to combined therapies. The effectiveness of TTFields in GBM treatment has been demonstrated through several post-registration studies, advocating for continued research to optimize overall survival (OS) and progression-free survival (PFS) in patients, as opposed to focusing solely on quality of life.
| S-EPMC10616854 | biostudies-literature
Project description:Tumor treating fields (TTFields) are an integral treatment modality in the management of glioblastoma and extend overall survival when combined with maintenance temozolomide in newly diagnosed patients. Complexities exist regarding correct selection of imaging sequences with which to perform TTFields treatment planning. Guidelines are warranted first, to facilitate treatment planning standardization across medical disciplines and institutions, to ensure optimal TTFields delivery to the tumor and peritumoral brain zone while maximizing patient safety, and also to mitigate the risk of premature cessation of a potentially beneficial treatment. This summary guideline outlines methods for starting patients on TTFields, for monitoring patient response to therapy and provides a framework for evaluating when therapy should be re-planned, based on the extent of sequential imaging changes.
| S-EPMC6027938 | biostudies-literature
Project description:PurposeTumor Treating Fields (TTFields) are delivered by transducer arrays applied to scalp or body surface for treatment of multiple malignancies. Dermatologic complications are thought to be related to hydrogel situated between the electrodes and scalp or skin to facilitate electric field penetration. High intensity of TTFields on these surfaces may also be a contributing factor. We explored conductivity changes in the hydrogel and skin to improve TTFields coverage and penetration.MethodsMagnetic resonance imaging datasets from 12 glioblastoma patients and attenuation-corrected positron emission tomography-computed tomography datasets from 3 non-small cell lung and 2 ovarian carcinoma patients were used to segment anatomic structures. Finite element mesh models were generated and solved for distribution of applied electric fields, rate of energy deposition, and current density at the gross tumor volume (GTV) and clinical target volume (CTV). Electric field-volume, specific absorption rate-volume, and current density-volume histograms were generated, by which plan quality metrics were used to evaluate relative differences in field coverage between models at various hydrogel and skin conductivities.ResultsBy varying conductivity of hydrogel, TTFields coverage at GTV or CTV increased up to 0.5 S/m for head and 1.0 S/m for thorax and pelvis models, and no additional increase was observed beyond these saturation points. Although scalp hotspots increased or decreased by +1.5%, -0.1%, and -0.9% in E5%, SAR5%, and CD5%, the skin hotspots increased by as much as +23.5%, +45.7%, and +20.6%, respectively. When altering conductivity of the entire scalp, TTFields coverage peaked near 1 S/m at the GTV or CTV for the head models. TTFields coverage in both the GTV and scalp increased up to 1 S/m for the head models but plateaued thereafter. Contouring under the scalp increased scalp hotspots by +316% in E5% at 1 S/m compared to altering the conductivity of the entire scalp. GTV hotspots decreased by +17% in E5% at 1 S/m.ConclusionTTFields delivery can be modulated by the conductivity of hydrogel and scalp/skin at the transducer-scalp or transducer-skin interface. Optimizing this aspect of TTFields delivery may increase tumor control while minimizing toxicity at the scalp or skin.
| S-EPMC11891368 | biostudies-literature
Project description:PurposeThis study investigates the biological effect of Tumor Treating Fields (TTFields) on key drivers of glioblastoma's malignancy-tumor microtube (TM) formation-and on the function and overall integrity of the tumor cell network.MethodUsing a two-dimensional monoculture GB cell network model (2DTM) of primary glioblastoma cell (GBC) cultures (S24, BG5 or T269), we evaluated the effects of TTFields on cell density, interconnectivity and structural integrity of the tumor network. We also analyzed calcium (Ca2+) transient dynamics and network morphology, validating findings in patient-derived tumoroids and brain tumor organoids.ResultsIn the 2DTM assay, TTFields reduced cell density by 85-88% and disrupted network interconnectivity, particularly in cells with multiple TMs. A "crooked TM" phenotype emerged in 5-6% of treated cells, rarely seen in controls. Ca2+ transients were significantly compromised, with global Ca2+ activity reduced by 51-83%, active and periodic cells by over 50%, and intercellular co-activity by 52% in S24, and almost completely in BG5 GBCs. The effects were more pronounced at 200 kHz compared to a 50 kHz TTFields. Similar reductions in Ca2+ activity were observed in patient-derived tumoroids. In brain tumor organoids, TTFields significantly reduced tumor cell proliferation and infiltration.ConclusionOur comprehensive study provides new insights into the multiple effects of Inovitro-modeled TTFields on glioma progression, morphology and network dynamics in vitro. Future in vivo studies to verify our in vitro findings may provide the basis for a deeper understanding and optimization of TTFields as a therapeutic modality in the treatment of GB.
| S-EPMC11457690 | biostudies-literature
Project description: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.
| S-EPMC6884888 | biostudies-literature