Tumor-treating Fields Research Articles

HGG-29. How I treat recurrent pediatric high-grade glioma (HGG): A Europe-wide survey study.

PURPOSE: Prognosis of pediatric high-grade gliomas (pedHGG) is dismal, and there is no standard of care treatment in case of recurrence/progression. We aimed to gain an overview of different treatment strategies in the setting of recurrent/progressing pedHGG. METHODS: In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on different therapeutic options in four real-world case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS: One hundred and thirty-nine clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further active (multimodal) oncological treatment in three out of four cases and chose palliative care with pure symptom control measures only in one case (gliomatosis cerebri and marked symptoms). Depending on the case, 8-92% of experts would initiate a re-resection (maximal safe resection in case of localized hemispheric pedHGG), combined with molecular diagnostics, and 55-77% recommended (re-)irradiation, preferably local radiotherapy >20 Gy (or craniospinal irradiation in one case with disseminated spinal HGG, 65%). Throughout all case scenarios, most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitors, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% advocated immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSIONS: In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a standard (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressive HGG.

PANOVA-3: A phase 3 study of tumor-treating fields with gemcitabine and nab-paclitaxel for frontline treatment of locally advanced pancreatic adenocarcinoma.

TPS4187 Background: Tumor Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150–200 kHz) alternating electric fields are delivered to the tumor via skin-placed arrays. In vitro, TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines (Giladi M, et al. Pancreatology 2014;14:54–63). The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC) (Rivera F, et al. Pancreatology 2019;19:64–72). These data indicate that TTFields with GnP warrant phase 3 evaluation. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. Planned enrollment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0–2, and no prior treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumors V1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 106 sites in Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Clinical trial information: NCT03377491.

The PROTECT Study: A phase II, open-label trial of prophylactic skin toxicity therapy with clindamycin and triamcinolone in patients with glioblastoma treated with tumor-treating fields.

TPS2084 Background: Glioblastoma Multiforme (GBM), is the most common and aggressive brain tumor. Tumor Treatment Fields (TTFields) is a noninvasive, regional antimitotic treatment modality approved for the treatment of recurrent and newly diagnosed GBM by the US Food and Drug Administration. TTFields delivers low intensity (1-3 V/cm), intermediate frequency (100-300 kHz), alternating electric fields to the tumor through noninvasive transducer arrays placed on the skin, around the region of the body containing the tumor. During mitosis, TTFields disrupt the formation of the mitotic spindle during metaphase resulting in apoptosis. Dermatologic adverse events (AEs) to TTFields include dermatitis and infections and were reported in 54% of patients in a phase III trial. Topical triamcinolone and clindamycin have demonstrated anecdotal benefit because of their anti-inflammatory and antimicrobial activity. Pre-clinical studies have shown no negative effect on impedance when applied onto skin under the arrays. The effect of topical triamcinolone and clindamycin for the prevention of skin AEs to TTFields has not been studied prospectively. Methods: We are conducting a phase II multicenter clinical trial in patients receiving standard-of-care TTFields therapy for GBM to determine the efficacy of a prophylactic intervention: topical clindamycin 1% solution and triamcinolone 0.1% lotion in preventing grade ≥2 epicutaneous device-related events. Eligible patients must be ≥18 years of age, newly diagnosed with GBM and initiating TTFields within 7 days of study enrollment. The primary objective is to determine the effect of topical clindamycin 1% and triamcinolone 0.1% on the prevention of grade ≥2 device-related skin AEs. Secondary objectives include investigating the effect of study agents on skin-related quality of life (using the PRO-CTCAE modules for rash, ulcer, and pruritus), evaluating the efficacy of study agents applied to the scalp at every array change by standardized photography evaluated by a blinded investigator, measuring the duration of skin toxicities and usage of the TTFields device, measuring the duration of treatment interruptions and time to first grade ≥ 2 skin events, determining the bacterial flora of scalp infections, and determining the effect of study agents on TTFields’ impedance. Patients will be on study for 90 days. An end-of-study assessment will occur on day 90, and a post-treatment visit will occur on day 120. The first patient was enrolled on October 21, 2020 and hitherto, 8 patients have been consented. Participating sites include Memorial Sloan Kettering Cancer Center, Columbia University Medical Center, Tufts University Medical Center, Northwestern University, Washington University, University of Cincinnati, and John Theurer Cancer Center - Hackensack Meridian Health. Clinical trial information: NCT04469075.

Predicting access to postoperative treatment after glioblastoma resection: an analysis of neighborhood-level disadvantage using the Area Deprivation Index (ADI).

Social determinants of health (SDoH)-socioeconomic and environmental factors-impact outcomes. The Area Deprivation Index (ADI), a composite of seventeen SDoH factors, has been correlated with poorer outcomes. We aimed to compare outcomes and treatment access for glioblastoma, a universally fatal malignant brain tumor, in patients more (ADI 34-100%) versus less disadvantaged (ADI 0-33%). A 5-year retrospective study of Rhode Island Hospital and Mayo Clinic databases was conducted from 2012 to 2017 for patients ≥ 18years with glioblastoma. Patient addresses were matched to ADI percentiles and grouped into more (top 66% ADI) and less disadvantaged. Adjusted multivariable regressions were used to compare outcomes between groups. A total of 434 patients met inclusion; 92.9% were insured, 56.2% were more disadvantaged (n = 244), and the more disadvantaged cohort was younger on average (62years). After adjustment, the more disadvantaged group had decreased odds of receiving gross total resection (adjusted odds ratio (aOR) 0.43, 95% CI [0.27-0.68]; p < 0.001). This cohort also had decreased odds of undergoing chemotherapy (aOR 0.51[0.26-0.98]), radiation (aOR 0.39[0.20-0.77]), chemoradiation (aOR 0.42[0.23-0.77]), tumor-treating fields (aOR 0.39[0.16-0.93]), and clinical trial participation (aOR 0.47[0.25-0.91]). No differences in length of survival or postoperative Karnofsky Performance Status Scale were observed. More disadvantaged glioblastoma patients had decreased odds of receiving gross total resection. They also exhibited decreased odds of receiving standard of care like chemoradiation as well as participating in a clinical trial, compared to the less disadvantaged group. More research is needed to identify modifiable SDoH barriers to post-operative treatment in disadvantaged patients with glioblastoma.

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors.

SUMMARYGlioblastoma multiforme (GBM) is the most aggressive and fatal disease of all brain tumor types. Most therapies rarely provide clinically meaningful outcomes in the treatment of GBM. Although antibody-drug conjugates (ADCs) are promising anticancer drugs, no ADCs have been clinically successful for GBM, primarily because of poor blood-brain barrier (BBB) penetration. Here, we report that ADC homogeneity and payload loading rate are critical parameters contributing to this discrepancy. Although both homogeneous and heterogeneous conjugates exhibit comparable in vitro potency and pharmacokinetic profiles, the former shows enhanced payload delivery to brain tumors. Our homogeneous ADCs provide improved antitumor effects and survival benefits in orthotopic brain tumor models. We also demonstrate that overly drug-loaded species in heterogeneous conjugates are particularly poor at crossing the BBB, leading to deteriorated overall brain tumor targeting. Our findings indicate the importance of homogeneous conjugation with optimal payload loading in generating effective ADCs for intractable brain tumors.

Lucanthone Targets Lysosomes to Perturb Glioma Proliferation, Chemoresistance and Stemness, and Slows Tumor Growth In Vivo.

Glioblastoma is the most common and aggressive primary brain tumor in adults. Median survival time remains at 16-20 months despite multimodal treatment with surgical resection, radiation, temozolomide and tumor-treating fields therapy. After genotoxic stress glioma cells initiate cytoprotective autophagy, which contributes to treatment resistance, limiting the efficacy of these therapies and providing an avenue for glioma recurrence. Antagonism of autophagy steps has recently gained attention as it may enhance the efficacy of classical chemotherapies and newer immune-stimulating therapies. The modulation of autophagy in the clinic is limited by the low potency of common autophagy inhibitors and the inability of newer ones to cross the blood-brain barrier. Herein, we leverage lucanthone, an anti-schistosomal agent which crosses the blood-brain barrier and was recently reported to act as an autophagy inhibitor in breast cancer cells. Our studies show that lucanthone was toxic to glioma cells by inhibiting autophagy. It enhanced anti-glioma temozolomide (TMZ) efficacy at sub-cytotoxic concentrations, and suppressed the growth of stem-like glioma cells and temozolomide-resistant glioma stem cells. In vivo lucanthone slowed tumor growth: reduced numbers of Olig2+ glioma cells, normalized tumor vasculature, and reduced tumor hypoxia. We propose that lucanthone may serve to perturb a mechanism of temozolomide resistance and allow for successful treatment of TMZ-resistant glioblastoma.

Efficacy and safety of tumor-treating fields in recurrent glioblastoma: a systematic review and meta-analysis.

Tumor-treating fields (TTF) is a novel cancer treatment that uses alternating electric fields to interfere with tumor cell mitosis. It has been approved by the U.S. food and drug administration for the treatment of recurrent glioblastoma (rGBM). We designed this meta-analysis to evaluate the efficacy and safety of TTF in the treatment of rGBM. The study was based on the PRISMA guideline. Systematic retrieval was performed in PubMed, Cochrane Library, and Embase databases. The outcomes were overall survival (OS) hazard ratio (HR), 1-year survival rate, and cutaneous toxicity. These studies included a total of 1048 rGBM patients who received TTF treatment. The overall survival time between the TTF group and the control group was HR 0.75 ([95%CI 0.63 to 0.89]; P = 0.001). Pooled 1-year overall survival rate and incidence of cutaneous toxicity were 0.47 and 0.48, respectively. Data were insufficient to evaluate the effect of MGMT methylation status and tumor recurrence times on heterogeneity. TTF therapy is effective for recurrent glioblastoma. However, most relevant trials should assess rGBM patient baseline characteristics such as age, KPS, MGMT methylation status, and number of tumor recurrence,. In addition, the risk of rashes caused by long-term wearing of devices should also be considered.

Congress of Neurological Surgeons systematic review and evidence-based guidelines update on the role of cytotoxic chemotherapy and other cytotoxic therapies in the management of progressive glioblastoma in adults.

These recommendations apply to adult patients diagnosed with progressive glioblastoma (pGBM). QUESTION (Q1): In adult patients with pGBM does the use of temozolomide (TMZ) with alternative dosing or the use of TMZ in combination with other cytotoxic treatments result in increased overall survival compared to other chemotherapy? Level III: Adult patients with pGBM might derive benefit in treatment with TMZ, especially those who progress after more than 5months of TMZ-treatment free interval. Combination of TMZ with other cytotoxic agents such as nitrosourea, cisplatin, electrohyperthermia, or tamoxifen is not suggested in adult patients with pGBM as a stand-alone therapy. There is insufficient data to make a recommendation about which alternative TMZ dosing provides the best benefits. QUESTION (Q2): In adult patients with pGBM does the use of systemic or in situ nitrosourea result in increased overall survival compared to other chemotherapy? Level III: In the setting of pGBM, fotemustine is suggested in elderly patients with methylated MGMT promoter status. There is insufficient evidence to compare fotemustine to other nitrosoureas. There is insufficient evidence to make a recommendation about the use of in situ nitrosourea in patients with pGBM who underwent the Stupp regimen. QUESTION (Q3): In adult patients with pGBM does the use of platinum compounds and topoisomerase result in increased survival compared to other chemotherapy? Level III: Other chemotherapy including platinum compounds and topoisomerase inhibitors are not suggested to be used in adult patients with pGBM. Other cytotoxic therapies like perillyl acohol or ketogenic diet are not suggested for use in adult patients with pGBM as a stand-alone therapy. QUESTION (Q4): In adult patients with pGBM does the use of tumor treating field (TTF) result in increased overall survival compared to chemotherapy? Level III: The use of TTF with other chemotherapy may be considered when treating adult patients with pGBM. There is insufficient evidence to recommend TTF to increase overall survival in adult patients with pGBM. QUESTION (Q5): In adult patients with pGBM does the use of oncolytic virotherapy result in increased survival compared to chemotherapy? Level III: Oncolytic virotherapy is not suggested in patients with pGBM.

Application of the Taguchi method to explore a robust condition of tumor-treating field treatment.

Tumor-treating fields have potential as minimally invasive cancer treatment. This study aimed to explore the optimum tumor-treating field conditions that minimize unpredicted variations in therapeutic outcomes resulting from differences in cell size and electrical properties. The electric field concentration that induces a dielectrophoretic force near the division plane of a mitotic cell was calculated by finite element analysis for 144 cases, based on different combinations of six noise factors associated with cells and four controllable factors including frequency, as determined by the Taguchi method. Changing the frequency from 200 to 400 kHz strongly increased robustness in producing a dielectrophoretic force, irrespective of noise factors. However, this frequency change reduced the force magnitude, which can be increased by simply applying a higher voltage. Based on additional simulations that considered this trade-off effect, a frequency of 300 kHz is recommended for a robust TTF treatment with allowable variations. The dielectrophoretic force was almost independent of the angle of applied electric field deviated from the most effective direction by ±20 degrees. Furthermore, increased robustness was observed for extracellular fluid with higher conductivity and permittivity. The Taguchi method was useful for identifying robust tumor-treating field therapy conditions from a considerably small number of replicated simulations.

Characteristics and trends of globally registered glioma clinical trials in the past 16 years.

Background:Advancement in the treatment of glioma has been vacant since temozolomide has proved its therapeutic value in glioblastoma in 2005.Aim:To help investigators understand the landscape of glioma clinical research, we analyzed the characteristics and trends of globally registered glioma trials in the past decades.Methods:This is a cross-sectional analysis of glioma trials registered on ClinicalTrials.gov between January 2006 and December 2021. Characteristics regarding phase, enrollment number, study design and type, funding source, tumor site, pathology, patient status, age of population, trial purpose, and participating country were abstracted, and chronological shifts were analyzed.Results:There were 1531 registered glioma trials involved 58 participating countries. The trial purpose concerning surgery, radiotherapy, chemotherapy, targeted therapy, tumor-treating fields, immunotherapy, other antiglioma therapy and non-antiglioma research trial accounts for 3.5%, 6.5%, 9.5%, 28.9%, 2.0%, 16.4%, 12.5%, and 20.6%, respectively. In the past 16 years, the numbers of chemotherapy and targeted therapy trials declined; tumor-treating fields and immune checkpoint inhibitor application trials sprang at the latter half period; Immunotherapy, other antiglioma therapy and non-antiglioma research trials escalated (all above ptrend < 0.005). The trend also showed the phased trials registered diminishingly and that the trials which focused on glioblastoma registered incrementally (those two ptrend < 0.05). Among 784 drug therapy trials, it was included 45 cytotoxic drugs, 186 targeted drugs, 19 immune checkpoint inhibitors, 78 other drugs, and five immunomodulatory drugs. Two trials belonged to Bayesian adaptive randomized design. By the end of December 2021, 309 trials had publications. Only everolimus and tumor-treating fields exhibited meaningful survival benefit in specific glioma patients in phase 3 trials.Conclusion:Meaningful effective treatments regarding drugs or methods for glioma were difficult to be found. Bayesian adaptive platform trials may accelerate clinical research in glioma. Development of novel treatment modalities for glioma is still challenged.

Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields.

BackgroundThe genomic and overall biologic landscape of glioblastoma (GB) has become clearer over the past 2 decades, as predictive and prognostic biomarkers of both de novo and transformed forms of GB have been identified. The oral chemotherapeutic agent temozolomide (TMZ) has been integral to standard-of-care treatment for nearly 2 decades. More recently, the use of non-pharmacologic interventions, such as application of alternating electric fields, called Tumor-Treating Fields (TTFields), has emerged as a complementary treatment option that increases overall survival (OS) in patients with newly diagnosed GB. The genomic factors associated with improved or lack of response to TTFields are unknown.MethodsWe performed comprehensive genomic analysis of GB tumors resected from 55 patients who went on to receive treatment using TTFields, and compared results to 57 patients who received standard treatment without TTFields.ResultsWe found that molecular driver alterations in NF1, and wild-type PIK3CA and epidermal growth factor receptor (EGFR), were associated with increased benefit from TTFields as measured by progression-free survival (PFS) and OS. There were no differences when stratified by TP53 status. When NF1, PIK3CA, and EGFR status were combined as a Molecular Survival Score, the combination of the 3 factors significantly correlated with improved OS and PFS in TTFields-treated patients compared to patients not treated with TTFields.ConclusionsThese results shed light on potential driver and passenger mutations in GB that can be validated as predictive biomarkers of response to TTFields treatment, and provide an objective and testable genomic-based approach to assessing response.

The Impact of Tumor Treating Fields on Glioblastoma Progression Patterns

Tumor-treating fields (TTFields) are an antimitotic treatment modality that interfere with glioblastoma (GBM) cell division and organelle assembly by delivering low-intensity, alternating electric fields to the tumor. A previous analysis from the pivotal EF-14 trial demonstrated a clear correlation between TTFields dose density at the tumor bed and survival in patients treated with TTFields. This study tests the hypothesis that the antimitotic effects of TTFields result in measurable changes in the location and patterns of progression of newly diagnosed GBM. Magnetic resonance images of 428 newly diagnosed GBM patients who participated in the pivotal EF-14 trial were reviewed, and the rates at which distant progression occurred in the TTFields treatment and control arm were compared. Realistic head models of 252 TTFields-treated patients were created, and TTFields intensity distributions were calculated using a finite element method. The TTFields dose was calculated within regions of the tumor bed and normal brain, and its relationship with progression was determined. Distant progression was frequently observed in the TTFields-treated arm, and distant lesions in the TTFields-treated arm appeared at greater distances from the primary lesion than in the control arm. Distant progression correlated with improved clinical outcome in the TTFields patients, with no such correlation observed in the controls. Areas of normal brain that remained normal were exposed to higher TTFields doses compared with normal brain that subsequently exhibited neoplastic progression. Additionally, the average dose to areas of the enhancing tumor that returned to normal was significantly higher than in the areas of the normal brain that progressed to enhancing tumor. There was a direct correlation between TTFields dose distribution and tumor response, confirming the therapeutic activity of TTFields and the rationale for optimizing array placement to maximize the TTFields dose in areas at highest risk of progression, as well as array layout adaptation after progression.

COT-7 Online supports for opening of the tumor treating field

Background: EF-14 trial showed the efficacy of tumor treating fields (TTF), and TTF was approved as a standard therapy for glioblastoma in Japan. In TTF opening, Device Support Specialist (DSS) explains how to use it for the patient and the family. Because there is no DSS in Yamaguchi prefecture, DSS has to come to our hospital across other prefectures. On the other hand, COVID-19 is still spreading and it is sometimes tough to move from a big city to countryside. Here, we would present the experiences of TTF opening with online DSS support. Method: From June 2020, Zoom was used for 4 patients, and from June 2021, iPad/Face-Time was used for one patient. TTF was introduced via online DSS support with direct support from our nurse in our out clinic. After that, initial times of TTF change were performed via online DSS support in patient’s home. Two patients who used Zoom had trouble to connect to internet, however finally completed with relative helps.Conclusion: Online medicine should be absolutely spreading in country sides. Now, we change from Zoom to iPad, because the old patients in country sides were hard to use internet utility. We should make efforts to provide patients more brief methods of online support.

PEDT-9 A study of NovoTTF-100A to expand the regulatory indication for childhood glioblastoma through a pediatric clinical trial based on the Advanced Medical Care system

Background: Tumor-treating fields (TTF) are alternating electric fields applied continuously to the brain by attaching 2-pair arrays on the scalp. Although TTF therapy has demonstrated efficacy against supratentorial glioblastoma (GBM) in adults, its safety and efficacy in children have not been confirmed. In Japan, off-label use of medical devices is almost impossible because the national health insurance system does not cover the cost of off-label use of drugs and medical devices. Therefore, TTF therapy cannot be applied to the treatment of pediatric GBM.[Objectives] The investigator-initiated clinical trial aims to expand regulatory approval of TTF therapy for pediatric GBM treatment based on safety and exploratory efficacy data. Methods: Patients aging between 5 and 17 years with histopathological diagnosis of GBM (either newly diagnosed or first-recurrence), which located in the supratentorial region would be included. All the patients will receive TTF therapy for 28 days per course for up to 26 courses until the end-of-therapy criteria are met. The primary endpoint is the adverse event rate with causality. The secondary endpoints include various time-to-event measures and QoL. In total ten patients will be enrolled. Current Status: Discussions with the Pharmaceuticals and Medical Devices Agency (PMDA) led to a tentative consensus that the accumulated data on the efficacy of NovoTTF-100A for adult GBM may be extrapolatable to pediatric GBM if the trial is able to demonstrate efficacy equivalent to that found in previous, adult studies. On the other hand, the combination of the pediatric safety data gathered in this trial and the findings of international studies, including clinical trials and post-marketing surveillance studies, may expedite approval of the device for pediatric GBM treatment. The trial started patient enrollment in April, 2021 with the supervision of the Advanced Medical Care administration system and is currently awaiting the first eligible patient.

QOLP-10. A LONGITUDINAL OBSERVATIONAL STUDY OF EXERCISE BEHAVIOR IN GLIOBLASTOMA PATIENTS TREATED WITH TUMOR-TREATING FIELDS

Abstract Glioblastoma (GBM) patients can use tumor-treating fields (TTFs) with adjuvant temozolomide (TMZ) to treat their disease. TTFs involve wearing transfixed transducers to the shaved scalp, and the transducers are wired to a battery pack that is either fixed or carried (weighing 2.7 pounds). EF-14 clinical trial did evaluate health-related quality of life with standardized patient-report outcome measures but did not measure exercise behavior. We sought to evaluate the exercise behavior of GBM patients using TTFs. We consented GBM patients who intended to use TTFs with adjuvant TMZ after completion of chemoradiation. After informed consent and before starting TTFs, patients completed a self-administered questionnaire, Godin Leisure-Time Exercise Questionnaire, to assess exercise behavior/physical function. To calculate our primary outcome of total exercise behavior, the frequency of exercise sessions per week within each intensity category was multiplied by the average reported duration, weighted by an estimate of the MET, summed across all intensities, and expressed as average MET-hr/wk. Prior work has defined that physical function can be compared as &amp;lt; 9 MET-h/wk vs. ≥ 9 MET-h/wk. We evaluated at baseline and up to 24-week exercise behavior in patients with TTFs vs. historical controls not using TTFs. We enrolled 19 total GBM patients, with 14 proceeding to use TTFs. Of the 14 patients on TTFs, seven patients (50%) completed ≥ 9 MET-h/wk of exercise, and this level was maintained 8, 16, and 24 weeks after starting TTFs. Six months after the completion of chemoradiation, mean MET-h/wk was decreased in the TTFs group (n=6) (10.71 sd=7.06) vs. historical controls (n=38) (27.35 sd=46.94). TTFs did not interfere with exercise behavior in our GBM cohort, but when compared to GBM patients not utilizing TTFs, there could be a long-term impact on exercise behavior. More research is needed to evaluate exercise behavior in GBM patients using TTFs.

CTNI-44. DOSIMETRIC IMPACT OF TUMOR TREATING FIELDS ON CONCURRENT RADIATION THERAPY FOR PEDIATRIC BRAIN TUMORS

Abstract INTRODUCTION Early results suggest that tumor treating fields (TTF) concurrent with radiotherapy (RT) for glioblastoma yields acceptable dosimetry in adults; the impact on RT dose distribution in children is unknown. This study was undertaken to evaluate the dosimetric impact of TTF on concurrent photon RT for children with brain tumors. METHODS CT scans of an anthropomorphic pediatric head phantom (approximately 15-year-old) and an infant-head-sized spherical phantom were acquired with and without TTF attached. For each phantom, simulated supratentorial tumor targets were initially contoured on CT datasets acquired without TTF attached. Treatment plans using volumetric modulated arc therapy were created to deliver 60Gy and 50Gy to the gross tumor volume (GTV) and clinical tumor volume (CTV), respectively, in 30 fractions. The dose distributions of the same treatment plans were then re-computed with TTF attached. Target coverage metrics were compared between dose distributions with and without TTF. To measure skin dose, treatment plans were delivered with thermoluminescent dosimeters placed on the phantoms at various locations, with and without TTF attached. RESULTS The presence of TTF slightly reduced target coverage. For the two phantoms studied, D95 of the CTV was reduced by 0.65% and 1.03%, and D95 of the GTV was reduced by 0.7% and 1.05%, respectively. Electrodes under the direct beam path increased skin dose by an average of 43.3% (0.3Gy – 20.7Gy), but all skin dose measurements stayed within tolerances. TTF electrodes out of the RT field did not cause an increase in measured dose. CONCLUSIONS The dosimetric impact of TTF on pediatric head phantoms receiving concurrent RT resembles that reported in adult studies. Although the tumor dose is not significantly affected, the skin dose notably increases due to the bolus effect from the TTF electrodes, which may be mitigated by skin-sparing planning and shifting of the device during RT.

NIMG-30. PATHOLOGICAL VALIDATION OF CONTRAST ENHANCEMENT AT AUTOPSY BETWEEN PATIENTS TREATED AND UNTREATED WITH CHEMOTHERAPY AND RADIATION

Abstract Tumor heterogeneity in glioblastoma complicates delineation of active tumor using standard MR imaging. Pseudo-progression following treatment with chemotherapy and radiation (chemoRT) further complicates how tumors appear. T1-weighted subtraction maps (T1S) have been used to better identify subtly enhancing regions containing infiltrative tumor. This study examines the differences in tumor appearance between patients treated with chemoRT compared to a cohort opting out at autopsy, to understand how chemoRT changes contrast enhancement on MRI. Ten patients diagnosed with glioblastoma were recruited for whole brain donation for this study. Three patients received no treatment (chemoRT-), and seven received a combination of chemoRT and additional treatments (chemoRT+), including but not limited to bevacizumab (Bev) and tumor treating fields (TTF). Large tissue samples were taken at autopsy from whole brain samples sliced axially to align with the last clinical MRI using patient-specific 3D-printed slicing jigs. All tissue samples were hematoxylin and eosin (HE) stained and digitized at 40X resolution (27 total samples). The whole slide images (WSI) were annotated to outline regions containing necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor. T1S were created for each patient by subtracting intensity normalized T1-weighted images from T1 post-contrast images (T1C). The annotated WSIs were aligned and resampled into MRI space using a custom software. A mixed effect model was used to compare the T1S intensity between chemoRT +/- cohorts within each pathological annotation, incorporating a random effect for subject. Mean T1S intensity was greater in untreated subjects when compared to chemoRT-subjects within each pathological annotation, including necrosis without pseudopalisading cells, tumor with pseudopalisading necrosis, and infiltrative tumor (p&amp;lt; 0.001). We show that chemoRT reduces the contrast enhancement in all aspects of pathologically validated tumor compartments, including infiltrative tumor. Future research is needed to examine if other patterns are evident in additional MR sequences.

EXTH-47. SAFETY AND EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION ON GLIOBLASTOMA MEASURED IN VITRO

Abstract BACKGROUND Although gross total resection (GTR) with chemoradiation is the standard of care for treating glioblastoma (GBM), tumor infiltration and treatment sequelae can impair activity of eloquent regions. Transcranial magnetic stimulation (TMS) has been explored as an adjunct therapy to rehabilitation for post-stroke motor deficits. TMS could be effective for postoperative rehabilitation in GBM, but its effect on GBM cells has not been evaluated. While TMS utilizes magnetic fields to induce electrical currents at low frequencies to cause neuronal excitation or inhibition, tumor-treating fields (TTF) utilize electrical currents with intermediate frequency to exert anti-mitotic effects, demonstrating promise as an adjunctive therapy in recurrent GBM. Although similarities exist between electrical and magnetic fields, the effects of magnetically induced electrical currents at low frequencies via TMS must be studied systematically in vitro on GBM cell lines. METHODS We studied the effect of theta burst stimulation (TBS), a form of patterned TMS, on in vitro G55 cell viability using colony forming assays. We compared TMS-treated cells to controls using a combination of parameters: continuous versus intermittent TBS (cTBS and iTBS), 300 versus 600 pulses, stimulation intensity of 32% versus 60%, and no pre-TMS chemotherapy versus 100 nM or 100 µM temozolomide (TMZ). Viability measurements between controls and TMS were analyzed using analysis of variance (ANOVA). Independent t-tests were used to analyze effects of stimulation parameters on viability percent difference within each TMZ condition. RESULTS There was no statistically significant increase in viability between control and TMS conditions for any of the stimulation parameters (+/- TMZ) while some showed decreased viability of GBM cells. CONCLUSIONS TMS did not significantly increase GBM viability compared to controls. Future studies include validation in other cell lines and characterization of the effects of stimulation parameters in conjunction with TMZ and dexamethasone, (often administered concurrently with GBM treatment).

CTIM-33. PHASE II TRIAL OF VACCINE IMMUNOTHERAPY IN PRIMARY GLIOBLASTOMA: ADJUNCTIVE AUTOLOGOUS DENDRITIC CELLS PULSED WITH LYSATE FROM IRRADIATED SELF-RENEWING AUTOLOGOUS TUMOR CELLS (AV-GBM-1)

Abstract In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age &amp;lt; 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS &amp;gt; 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development. Clinicaltrials.gov NCT03400917.

CTNI-38. PriCoTTF TRIAL: A PHASE I/II TRIAL OF TTFIELDS PRIOR AND CONCOMITANT TO RADIOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA

Abstract TTFields therapy is applied at 200 kHz by arrays that are placed at the patients’ scalp. In the phase 3 EF-14 trial, survival rates were significantly improved when adding tumor-treating fields (TTFields) to adjuvant temozolomide-based chemotherapy in patients with newly diagnosed glioblastoma (nGBM). Preclinical studies showed that combination of TTFields and radiotherapy synergistically impaired glioblastoma cell growth. Here, we present the PriCoTTF trial, which is enrolling nGBM patients and will assess the safety and efficacy of TTFields initiated prior and concomitant to radiochemotherapy. Following surgery and wound-healing, TTFields therapy is initiated in adult nGBM patients. TTFields therapy continues throughout radiochemotherapy and adjuvant chemotherapy for a total of approximately 9 months. During radiotherapy, the arrays - through which TTFields is delivered - remain on the patients’ scalp. Totally, thirty-three patients are planned to be enrolled in two treatment arms. In arm A, 20 patients receive normo-fractionated radiotherapy, whereas in the elderly arm, arm B, 13 patients receive hypo-fractionated radiotherapy. The primary endpoint of this trial is safety and tolerance that will be gauged by a set of pre-specified treatment-limiting toxicities. Secondary endpoints include the frequency of adverse events, progression-free survival (PFS), and overall survival (OS). The trial is currently enrolling patients at four sites in Germany. At the time of abstract submission, 9 patients enrolled in Arm B. Patient recruitment for arm A has been completed with. We will present initial practical experiences as well as preliminary safety and tolerance data. There is a biological rationale for combining TTFields and radiotherapy to further improve survival of GBM patients. In the presented phase I/II trial, the safety and efficacy of TTFields initiated prior and concomitant to RT in nGBM will be assessed. In addition, initial efficacy data (phase II) may serve as a rationale for a putative randomized phase III trial.