Tumor Treating Fields Therapy Research Articles

10P Efficacy of tumor treating field therapy alone and in combination with doxorubicin in cellular model of breast cancer

Background Tumor treating fields (TTFs) are alternating fields with low intensity and intermediate frequency, that are used as a novel treatment for cancer therapy. TT Fields lead to disruption in mitotic process and inhibit the proliferation of cancer cells. In the present study the effect of TTF therapy in cellular model of breast cancer is investigated. For this goal TTFields alone and in combination with doxorubicin as a chemical drug were examined. Methods MDA-MB-231 human breast cancer cells was exposed to TT Fields for a duration of30hours.TTFields also applied when cells were treated with doxorubicin in IC10 dose. The cells proliferation ratio was assessed after 72h. Results Treatment with tumor treating fields inhibits the proliferation of cancer cells significantly. The optimal frequency that caused the most inhibitory effect was determinedtobe150kHz.CombinationofTTFtherapywithusingofoptimalfrequency and treatment with doxorubicin in IC10 dose led to further decrease in proliferation, compared to TTF therapyalone. Moreover, the sensitivity to chemotherapeutic agent was increased by the aid of TT Fields. Conclusions These findings demonstrated that TT Fields contain efficiency to arrest cancer cells proliferation. These results also show that TT Fields can support chemical drug efficiency. Our studies indicate that, using TT Fco-administrated with doxorubicin can be used as an alternative strategy for cancer therapy in breast cancer cases to improve the effects of the drugs and increase the sensitivity of cancer cells. Legal entity responsible for the study Ministry of Science, Research and Technology Tehran University Funding Biology Department of Tehran University Disclosure All authors have declared no conflicts of interest.

NIMG-37. IMAGING THE EARLY METABOLIC RESPONSE DURING TUMOR-TREATING FIELDS THERAPY IN RECURRENT GLIOBLASTOMA

Tumor-treating fields (TTF) therapy is an innovative treatment approach for newly diagnosed and recurrent glioblastoma. In this study we evaluated whether positron emission tomography with alpha[11C]-methyl-L-tryptophan (AMT-PET) would detect early metabolic responses during the first 3 months of TTF therapy. Five patients with MRI-detected recurrent glioblastoma being treated with temozolomide underwent AMT-PET scanning prior to delivery of TTF. Four of the 5 patients had >75% compliance with the device and underwent a repeat PET scan 1.5 to 3 months later. Interval changes of tumoral tryptophan uptake and PET-based tumor volumes (based on a previously defined threshold) were measured and compared to changes in MRI enhancement. Three patients showed an early metabolic response reflected by interval decrease of tumoral tryptophan uptake and PET-based tumor volumes during the follow-up period. Patients #1 and #2 who received TTF therapy in addition to maintenance temozolomide showed a ≥25% decrease of PET-based tumor volumes 1.5 and 3 months later, respectively, followed by a delayed MRI response 2 months after the second PET scan. In the other two patients, TTF therapy was combined with bevacizumab. Patient #3 showed markedly decreased tumoral AMT uptake and reduced PET-based tumor volume, along with stable MRI contrast enhancement after 3 months, which continued for 3 additional months before progression. Patient #4, with a much larger baseline tumor volume than the other three patients, showed an increase in the PET-based tumor volume during a 2-month follow-up. MRI showed a steady increase in the volume of contrast enhancement both during and after the AMT-PET follow-up period. These preliminary data demonstrate an early metabolic response to TTF therapy in 3 out of 4 the patients with recurrent glioblastoma who maintained good compliance with the device. This metabolic response seems to precede a subsequent MRI response.

Enhancing Predicted Efficacy of Tumor Treating Fields Therapy of Glioblastoma Using Targeted Surgical Craniectomy: A Computer Modeling Study.

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.

Efficacy and Safety of Treating Glioblastoma With Tumor-Treating Fields Therapy.

Glioblastoma (GBM) is a highly aggressive astrocytoma with a dismal prognosis. Since 1976, only three chemotherapeutic agents have been approved for the treatment of GBM. Tumor-treating fields (TTFields) therapy, delivered via a noninvasive device, is a new therapy approved for use in patients with recurrent GBM and in combination with temozolomide for the treatment of newly diagnosed GBM. This article reviews the mechanism of action and findings from preclinical and clinical studies supporting the use of TTFields for patients with newly diagnosed and recurrent GBM. This article provides an overview of published literature on the efficacy and safety of treating GBM with TTFields. For the first time in more than a decade, patients with GBM have a noninvasive treatment option that has been shown to increase progression-free survival and overall survival with minimal adverse events.

The cost-effectiveness of tumor-treating fields therapy in patients with newly diagnosed glioblastoma.

There is strong concern about the costs associated with adding tumor-treating fields (TTF) therapy to standard first-line treatment for glioblastoma (GBM). Hence, we aimed to determine the cost-effectiveness of TTF therapy for the treatment of newly diagnosed patients with GBM. We developed a 3-health-state Markov model. The perspective was that of the French Health Insurance, and the horizon was lifetime. We calculated the transition probabilities from the survival parameters reported in the EF-14 trial. The main outcome measure was incremental effectiveness expressed as life-years gained (LYG). Input costs were derived from the literature. We calculated the incremental cost-effectiveness ratio (ICER) expressed as cost/LYG. We used 1-way deterministic and probabilistic sensitivity analysis to evaluate the model uncertainty. In the base-case analysis, adding TTF therapy to standard of care resulted in increases of life expectancy of 4.08 months (0.34 LYG) and €185 476 per patient. The ICER was €549 909/LYG. The discounted ICER was €596 411/LYG. Parameters with the most influence on ICER were the cost of TTF therapy, followed equally by overall survival and progression-free survival in both arms. The probabilistic sensitivity analysis showed a 95% confidence interval of the ICER of €447 017/LYG to €745 805/LYG with 0% chance to be cost-effective at a threshold of €100 000/LYG. The ICER of TTF therapy at first-line treatment is far beyond conventional thresholds due to the prohibitive announced cost of the device. Strong price regulation by health authorities could make this technology more affordable and consequently accessible to patients.

Sensitivity Analysis of Permittivity and Conductivity on Tumor Treating Fields Therapy for Recurrent Glioblastoma (P6.302)

Sensitivity Analysis of Permittivity and Conductivity on Tumor Treating Fields Therapy for Recurrent Glioblastoma (P6.302)

Tumor treating field therapy in combination with bevacizumab for the treatment of recurrent glioblastoma.

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1.Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians’ choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10.There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

Tumor Treating Field Therapy in Combination with Bevacizumab for the Treatment of Recurrent Glioblastoma

A novel device that employs TTF therapy has recently been developed and is currently in use for the treatment of recurrent glioblastoma (rGBM). It was FDA approved in April 2011 for the treatment of patients 22 years or older with rGBM. The device delivers alternating electric fields and is programmed to ensure maximal tumor cell kill1. Glioblastoma is the most common type of glioma and has an estimated incidence of approximately 10,000 new cases per year in the United States alone2. This tumor is particularly resistant to treatment and is uniformly fatal especially in the recurrent setting3-5. Prior to the approval of the TTF System, the only FDA approved treatment for rGBM was bevacizumab6. Bevacizumab is a humanized monoclonal antibody targeted against the vascular endothelial growth factor (VEGF) protein that drives tumor angiogenesis7. By blocking the VEGF pathway, bevacizumab can result in a significant radiographic response (pseudoresponse), improve progression free survival and reduce corticosteroid requirements in rGBM patients8,9. Bevacizumab however failed to prolong overall survival in a recent phase III trial26. A pivotal phase III trial (EF-11) demonstrated comparable overall survival between physicians’ choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm10. There is currently an unmet need to develop novel approaches designed to prolong overall survival and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the two currently approved treatment modalities namely bevacizumab and TTF Therapy. These two treatments are currently approved as monotherapy11,12, but their combination has never been evaluated in a clinical trial. We have developed an approach for combining those two treatment modalities and treated 2 rGBM patients. Here we describe a detailed methodology outlining this novel treatment protocol and present representative data from one of the treated patients.

Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.

1214 - A Phase II Clinical Trial of Tumor Treating Field (TTF) Therapy Concomitant to Pemetrexed for Advanced Non-Small Cell (NSCLC) Lung Cancer

ABSTRACT Background TTF therapy is a novel, non-invasive treatment modality for solid tumors recently approved by FDA for recurrent GBM. It uses intermediate frequency alternating electric fields to inhibit tumor growth, by mitotic spindle and plasma membrane integrity disruption during cytokinesis. Pemetrexed is a folate antimetabolite used as a first/second line and as a maintenance therapy for non-squamous NSCLC patients. Preclinical studies in NSCLC models demonstrated that TTF therapy and pemetrexed had additive efficacy, with no increase in toxicity. The current trial tested TTF therapy concomitant to pemetrexed in NSCLC patients. Methods A single arm, multi-center, prospective trial was performed in 42 stage IIIB (with pleural effusion) and IV NSCLC patients, following progression after at least one prior chemotherapy. Patients received continuous 150 KHz TTF therapy (12 h/day) using the NovoTTF-100L system (NovoCure, Israel), concomitant to pemetrexed (Alimta™, Eli Lilly) q3w, until progression. Pemetrexed was in use for squamous histology when the study opened. Results The trial included 35 patients with non-squamous histology and 7 patients with squamous histology. TTF Therapy was well tolerated by all patients enrolled in the trial, with high compliance (11 h/day). No TTF-related adverse events were reported apart from dermatitis caused by the application of transducer arrays. Median progression free survival was 22.7 and 10.3 weeks for non-squamous and squamous histology, respectively. Seven patients who initially had in-field-only disease (including squamous histology) had distant metastases before progressing in-field. Median overall survival was 12.4 and 13.8 months for nonsquamous and squamous histology, respectively. One- and two- year-survival was 53% and 27%, respectively. Conclusions TTF therapy concomitant to pemetrexed was well tolerated and safe for patients with advanced NSCLC, of all histologies. Efficacy indices are promising, in view of the poor outcome previously reported for similar populations. This first clinical trial involving TTF as a treatment for NSCLC patients suggests that it should be further studied in larger clinical trials for squamous and nonsquamous NSCLC Disclosure M. Salzberg: Medpace Inc. is a contracted Contract Research Organization (CRO) for Novocure Ltd. All other authors have declared no conflicts of interest.

Noninvasive Application of Alternating Electric Fields in Glioblastoma: A Fourth Cancer Treatment Modality

Tumor treating fields (TTF) therapy is a novel antimitotic, electric field-based treatment for cancer. This nonchemical, nonablative treatment is unlike any of the established cancer treatment modalities, such as surgery, radiation, and chemotherapy. Recently, it has entered clinical use after a decade of intensive translational research. TTF therapy is delivered to patients by a portable, battery-operated, medical device using noninvasive transducer arrays placed on the skin surface surrounding the treated tumor. TTF therapy is now a U.S. Food and Drug Administration (FDA)-approved treatment for patients with recurrent glioblastoma (GBM) who have exhausted surgical and radiation treatments. This article will introduce the basic science behind TTF therapy, its mechanism of action, the preclinical findings that led to its clinical testing, and the clinical safety and efficacy data available to date, as well as offer future research directions on this novel treatment modality for cancer.