Electric Tumor Treatment Fields

Number: 0827

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Table Of Contents

Policy Applicable CPT / HCPCS / ICD-10 Codes Background References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses electric tumor treatment fields.

  1. Medical Necessity

    Aetna considers interventions for electric tumor treatment fields (ETTF) medically necessary when all of the following selection criteria are met:

    1. The member has histologically confirmed (World Health Organization (WHO) grade IV astrocytoma), newly diagnosed, supratentorial glioblastoma; and
    2. The member has received initial treatment with maximal debulking surgery (when feasible), followed by chemotherapy and radiotherapy; and
    3. Tumor treatment field therapy is initiated within 7 weeks from the last dose of concomitant chemotherapy or radiotherapy, whichever is later; and
    4. The member has no evidence of progression by Response Assessment in Neuro-Oncology (RANO) criteria; and
    5. The member has a Karnofsky Performance Score (KPS) of at least 70; and
    6. The member will use tumor treatment field therapy (TTFT) for an average of 18 hours per day; and
    7. The member is 22 years of age or older; and
    8. Confirmation of non-pregnant status for women of child-bearing age; and
    9. Absence of intracranial shunt or other implanted intracranial device.

    Note: Continued coverage of tumor treatment field therapy (TTFT) (E0766) beyond the first 3 months of therapy requires that no sooner than the 60th day but no later than the 91st day after initiating therapy, the treating practitioner must conduct a clinical re-evaluation and document that the beneficiary is continuing to use and is benefiting from TTFT.

    Documentation of clinical benefit is demonstrated by:

    1. In-person clinical re-evaluation by the treating practitioner; and
    2. Objective evidence of adherence to therapy, reviewed by the treating practitioner.

    Adherence to therapy is defined as the use of TTFT for an average of 18 hours per day (excluding days the treating practitioner has documented a medical need to limit or interrupt treatment).

  2. Experimental, Investigational, or Unproven

    Aetna considers the following devices and interventions for ETTF experimental, investigational, or unproven because the effectiveness of these approaches has not been established:

    1. Devices to generate ETTF for the treatment of other malignant tumors (e.g., breast, lung, melanoma, osteosarcoma, ovarian cancer, pleural mesothelioma, pancreatic cancer, salivary gland tumors (e.g., parotid adenoid cystic carcinoma), and solid tumor brain metastases; not an all-inclusive list) and for all other indications;
    2. Combined ETTF therapy and chemo-immuno-therapy other than temozolomide (e.g., 6-thioguanine, bevacizumab, capecitabine, celecoxib, cisplatin, cyclophosphamide, dacarbazine, doxorubicin, lomustine, paclitaxel, pemetrexed, and zinc oxide nanoparticles; not an all-inclusive list) for the treatment of other malignant tumors (including breast cancer, colorectal cancer, and hepatocellular cancer).

Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code Code Description

Information in the [brackets] below has been added for clarification purposes. &nbspCodes requiring a 7th character are represented by “+”:

HCPCS codes covered if selection criteria are met:

A4555 Electrode/transducer for use with electrical stimulation device used for cancer treatment, replacement only E0766 Electrical stimulation device used for cancer treatment, includes all accessories, any type J8700 Temozolomide, oral, 5 mg J9328 Injection, temozolomide, 1 mg

HCPCS codes not covered for indications listed in the CPB:

Zinc oxide nanoparticles – no specific code

ICD-10 codes covered if selection criteria are met:

C71.0 – C71.9 Malignant neoplasm of brain [supratentorial glioblastomas (WHO grade IV astrocytomas)]

ICD-10 codes not covered for indications listed in the CPB (not all inclusive):

C08.0 – C08.9 Malignant neoplasm of other and unspecified major salivary glands C11.0 – C11.9 Malignant neoplasm of nasopharynx C15.3 – C15.9 Malignant neoplasm of esophagus C16.0 – C16.9 Malignant neoplasm of stomach C18.0 – C18.9 Malignant neoplasm of colon C19 – C21.8 Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal C22.0 Liver cell carcinoma C22.1 Intrahepatic bile duct carcinoma C23 – C24.9 Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract C25.0 – C25.9 Malignant neoplasm of pancreas C31.0 – C31.9 Malignant neoplasm of accessory sinuses (paranasal) C33 – C34.92 Malignant neoplasm trachea, bronchus, and lung C37 Malignant neoplasm of thymus C41.0 – C41.9 Malignant neoplasm of bone and articular cartilage of other and unspecified sites C43.0 – C43.9 Malignant neoplasm of skin C45.0 Mesothelioma of pleura C46.1 Kaposi’s sarcoma of soft tissue C49.0 – C49.9 Malignant neoplasm of peripheral nerves, autonomic nervous system and other connective and soft tissue C50.011 – C50.929 Malignant neoplasm of breast C53.0 – C53.9 Malignant neoplasm of cervix uteri C54.0 – C54.9 Malignant neoplasm of corpus uteri C56.1 – C56.9 Malignant neoplasm of ovary C57.00 – C57.02 Malignant neoplasm of fallopian tube C61 Malignant neoplasm of prostate C64.1 – C66.9C68.0 – C68.9 Malignant neoplasm of kidney and other and unspecified urinary organs C73 Malignant neoplasm of thyroid gland C79.31 Secondary malignant neoplasm of brain [solid tumor brain metastases] D00.00 – D09.9 Carcinoma in situ D11.0 – D11.9 Benign neoplasm of major salivary glands

Background

Electric tumor treating fields (ETTF), also known as alternating electrical field therapy, are low-intensity (1 to 2 V/cm), intermediate-frequency (100 to 200 kHz), alternating electric fields employed for the treatment of malignant tumors. ETTFs are delivered to a malignant tumor site via insulated electrodes placed around the region of the body containing the tumor. This novel treatment modality has been shown to be effective for glioblastoma (GBM) shown promise in pilot clinical trials in patients with other advanced stage solid tumors.

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Kirson et al (2007) reported the findings of a pilot clinical trial examining the effects of ETTF in 10 patients with recurrent GBM. Median time to progression (TTP) in these patients was 26.1 weeks and median overall survival (OS) was 62.2 weeks. The authors noted that these TTP and OS values were more than double the reported medians of historical control patients. No device-related serious adverse events (AEs) were seen after more than 70 months of cumulative treatment in all of the patients. The only device-related AE observed was a mild-to-moderate contact dermatitis beneath the field delivering electrodes. The authors concluded that ETTF are a safe and effective new treatment modality that effectively slows down tumor growth in-vitro, in-vivo, as well as in human cancer patients.

In a pilot study, Salzberg and colleagues (2008) evaluated the safety, tolerability, and effectiveness of ETTF treatment in patients with locally advanced or metastatic solid tumors using the NovoTTF-100A device. A total of 6 patients were heavily pre-treated with several lines of therapy; no additional standard treatment option was available to them. Electric tumor treating fields treatment using continuous NovoTTF-100A lasted a minimum of 14 days and was well-tolerated. No related serious AEs occurred. Outcomes showed 1 partial response of a treated skin metastasis from a primary breast cancer, 3 cases where tumor growth was arrested during treatment, and 1 case of disease progression. One mesothelioma patient experienced lesion regression near ETTF with simultaneous tumor stability or progression in distal areas. The authors concluded that although the number of patients in this study was small, the lack of therapy toxicity and the effectiveness observed in data gathered to date indicate the potential of ETTF as a new treatment modality for solid tumors, thus, warranting further investigation.

On April 15, 2011, the Food and Drug Administration (FDA) approved the NovoTTF-100A System (Novocure, Portsmouth, NH) for the treatment of adults with GBM that recurs or progresses after receiving chemotherapy and radiation therapy. The NovoTTF-100A System is not intended to be used in combination with other cancer treatments. It should only be used after other treatments have failed. The FDA-approved indication for use is: “The NovoTTF-100A System is intended as treatment for adult patients (22 years of age or older) with histologically confirmed glioblastoma multiforme (GBM), following histologically or radiologically confirmed recurrence in the supra-tentorial region of the brain after receiving chemotherapy. The device is intended to be used as a monotherapy, and is intended as an alternative to standard medical therapy for GBM after surgical and radiation options have been exhausted.”

The approval was based on data presented to the FDA from a multi-national, randomized, controlled study. The expedited pre-market approval (PMA) includes a requirement for a post-market non-randomized, unblinded, concurrent control study of NovoTTF-100A in patients with recurrent GBM. The primary question to be addressed by the study (FDA, 2011): “Is the overall survival of patients treated with NovoTTF-100A non-inferior to the survival of patients treated with the best standard of care (chemotherapy)”?

The first randomized clinical study of ETTF did not reach its primary end-point of improved survival compared to active chemotherapy (Stupp et al, 2012; Novocure, 2012). This study was funded and sponsored by the device manufacturer, Novocure, Ltd. Subjects for this study were age 18 years or older with histologically confirmed glioblastoma (World Health Organization grade IV astrocytoma) with radiologically confirmed disease progression. Patients had a Karnofsky performance status greater than or equal to 70 %, and adequate hematologic, renal and hepatic function (absolute neutrophil count greater than or equal to 1,000/mm3, hemoglobin greater than or equal to 100 g/L, platelet count greater than or equal to 100,000/mm3, serum creatinine level less than or equal to 1.7 mg/dL, total serum bilirubin less than or equal to the upper limit of normal, and liver function values less than 3 times the upper limit of normal. Prior therapy must have included radiotherapy (with and without concomitant and/or adjuvant temozolomide). Patients with infra-tentorial tumor location were excluded, as were patients with implanted electronic medical devices (e.g. pacemaker, programmable ventriculo-peritoneal shunt). Patients were randomized in a 1:1 ratio to receive either NovoTTF-100A without chemotherapy or the physician’s choice of active chemotherapy (active control). Chemotherapy agents considered as best standard of care (BSC) during the study included platinum-based chemotherapy (i.e., carboplatin); nitrosureas; procarbazine; combination of procarbazine, lomustine and vincristine; temozolomide; and bevacizumab. For patients assigned to Novo-TTF, uninterrupted treatment was recommended, although patients were allowed to take treatment breaks of up to 1 hour, twice per day, for personal needs (e.g., shower). In addition, patients assigned to Novo-TTF were allowed to take 2 to 3 days off treatment at the end of each of 4 week (which is the minimal required treatment duration for TTF therapy to reverse tumor growth). A period of 28 days of treatment with ETTF was considered 1 full treatment course. The primary end-point of the study was OS. Secondary end-points included PFS rates at 6-months; median time to progression (TTP), 1-year survival rate; quality-of-life; and radiological response. Subjects were seen in clinic monthly, and magnetic resonance imaging (MRI) was performed after 2, 4 and 6 months from initiation of treatment and subsequent MRIs were done according to local practice until disease progression. Medical follow-up continued for 2 months after disease progression. Monthly telephone interviews with the subjects’ caregivers were used to evaluate subject mortality rates. A total of 28 clinical centers enrolled 237 adult subjects with 120 subjects randomized to the NovoTTF treatment group and 117 subjects randomized to the BSC group. A total of 30 subjects never started on trial (4 in the treatment group and 26 in the BSC group); 207 subjects started on trial, with 79 % discontinuation rate (n = 47 deaths; n = 49 deterioration of condition; and n = 68 study requirements of 2 additional clinic visits after disease progression were completed). Consent was withdrawn before completing 2 months of post-progression follow-up in 20 subjects. Adverse events led to 20 additional subject withdrawals. Non-compliance with follow-up was attributed to 3 subjects. The proportions were similar between the NovoTTF-100A group and the BSC group of subjects who did not complete the protocol-defined follow-up due to withdrawal of consent, non-compliance, or AEs. An average of 4.2 months of TTF treatment per subject was completed for the 116 subjects in the active treatment cohort. Complete vital statistics were known for 93 % (221 subjects) at the end of the study. There were 202 known deaths and 19 subjects (ETTF = 9; BSC = 10) were still alive 6 months after the last subject was randomized; 16 (7 %) subjects were lost to follow-up.

The trial did not reach its primary end-point of improved survival compared to active chemotherapy (Stupp et al, 20112; Novocure, 2012). In addition, differences in response rates, PFS at 6 months, and reduction in risk of death were not statistically significant. Quality of life analyses favored ETTF therapy in most domains. The differences in median OS between patients in the NovoTTF-100A group and the BSC group were not statistically significant. According to the FDA, the median OS is 6.3 months (95 % confidence interval [CI]: 5.6 to 7.8) in the NovoTTF-100A group and 6.4 months (95 % CI: 5.2 to 7.4) in the BSC group (log rank p = 0.98; Wilcoxon p = 0.72). The hazard ratio (HR) is 1.0 (95 % CI: 0.76 to 1.32) (test for proportional hazards p = 0.45). In the active chemotherapy control arm of the trial, survival was not significantly affected by the choice of chemotherapy. The Kaplan-Meier survival curve for the 2 treatment groups appeared to be very similar during the first 12 months of follow-up. Between 12 and 24 months, the survival curves separated slightly in favor or the BSC control group. There were no statistically significant differences in secondary end-points of 1-year survival, PFS, radiologic response rates, and median TTP. Mild-to-moderate (grade 1 and 2) contact dermatitis on the scalp beneath the transducer arrays occurred in 16 % of ETTF patients. Patients receiving active control chemotherapy experienced toxicity related to pharmacologic mechanism of the agents used: gastrointestinal (30 % versus 8 %), hematological (19 % versus 4 %) and infectious (12 % versus 4 %). Longitudinal Quality of Life (QOL) was available in only 27 % of subjects (63 patients) who remained on study therapy for 3 months and for whom QOL data were available. In the domains of global health and social functioning, no meaningful differences between chemotherapy and ETTF were observed. However, cognitive, emotional, and role functioning favored ETTF, whereas physical functioning favored chemotherapy. Symptom scale analysis is in accordance to treatment-associated toxicity; appetite loss, diarrhea, constipation, nausea and vomiting were directly related to the chemotherapy administration. Increased pain and fatigue was reported in the chemotherapy-treated patients and not in the ETTF treatment group.

Commenting on the trial by Stupp et al, Debonis et al (2012) stated that the study was designed for superiority; although well conducted, it might not have shown it for a limited compliance in the ETTF group. Debonis et al (2012) stated that, even with this limitation, the trial by Stupp et al has shown at least equivalence of ETTF to chemotherapy, with a decreased toxicity and increased quality of life favoring ETTF.

The manufacturer initiated a subsequent randomized clinical trial enrolling newly diagnosed glioblastoma patients after completion of standard radiochemotherapy, parallel to starting the adjuvant or maintenance temozolomide chemotherapy (Stupp et al, 2012). Patients randomized to the experimental arm received ETTF in addition to maintenance temozolomide. In an abstract, Stupp et al (2014) reported on an interim analysis of this international, multi-center, prospective, randomized phase III trial in newly diagnosed GBM patients. After completion of radiotherapy (RT) with concomitant temozolomide (TMZ), patients were randomized (2:1) to adjuvant TMZ with NovoTTF or adjuvant TMZ alone. The primary end-point was PFS, with OS an important secondary end-point. Analysis was by intention-to-treat. The investigators reported on a pre-specified interim analysis of the first 315 patients randomized, after a minimum follow-up of 18 months (range of 18 to 60 months). Investigators randomized 210 patients NovoTTF/TMZ and 105 to TMZ alone. Patient characteristics were balanced: median age of 57 and 58 years, tumor resection in 89 and 90 %, Karnofsky Performance Score (KPS) 90 %, for the NovoTTF and the control arms, respectively. MGMT promoter methylation status was assessable centrally in 60 % of patients; of these 39 % and 41 % were methylated. Adverse events (AE) were comparable between treatment arms. The most common device-related AE was skin irritation in 45 % of patients (all grades, severe 2 %). Severe seizures were observed at a frequency of 7 % in both arms. Median PFS was 7.1 months [mo] (95 % CI: 5.9 to 8.2) and 4.0 mo (CI: 3.0 to 4.3; HR 0.63, p = 0.001), OS was 19.6 mo (CI: 16.5 to 24.1) and 16.6 mo (CI: 13.5 to 19.1) (HR 0.75, p = 0.034), both favoring NovoTTF. This translated into a 24-mo survival rate of 43 % (CI: 36 to 50 %) and 29 % (CI: 21 to 39 %) for the NovoTFF/TMZ and the TMZ alone arm, respectively. The investigators stated that the trial met its primary and main secondary end-points, and was closed to accrual after this interim analysis. The investigators concluded that adjuvant TMZ chemotherapy and NovoTTF provided a clinically and statistically significant improvement in PFS and OS, and should become the new standard of care against GBM.

The National Comprehensive Cancer Network (NCCN, 2013) had a Category 2B recommendation to consider the use of ETTF for persons with local, diffuse or multiple recurrences of glioblastoma. This was changed to a Category 3 recommendation in 2014 (NCCN, 2014). NCCN guidelines explain that approval of tumor treating fields (TTF) for recurrent glioblastoma was based on results of a clinical trial that randomized 237 patients to TTF or chemotherapy. Similar survival was observed in the 2 arms, and TTF therapy was associated with lower toxicity and improved quality of life. Due to the lack of efficacy, not all NCCN panelists recommended the treatment. This was subsequently changed to a category 2B recommendation in 2015 (NCCN, 2015).

Medicare Durable Medical Equipment Medicare Administrative Contractor (DME MAC) considers tumor treatment field therapy not reasonable and necessary for Medicare beneficiaries (NHIC, 2014).

On October 5, 2015, the FDA approved an expanded indication for the Optune device (using alternating electrical fields called “tumor treatment fields” [TTFields]) to treat patients with newly-diagnosed GBM. It is administered along with temozolomide (TMZ) following standard treatments that include surgery, chemotherapy, and radiation therapy. In the clinical study used to support the expanded indication, patients treated with the device and TMZ lived on average 3 months longer than those treated with the drug alone. Optune was initially approved in 2011 to treat patients with GBM that recurred or progressed after chemotherapy. With this expanded indication, Optune can be used as part of a standard treatment for GBM before the disease progresses. For newly diagnosed GBM, Optune is not intended to be used as a substitute for standard treatments, but rather as an adjunct therapy. The device is portable and can be powered with batteries or plugged into an electrical outlet. Patients can use the device at home or work, allowing them to continue their normal daily activities.

The FDA based its approval of the expanded indication of the Optune device on results from a clinical trial involving 695 patients newly diagnosed with GBM that compared those who used Optune with TMZ to those receiving TMZ alone. Patients who used the device along with TMZ lived, on average, about 7 months with no disease progression compared to 4 months for those who had the drug alone. The Optune plus TMZ group survived for an average of 19.4 months after diagnosis compared to 16.6 months for those who were treated with only TMZ. The most common side effect experienced with Optune was skin irritation. Clinical trial participants also experienced a slightly higher incidence of neurological side effects, including convulsions and headaches, compared to subjects receiving TMZ alone. Patients should not use the Optune system if they have an active implanted medical device or a skull defect, have an underlying skin condition involving the scalp or have a known sensitivity to conductive hydrogels, such as those used on electrocardiogram stickers.

Electric tumor treating fields technology is also being studied as a treatment for other solid tumors (e.g., melanoma and non-small cell lung cancer). However, there is a paucity of published evidence from randomized controlled trials examining the long-term safety and effectiveness of ETTF as a treatment of tumors.

Davis et al (2013) stated that TTFields therapy has been demonstrated in multiple cell lines when the appropriate frequency was utilized. A phase III trial of TTFields monotherapy compared to active chemotherapy in recurrent glioblastoma patients established that TTFields therapy is associated with minimal toxicity, better quality of life, and comparable efficacy to chemotherapy. Ongoing and future trials will evaluate TTFields in newly diagnosed glioblastoma, solid tumor brain metastases, non-small cell lung cancer, and ovarian and pancreatic cancers.

The NovoTAL System is a workstation-based software tool that uses MRI head morphology, tumor size and location measurements, and tissue di-electric properties to optimize TTFields distribution and intensity within the brain tumor. This system is part of the NovoTTF electronic tumor treatment fields treatments used for the treatment of GBM.

Melanoma

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Li and colleagues (2016) proposed a method of using electrical stimulation for treatment of malignant melanoma through directly spray-printing liquid metal on skin as soft electrodes to deliver low intensity, intermediate frequency electric fields. With patterned conductive liquid metal components on mice skin and under assistance of a signal generator, a sine wave electrical power with voltage of 5 V and 300 kHz could be administrated on treating malignant melanoma tumor. The experiments demonstrated that tumor volume was significantly reduced compared with that of the control group. Under the designed parameters (signal: sine wave, signal amplitude Vpp: 5 V and Vpp: 4 V, frequency: 300 kHz) of Tumor treating fields (TTFields) with the sprayed liquid metal electrode, 4 mice tumor groups became diminishing after 1 week of treatment. The only device-related side effect as seen was a mild-to-moderate contact dermatitis underneath the field delivering electrodes. The scanning electron microscope (SEM) images and pathological analysis demonstrated the targeted treating behavior of the malignant melanoma tumor. Further, thermal infrared imaging experiments indicated that there was no evidence of heating effects in the course of treatment. Besides, the liquid metal was easy to remove through medical alcohol. The authors concluded that tumor treating fields through liquid metal electrode could offer a safe, straightforward and effective treatment modality that slowed down tumor growth i- vivo. They stated that these promising results also raised the possibility of applying spray-printing TTFields as an easy going physical way for future cancer therapy.

Combination of ETTF and Chemo-Immuno-Therapy for Other Malignant Tumors

In a pilot, in-vitro and in-vivo, clinical trial, Kirson et al (2009) examined the effectiveness and toxicity of combining TTFields with chemotherapeutic treatment. Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, these researchers studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. The effectiveness of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index less than or equal to 1). The sensitivity to chemotherapeutic treatment was increased by 1 to 3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 to 1,316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields-related systemic toxicity was observed in any of these patients, nor was an increase in temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with temozolomide treatment led to a PFS of 155 weeks and OS of 39+ months. The authors concluded that these results indicated that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic effectiveness and sensitivity without increasing treatment related toxicity.

Pless et al (2013) noted that TTFields exhibit anti-mitotic activity in cancer cells, and promising pre-clinical data have led to a single-arm phase I/II clinical trial in patients with non-small cell lung cancer (NSCLC). A total of 42 inoperable stage IIIB (with pleural effusion) and stage IV NSCLC patients who had had tumor progression received intravenous pemetrexed 500 mg/m(2) q3w together with daily TTFields therapy until disease progression. The primary end-point was time to “in-field” progression. Median age for all patients was 63 years, 76 % had stage IV disease, 78 % had adenocarcinoma and 17 % had performance status of 2. The median time to in-field progression was 28 weeks and the median time to systemic progression was 22 weeks. Six patients (14.6 %) had a partial remission (PR) and 20 had stable disease (SD) (48.8 %). Median OS was 13.8 months and 1 year survival rate was 57 %. There were no TTFields-related serious adverse events. The authors concluded that the combination of TTFields and pemetrexed as a second-line therapy for NSCLC is safe and potentially more effective than pemetrexed alone. They stated that TTFields improved disease control within the treatment field and a phase III study is planned to further investigate its role as a novel treatment in NSCLC.

Giladi et al (2014) stated that 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 safety and effectiveness for current management approaches. Tumor-treating fields are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. These researchers 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. They 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. The authors concluded that these findings suggested that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC. They stated that further prospective studies to examine the optimal combinations of therapy are needed.

Omar (2014) stated that prior to the approval of the TTF System, the only FDA approved treatment for recurrent GBM (rGBM) was bevacizumab. By blocking the vascular endothelial growth factor (VEGF) pathway, bevacizumab can result in a significant radiographic response (pseudo-response), improve PFS and reduce corticosteroid requirements in rGBM patients. Bevacizumab however failed to prolong OS in a recent phase III trial. A pivotal phase III trial (EF-11) demonstrated comparable OS between physicians’ choice chemotherapy and TTF Therapy but better quality of life were observed in the TTF arm. There is currently an unmet need to develop novel approaches designed to prolong OS and/or improve quality of life in this unfortunate patient population. One appealing approach would be to combine the 2 currently approved treatment modalities namely bevacizumab and TTF Therapy. These 2 treatments are currently approved as monotherapy, but their combination has never been evaluated in a clinical trial.

Wong et al (2015) treated a series of patients with NovoTTF-100A and bevacizumab alone (n = 34) or in combination with a regimen consisting of 6-thioguanine, lomustine, capecitabine, and celecoxib (TCCC) (n = 3). Compared to the former cohort, the latter cohort exhibited a trend for prolonged OS, median of 4.1 (0.3 to 22.7) months versus 10.3 (7.7 to 13.6) months, respectively (p = 0.0951), with 1 experiencing an objective response with a 50 % reduction in tumor size on MRI despite possessing a larger tumor size at baseline and more severe neurologic dysfunction than the median for either group. These preliminary observations illustrated the possibility of improving survival and achieving a response in patients with end-stage recurrent glioblastoma by biasing the tumor toward anti-tumor immunologic response with a combination of NovoTTF-100A and TCCC, as well as the continuation of bevacizumab in order to limit dexamethasone use due to its global immunosuppressive effect on the patient.

Lee and Kim (2022) noted that TTFields have been used singly or with chemoradiation for treating glioblastoma and mesothelioma but not yet for lung cancer. Survival rates in lung cancer remain abysmal despite advances in early diagnosis and targeted therapies. These investigators examined the effectiveness of TTFields in inhibiting lung cancer growth and metastasis, as well as the effectiveness of TTFields combined with irradiation (IR) and chemosensitivity-enhancing agents in an in-vitro model. They generated TTFields yielding 0 to 800 V sine-wave signals, 0.9 V/cm applied electric field intensity, and 150 kHz frequency. The human lung cancer cell lines A549 and H460 were used in this study. Cell viability, colony formation, cell death detection, and cell invasion assays were carried out to examine the effectiveness of TTFields; sensitization of lung cancer cells to TTFields by doxorubicin (DOX); and the combined effect of TTFields, DOX, and IR. Lung cancer cells showed a nearly 20 % decrease in cell viability at 1 V/cm and 150 kHz. In A549 and H460 cells, TTFields increased apoptosis via increased cleaved caspase3, hindered cell migration and invasion, and improved chemosensitivity to DOX. The combination of DOX and TTFields showed better anti-tumor results than those of each individually. However, the DOX/TTFields/IR combination was most effective in reducing the viability and migration of lung cancer cells. The authors concluded that TTFields as an adjuvant therapy offered probability for improving lung cancer patient outcomes. Moreover, these researchers stated that future studies using animal models and normal toxicity are needed to examine the roles of TTFields in lung cancer. They noted that further investigations will shed light on the underlying mechanisms regulating the anti-tumor effect of TTFields, and in turn contribute to the development of improved therapeutic strategies for lung cancer that will improve patient outcomes.

Osteosarcoma

Oh and colleagues (2020) noted that the prognosis of metastatic osteosarcoma (OS) remains poor with a less than 20 % survival rate, especially in cases of distant (non-lung) metastases. Tumor-treating field therapy is a novel electric field-based treatment that causes metaphase arrest and tumor cell death, with the advantage of reduced side effects compared to radiation and chemotherapy. TTF showed promise in glioblastoma and other solid tumors; however, few studies have examined its potential in the treatment of osteosarcoma. These researchers examined the mechanism of TTF-induced metastasis inhibition and cell death using in-vitro models. TTF (1.5 V/cm, 150 kHz) was applied to U2OS and KHOS/NP OS cell lines. Furthermore, a 3-dimensional (3D) culture system was established using these OS cell lines. Cell migration and invasion (i.e., metastatic potential) were examined using a wound-healing scratch assay and transwell assay, respectively. Western blotting of metastasis- and angiogenesis-related proteins was carried out. TTF suppressed the migration of and invasion by OS cells and inhibited the expression of epithelial markers; thus, preventing epithelial-mesenchymal transition (EMT), a hallmark of metastasis. Moreover, TTF prevented angiogenesis in human tumor endothelial cells and down-regulated matrix metalloproteinase-2 (MMP2) and VEGF expression. The authors concluded that TTF showed potential as an improved treatment for osteosarcoma, warranting further pre-clinical studies in animal models to support clinical trials. Moreover, these researchers stated that further research will develop an in-depth insight into the underlying mechanisms regulating the anti-tumor effect of TTF, which, in turn, will contribute to the development of improved therapeutic strategies for metastatic OS with improved patient outcomes.

Ovarian Cancer

In a phase-II, single-arm pilot clinical trial (the INNOVATE (EF-22) Study), Vergote and colleagues (2018) examined the safety and efficacy of TTFields (20-kHz) in combination with weekly paclitaxel (weekly for 8 weeks and then on days 1, 8, 15 of each subsequent 28-day cycle; starting dose 80 mg/m2) in 31 patients with recurrent, platinum-resistant ovarian carcinoma. The primary end-point was safety and secondary end-points included OS, PFS and response rate (RR). Median age was 60 years (range of 45 to 77), 24 patients (77 %) had serous histology, 16 patients (52 %) Eastern Cooperative Oncology Group (ECOG) performance score of 0 and 15 (48 %) ECOG 1, the median number of prior chemotherapy lines was 4 (range of 1 to 11). All patients received prior platinum-based chemotherapy and 30 (97 %) received prior taxanes. No serious AEs related to TTFields were reported. There was no increase in grade 3 to 4 AEs compared to the frequency of such events reported in the literature with single agent weekly paclitaxel; 26 patients (84 %) had the expected TTFields-related dermatitis but only 1 patient permanently discontinued TTFields due to dermatitis. The median PFS was 8.9 months, 7 patients (25 %) had PR and the clinical benefit rate was 71 %. The median OS was not reached: the 1-year survival rate was 61 %. The authors concluded that TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase-III clinical trial.

Combined ETTF Therapy and Radiation Therapy for the Treatment of Glioblastoma

Bokstein and colleagues (2020) stated that TTFields are a loco-regional, anti-mitotic treatment comprising low-intensity alternating electric fields. In the EF-14 study of newly diagnosed GBM (ndGBM), TTFields in combination with TMZ significantly improved survival versus TMZ alone. In pre-clinical studies TTFields had a radio-sensitizing effect and increased the efficacy of radiation therapy (RT). In a pilot study, these researchers prospectively evaluated the feasibility and safety of TTFields administered concurrently with RT and TMZ in ndGBM patients. Patients with histologically confirmed ndGBM were treated with TTFields/RT/TMZ followed by adjuvant TMZ/TTFields. TTFields (200 kHz) were delivered for greater than or equal to 18 hours/day with transducer arrays removed during RT delivery. RT was administered to the tumor bed in 30 fractions (total dose 60 Gy) combined with daily TMZ (75 mg/m2). In the adjuvant phase, patients received monthly TMZ (150 to 200 mg/m2 for 5 days) plus TTFields. Patients were followed for 24 months or until second disease progression. The primary outcome was safety of the combined therapies; secondary outcomes included PFS and OS; AEs were graded per CTCAE v4.0. A total of 10 patients were enrolled at a single center between April and December 2017. Median age was 60.2 years, median KPS was 90.0, and 80 % patients were men; 5 (50 %) patients had undergone tumor resection while the remainder had biopsy only; 8 patients experienced greater than or equal to 1 RT treatment delay; delays were unrelated to TTFields treatment. All patients experienced greater than or equal to 1 AE; 3 patients suffered from serious AEs (urinary tract infection [UTI], confusional state, and decubitus ulcer) that were considered unrelated to TTFields. The most common AE was skin toxicity, reported in 8 (80 %) patients; all were of low severity (CTCAE grade 1 to 2) and were reported as related to TTFields treatment. Median PFS from enrollment was 8.9 months; median OS was not reached at the time of study closure. The authors concluded that 80 % of patients experienced grade 1 to 2 TTFields-related skin toxicity. No other TTFields-related toxicities were observed without an increase in RT- or TMZ-related toxicities as a result of combining TTFields with these therapies. The main drawbacks of this study were that it was a single-center study with a small sample size (n = 10). Moreover, these researchers stated that these preliminary efficacy results were promising and warrant further investigation of concurrent TTFields/RT/TMZ treatment in ndGBM patients. They noted that based on the findings of this pilot study, a phase-II clinical trial enrolling 60 newly diagnosed GBM patients testing this regimen is underway.

Guberina and associates (2020) stated that TTFields are an anti-mitotic modality applying low-intensity (1 to 3 V/cm), intermediate-frequency (100 to 300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with RT were reported in the pre-clinical setting. In a phase-I clinical trial, these researchers examined the dosimetric consequences of TTFields applied during the course of radio-chemotherapy. Cone-beam-computed-tomography (CBCT) data from the first 7 patients of the PriCoTTF phase-I clinical trial were used in a pre-defined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT) treatment plans as well as geometric analysis of the transducer arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT’s routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield unit was assigned to the electrodes. After 6D fusion with the planning CT, the dose-distribution was re-calculated using a Boltzmann equation solver (Acuros XB) and a Monte Carlo dose-calculation engine. Over-dosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5 % of the pre-scribed dose in the first 2 mm below and also in deeper layers outside 1 cm2 at highest dose as obtained from dose-volume histogram comparisons. In the clinical target volume (CTV), under-dosage was limited to 2.0 % due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal component analysis (PCA) showed that the 1st principal position component of the variation of repeated array placement in the direction of the largest variations and the perpendicular second component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second principal component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. The authors concluded that from a dosimetric point of view, dose deviations in the CTV due to transducer arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radio-chemotherapy and concurrent TTFields.

Pleural Mesothelioma

In a prospective, multi-center, single-arm, phase-II clinical trial (STELLAR), Ceresoli and colleagues (2019) examined the activity of TTFields delivered to the thorax in combination with systemic chemotherapy for the front-line treatment of patients with unresectable malignant pleural mesothelioma. STELLAR was carried out at 12 European academic and non-academic sites (5 in Italy, 3 in Poland, 1 in France, 1 in Belgium, 1 in Spain, and 1 in the Netherlands) for treatment-naive patients with histologically confirmed unresectable malignant pleural mesothelioma. Patients were aged at least 18 years, had an ECOG performance status of 0 to 1, and at least 1 measurable or evaluable lesion according to modified Response Evaluation Criteria in Solid Tumors (RECIST) for mesothelioma. Patients received continuous TTFields at a frequency of 150 kHz to the thorax and concomitant chemotherapy with intravenous (i.v.) pemetrexed (500 mg/m2 on day 1) plus i.v. platinum (either cisplatin 75 mg/m2 on day 1 or carboplatin area under the curve 5 on day 1) every 21 days for up to 6 cycles. Patients not progressing after completion of chemotherapy received TTFields as maintenance treatment until progression, patient or physician decision, or unacceptable toxic effects. The primary end-point of the trial was OS. Survival analyses were carried out in the intention-to-treat (ITT) population, and safety analyses were carried out in all patients who received at least 1 day of TTFields treatment. Between February 9, 2015 and March 21, 2017, a total of 80 patients were enrolled in the study. Median follow-up was 12.5 months (inter-quartile range [IQR] 7.4 to 16.6). Median OS was 18.2 months (95 % CI: 12.1 to 25.8). The most common grade-3 or worse AEs were anemia (9 [11 %] patients), neutropenia (7 [9 %]), and thrombocytopenia (4 [5 %]). Skin reaction was the only AE associated with TTFields and was reported as grade 1 to 2 in 53 (66 %) patients, and as grade-3 in 4 (5 %) patients. No treatment-related deaths were observed. The authors concluded that the findings of this phase-II clinical trial showed encouraging OS results, with no increase in systemic toxicity. These researchers stated that TTFields (150 kHz) delivered to the thorax concomitant with pemetrexed and platinum was an active and safe combination for front-line treatment of unresectable malignant pleural mesothelioma; further investigation in a randomized trial is needed.

Pancreatic Cancer

Pfeifer et al (2021) stated that pancreatic ductal adenocarcinoma (PDAC) is a highly malignant tumor with a poor prognosis. More effective therapeutic options are urgently needed. The use of TTFields could inhibit cell division of PDAC carcinoma and is currently being examined in clinical trials. These researchers examined this new physical treatment under non-ideal conditions such as may occur during patient treatment. A total of 3 established human PDAC cell lines BxPC-3, gemcitabine-resistant BxPC-3 (BxGem), AsPC-1, and a non-malignant primary pancreatic cell line CRL-4023 were treated with TTFields in-vitro. MTT assays, electrical impedance measurement, cell staining with Annexin V/7AAD followed by FACS analysis, digital image analysis and immunohistochemistry were carried out. Treatment with TTFields smaller than 0.7 V/cm and field lines in the direction of mitotic spindle orientation significantly inhibited proliferation of all PDAC cells at 150 kHz, but significantly increased viability of AsPC-1 cells at all frequencies between 100 kHz and 300 kHz and that of BxPC-3 and BxGem cells at 250 kHz. Apoptosis or necrosis were not induced. The authors concluded that non-malignant CRL-4023 cells were not affected at 150 kHz; TTFields damaged PDAC cell lines but even favored their viability at very weak field strength and unfavorable frequency or inadequate field direction.

Zheng et al (2024) noted that TTFields therapy has shown effectiveness in the treatment of GBM, and holds potential for other cancers; however, its use in pancreatic cancer and the distribution of electric fields in the pancreas remain unexplored. These researchers examined the electric field distributions in pancreatic regions using different array configurations for TTFields therapy. Computational modelling was used to simulate electric field distributions, and quantitative analysis was carried out. Human body impedance measurements were employed to optimize the electric properties of the model. Various array configurations were examined to evaluate their impact on the electric field distributions. The study showed that well-positioned arrays, specifically the combination of 20-piece transducer arrays in anterior-posterior (A-P) orientation and 13-piece transducer arrays in left-right (L-R) orientation, consistently achieved electric fields exceeding the 1V/cm threshold in over 99.4 % of the pancreas. Even with a reduced number of transducers (13 pieces for both orientations), sufficient electric field coverage was achieved, exceeding the threshold in over 92.9 % of the pancreas. Furthermore, different array placements within the same orientation were examined to address clinical challenges such as skin rash and patient anatomical variations. The authors concluded that this study laid the groundwork for understanding TTFields distribution within the abdomen, offering insights into optimizing array configurations for improved electric field delivery. These investigators stated that these findings have the potential to guide practical designs of TTFields devices, enhance treatment effectiveness, and improve patient outcomes. They stated that these results offer promises of advancing TTFields therapy for pancreatic cancer towards clinical applications, and potentially enhancing treatment effectiveness and patient outcomes.

Combined Electric Tumor Treatment Fields Therapy and Zinc Oxide Nanoparticles

Shawki et al (2022) stated that cancer remains a leading cause of death worldwide, despite extraordinary progress; therefore, new cancer treatment modalities are needed. Tumor-treating fields (TTFs) use low-intensity, intermediate-frequency alternating electric fields with reported cancer anti-mitotic properties. Moreover, nanomedicine is a promising therapeutic option for cancer. Various types of cancer have been treated with nanoparticles (NPs); however, zinc oxide NPs (ZnO-NPs) exhibited biocompatibility. These investigators examined the activity of TTFs, a sub-lethal dose of ZnO-NPs, and their combination on hepato-cellular carcinoma (HepG2), the colorectal cancer cell line (HT-29), and breast cancer cell lines (MCF-7). The lethal effect of different ZnO-NPs concentrations was evaluated by sulforhodamine B sodium salt assay (SRB). The cell death percent was determined by flow cytometer, the genotoxicity was evaluated by comet assay, and the total antioxidant capacity was chemically measured. The results showed that TTFs alone caused cell death of 14 %, 8 %, and 17 % of HepG2, HT-29, and MCF-7, respectively; 10 µg/ml ZnO-NPs was the sub-lethal dose according to SRB results. The combination between TTFs and sub-lethal ZnO-NPs increased the cell death to 29 %, 20 %, and 33 % for HepG2, HT-29, and MCF-7, respectively, without reactive oxygen species increase. The authors concluded that increasing NPs potency by means of TTFs could be a novel technique in many biomedical applications.

References

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