GLIOBLASTOMA MULTIFORME (GBM)
Glioblastoma multiforme (GBM) is the most prevalent and most fatal malignant brain tumor in adults, accounting for nearly 15% of all brain cancers. GBMs account for 46.6% of all malignant tumors, with 12,150 new cases predicted annually. Malignant gliomas are histologically heterogeneous and invasive tumors that are derived from neuroglia, or glial cells, which support the central nervous system's neuron cells. GBMs are classified by the World Health Organization (WHO) as astrocytoma. The WHO provides a grading scale based on the most malignant regions of the tumors. Tumor grades depend on degree of nuclear atypia, mitotic activity, microvascular proliferation, and necrosis, with increased anaplasia, corresponding to higher tumor grades. The 2007 WHO classification of GBM is a grade IV, indicating the most severe cancer grade, exhibiting rapid tumor growth leading to exceedingly poor prognosis. Eighty percent of individuals diagnosed with GBM will progress to recurrent disease, even after the initial surgical options have been exhausted. Survival expectancy for individuals with newly diagnosed GBM averages between 14.6 to 16.7 months with 1-year survival rates of 35%. Following a GBM recurrence, the 1-year survival rate is only approximately 20%, and median survival ranges from 3 to 9 months. In 2021, the WHO updated their Classification of Central Nervous System (CNS) Tumors to include a combination of histological and molecular grading. Previously, glioblastomas were classified based on their histological presentation as grade IV astrocytomas. Glioblastomas are now divided into subgroups based on their isocitrate dehydrogenase (IDH) mutation. The two subgroups are Glioblastoma, IDH-wildtype, CNS WHO grade 4; and Astrocytoma, IDH-mutant, CNS WHO grade 4. Astrocytoma, IDH-mutant can have varying WHO grades, either, 2, 3, or 4 depending on their genetic analysis. The rationale was "the presence of CDKN2A/B homozygous deletion results in a CNS WHO grade of 4, even in the absence of microvascular proliferation or necrosis."
Prognosis is dismal and treatment options remain limited. The standard first-line treatment for a GBM is maximum surgical resection of the tumor. The National Comprehensive Cancer Network (NCCN) has developed clinical practice guidance for the treatment of GBM. Varying treatment protocols exist among the newly diagnosed and recurrent populations. GBM has a reoccurrence rate of 80%, and 2-year survival rates remain at 27% following initial diagnosis. Acknowledging these dismal treatment outcomes, research has been conducted on new therapeutic agents for the treatment of glioblastoma. Stupp et al. developed a new technology called tumor treating fields (TTFields) initially utilized and studied to treat the population with recurrent GBM disease.
TTFields is a technology utilizing electric activity through fields and currents to influence the polarity of molecules, ions, and the cell membranes found in biological organisms to exert an effect on cellular process and impact cell division. By exposing cancer cells to alternating electric fields of low intensity and intermediate frequency, cellular polarity and ionic energy could be manipulated. This mechanism of action purported by TTFields (alternating electric fields) could selectively arrest cancer cells by impairing normal mitosis and induce apoptosis in dividing cells. TTFields are shown to have no effect on nondividing cells. The electric fields interfere with cell division by causing misalignment of highly polarized subunits (microtubule monomers) in the mitotic spindle during the metaphase to anaphase transition and by dielectrophoretic movement of intracellular macromolecules and organelles during telophase. During cytokinesis, TTFields generate nonuniform intracellular fields, pulling organelles towards the neck that separates the newly forming daughter cells. In addition, TTFields interferes with the formation of the mitotic spindle by exerting forces on the charged tubulin subunits. Both processes lead to cell apoptosis and tumor growth inhibition. TTFields exert maximal effects when aligned to a cell’s mitotic axis. As a cell’s mitotic axis can occur randomly in any direction, additive cytotoxic effects are also observed when TTFields are applied in multiple sequential directions. The TTFields technology takes advantage of the special characteristics and geometrical shape of dividing cells, which make them susceptible to inhibiting cellular division during mitosis.
TTFields for the treatment of GBM are delivered via four transducer arrays onto the individual's shaved scalp that are connected to a portable, battery- or power supply–operated device (Optune, formerly the NovoTTF-100A system), which is preset to generate 200 kHz electric fields within the brain in two sequentially, perpendicular directions. The intensity of the field is also preset by the manufacturer at more than 0.7 V/cm. Treatment is intended to be continuous and take place in the home setting to allow the participants to maintain daily activities. Transducer arrays are supplied sterile, and prior to placement of the arrays, the scalp must be shaved carefully to limit the adverse effects (i.e., skin irritation, skin wounding). Although uninterrupted treatment is recommended, individuals can take treatment breaks of up to an hour, twice per day, for personal needs (i.e., shower).
The Optune system contains a separate software component for the use of clinical treatment planning. The NovoTAL™ system is a workstation-based software tool that uses MRI head morphology, tumor size and location measurements, and tissue dielectric properties to optimize the TTFields distribution and intensity within the tumor by determining the specific region of the brain to treat with the placement of paired arrays. The planning software is intended for use by physicians to prescribe electronic TTFields used for the treatment of GBM.
PEER-REVIEWED LITERATURE
TUMOR TREATING FIELDS FOR THE TREATMENT OF RECURRENT, SUPRATENTORIAL GLIOBLASTOMA MULTIFORME
Kirson et al. in 2007 evaluated a single-arm, pilot trial study on the safety and efficacy of TTFields treatment that was performed on 10 participants with recurrent GBM. Efficacy analysis was performed for individuals with recurrent GBM, focusing on time to disease progression (TTP), progression-free survival (PFS) at 6 months (PFS6), and overall survival (OS) as the primary outcomes for individuals treated with the NovoTTF-100A device. Based on such a small sample size, no statistical hypothesis tests were measured. This study measured PFS6, producing a result of 50% (23%–77%; 95% confidence interval [CI]). Ninety-five percent CIs of survival proportions were calculated using Kaplan–Meier survival curves. The initial pilot study reported two of the 10 participants surviving beyond the follow-up period, with the longest participant living for 124.0 weeks, differing from historical averages.
The seminal trial, which led to the US Food and Drug Administration (FDA) granting approval of TTFields, was a prospective, randomized, phase III trial (EF-11) conducted by Stupp et al. (2012). The EF-11 trial assessed TTFields as a monotherapy, without chemotherapy, compared to physician’s standard chemotherapy. A total of 237 participants were randomly assigned in a one-to-one ratio to receive either TTFields (n=120) or an active control entailing the best available chemotherapy prescribed at the local investigator’s discretion (n=117). Participants were all at least 24 years old, with an average age of 54, had Karnofsky performance scores (KPS) of 70 or higher with limited other comorbidities. The study design reported that participants would receive baseline examinations and be tested monthly in a laboratory. Magnetic resonance imagining (MRI) examinations were repeated every second month, and quality of life questionnaires were completed every third month. The researchers allowed any number of prior treatments or recurrences of disease without limits. More than 85% of trial participants had failed two or more prior lines of chemotherapy (i.e., ≥ second recurrence), and nearly 20% had failed (or had a recurrence) while being treated with bevacizumab prior to enrollment. Tumor response and progression were determined by a blinded central radiology review. This study was designed to demonstrate device superiority over the pharmaceutical control.
The trial's primary outcome was OS. Secondary endpoints were PFS, PFS6, 1-year survival rate, radiological response rate (RR), quality of life, and safety. OS and PFS were computed from randomization until event or censored at last follow-up utilizing Kaplan–Meier survival method, with two-sided log rank statistics for comparison. The study had an 80% power at a significance level of 0.05 to detect a 60% increase in median OS (hazard ratio [HR], 0.63). All analyses were performed using the intent-to-treat population of all randomized individuals; individuals lost to follow-up were censored at the time of last contact. Treatment compliance limitations were disproportionately observed in the study as only 78% (93/120) completed one full cycle of the TTFields. Nearly a quarter of all participants in the TTFields treatment arm were noncompliant and discontinued, or failed to begin treatment. A total of 113 of 117 participants (97%) in the active control group started chemotherapy, and all but one person completed one full treatment course. The study presented with follow-up limitations. Twenty-one participants randomly assigned to the control group failed to return to the treatment site, limiting information on disease progression and toxicity. Moreover, quality of life, a secondary outcome of the study, was only available for assessment on 63 (27%) of trial participants.
Compliance was recorded for those individuals in the TTFields arm who began treatment (n=116) by device downloads. The downloads recorded the treatment duration that TTFields therapy was delivered to each participant. The observed median compliance rate was 86% (41%–98%) during each treatment month, resulting into a mean duration use of 20.6 hours per day. The study acknowledged variance among the level of disease progression (i.e., first recurrence vs. multiple) by the participants but failed to produce comparisons amongst the control groups. Missing these comparisons limits the study's ability to determine the overall effectiveness of the TTFields as a monotherapy. Participants received either single agent or a combination of chemotherapeutic regimens. The percentage breakdown for the chemotherapy agents prescribed were as follows: individuals received bevacizumab (31%), or irinotecan (31%), followed by nitrosoureas (25%), carboplatin (13%), temozolomide (TMZ) (11%) or various other agents (5%). However, the study reported that among individuals treated with the active chemotherapy control, survival was not significantly affected by the choice of chemotherapeutic agent (P=0.66).
The statistical analysis of the survival data was tested for proportional hazards and the assumption of proportionality met using the Cox proportional hazards regression model. The Cox model was performed in two steps: first, all protocol prespecified baseline variables were tested directly for interactions with OS; then a reduced model was performed testing the effect of all variables with significant interaction (P<0.05) with OS together on the treatment effect of TTFields versus active chemotherapy. At a median follow-up of 39 months, 220 trial participants had succumbed to their disease (93%). The primary endpoint failed to demonstrate a significant increase in mean OS between the two treatments. Median survival failed to report statistical significance but was marginally higher in the TTFields group compared to active control chemotherapy (6.6 vs. 6.0 months, respectively). One-year survival proportion was 20% in both groups and was unable to demonstrate superiority over common chemotherapy treatments. The 2- and 3-year survival rates were reported as 8% (95% CI, 4–13) and 4% (95% CI, 1–8) versus 5% (95% CI, 3–10) and 1% (95% CI, 0–3) for TTFields versus active control, respectively. The reported HR was 0.86 (95% CI, 0.66–1.12) in favor of TTFields (P=0.27), indicating that TTFields may be at least equivalent and trending toward an improvement as compared to active chemotherapy. The trial failed to report statistically significant device superiority. Participants were not restricted based on prior treatments or recurrences. Many of the participants presented with advanced disease at trial initiation. As many as 40% of participants were included after the third disease occurrence, possibly decreasing the potential benefit from treatment. Trial results showed TTFields as a monotherapy provided similar, not superior, efficacy as best physician’s choice chemotherapy in individuals afflicted with recurrent GBM, albeit superior quality of life and less toxicity resulting from treatment with chemotherapy.
Secondary trial outcomes were presented without adjustment. Quality of life measures were assessed using the QLQ-C30 questionnaire with brain-specific module (BN-20), and the measurements were presented as the change from baseline to 3 months for each of the subscale domains and symptoms scale. The researchers reported that both cognitive and emotional functioning were higher in the TTFields group compared to the chemotherapy group, with no difference in global health. The researchers reported that more objective radiological responses (partial and complete responses) were seen in the TTFields group than in the active control chemotherapy group (14 vs. 7, respectively). PFS resulted marginally in favor of participants in the TTFields treatment group, with median PFS reported as 2.2 and 2.1 months for TTFields versus the active control group, respectively (HR, 0.81; 95% CI, 0.601.0–9; log rank P=0.16). Authors state PFS at 6 months was 21.4% (95% CI, 13.5–29.3) in the TTFields group and 15.1% (95% CI, 7.8–22.3) in the active control group (chi squared P=0.13). The authors were unable to claim statistical significance for the trial outcomes.
The seminal work was limited by the inability to be blinded, which could introduce bias and compromise the quality of life assessments. Participant knowledge of their active participation limits the pinnacle prognostic factor by creating bias. The disproportionate dropout rates are concerning. Many individuals stopped treatment prior to completing 1 month of treatment duration, and these individuals failed to be treated long enough to make substantial contributions to assist with determinations on device effectiveness. High rates of participant cross-over from chemotherapy into device treatment were observed in the study. Due to the nature of this disease and the dismal prognosis for individuals in this individual population, even marginal changes in OS and any increase in quality of life are clinically significant findings, as alternative to the current treatment modalities for individuals with recurrent GBM. Based on the slight improvement, trends observed in this trial suggest that treatment with TTFields may be considered an option.
Kanner et al. performed a post hoc analysis to study the intent-to-treat (ITT) population in the TTFields treatment versus the best physician’s choice chemotherapy. The authors report that OS was significantly affected by duration that the TTFields device was worn; this observation is not surprising because this treatment is without a half-life and would require continuous application of the device to demonstrate a reduction in tumor growth. Stratifying population size to augment the desired results, the post hoc analysis measured outcomes within the population who fully completed at least one cycle (4 weeks) of TTFields treatment. Based on those modifications, the researchers observed individuals who complied with treatment protocol of 18 or more hours daily (n=92) had significantly longer OS medians, 7.7 versus 4.5 months, than those who used treatment fewer than18 hours (n=28). Small sample sizes in the study diminish this power of the analysis, and the device may create adherence bias. However, a therapeutic response resulting in an observed mean OS increase of 3 months supports treatment effectiveness when compliance of the treatment protocol is adhered to.
A patient registry dataset (PRiDe) following 457 persons with recurrent GBM who received TTFields therapy was studied by Mrugala et al. in a real-world, phase IV setting. Additional information on the safety and effectiveness of the therapy was assessed in the dataset. The primary outcome of the registry evaluated median OS, tolerability of the device, participant compliance and survival, and other prognostic factors. Mrugala et al. reported OS and treatment using Kaplan–Meier methods and Cox proportional hazards model assessed participant characteristics and disease prognostic factors on survival. Evaluation was conducted with log-rank tests to compare OS and daily compliance, prior debulking surgery, KPS, number of recurrence, and prior bevacizumab use.
OS between the PRiDe participants and those treated in the seminal study with TTFields therapy, and physician’s best chemotherapy, increased from 9.6 versus 6.6 versus 6.0 months, respectively. OS rates at 1 and 2 years increased when compared to treatment arms (TTFields and chemotherapy) from the EF-11 study and PRiDe. As stated previously, evidence supported daily compliance as a prognostic factor in TTFields therapy. Participants who achieved the recommended daily compliance of 18 or more hours a day had significantly longer (P=0.0001) OS—13.5 months versus 4.0 months when individuals reported less than 18 hours. Subgroup analysis of individuals treated at first recurrence (n=152) demonstrated the longest median OS, resulting in 20 months. The OS reported in the first recurrence population is similar to more recent studies on the newly diagnosed, suggesting that TTFields may be an option as an effective therapy in GBM recurrence, if treatment is initiated at earliest recurrence.
The registry failed to evaluate participant use of combination therapy with TTFields and prescription programs, such as chemotherapy and anti–vascular endothelial growth factor agents. Outside of a clinical trial, the lack of recording information on other medical management regimens for participants resulted in critically missed analyses in demonstrating the effectiveness of TTFields as a therapy, potentially misrepresenting the true effectiveness of the device in the largest studied population. The registry highlights compliance as a key finding, supporting the adaptation of TTFields; however, it failed to record compliance data for more than one third of all device users. Device safety and tolerability was proven outside of observational settings. Consistent with other trials, the adverse event most commonly observed was associated with device-related skin irritation.
The registry presented with limitations, including lack of quality of life measures, as these were excluded in the real world follow-up, an important prognostic factor in overall health outcome from the original trial. Heterogeneity limitations exist within the registry as 67% of the total population were male (n=309), possibly significant considering the need to shave a user’s scalp for successful placement of the treatment arrays when utilizing this device.
TUMOR TREATING FIELDS FOR THE TREATMENT OF NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME
In 2015, Stupp et al. conducted a multicenter, open-label, randomized phase III trial designed to evaluate the efficacy and safety of TTFields following chemoradiation with TMZ for treatment of newly diagnosed glioblastoma. The trial enrolled 695 participants with histologically confirmed supratentorial glioblastoma, who were progression-free following debulking surgery or biopsy, and who have completed standard concomitant chemoradiotherapy with TMZ. These individuals were randomly assigned (2:1) to receive combination therapy of TTFields plus TMZ (n=466) or standard maintenance chemotherapy alone using TMZ (n=229). Randomization was stratified by participant characteristics: degree of resection and O6-methylguanine-DNA methyltransferase (MGMT) methylation status. The primary outcome was PFS in the intent-to-treat (ITT) population and was assessed by independent reviewers (80% power; HR, 0.78; allowing for 10% loss to follow-up; two-sided α level of 0.05). This study investigated shifted OS to a secondary outcome but with equal power (HR, 0.76; two-sided α = 0.05). To avoid an increase in the risk of a false-positive result, OS was to only be tested statistically if the PFS was achieved.
In October 2014, a safety monitoring committee reviewed the findings of an interim analysis reporting on the first 315 participants enrolled in the TTFields plus TMZ (n=210) and TMZ (n=105) treatment groups. Prespecified endpoints were achieved in the ITT population. After a median follow-up of 38 months (18–60 months), the median PFS in the TTFields plus TMZ arm was 7.1 months from randomization (95% CI, 5.9–8.2 months) compared to 4.0 months (95% CI, 3.3–5.2) in the control group (HR, 0.62; 98.7% CI, 0.43–0.89; stratified log-rank, P=0.001). OS in the per-protocol analysis also showed significant improvement. The combination therapy group (n=196) resulted in median OS of 20.5 months (95% CI, 16.7–25.0 months) compared to 15.6 months (95% CI, 13.3–19.1 months) in the TMZ alone group (n=84) ([HR], 0.64; 99.4% CI, 0.42–0.98; P=0.004). Based on the results of the interim analysis, the trial was terminated, and participants in the control group were allowed to receive TTFields. The termination resulted in 11 individuals in the interim analysis and 26 participants overall to cross over and receive TTF treatment. The study demonstrated that the addition of TTFields to TMZ treatment increased median PFS survival in the ITT population by 3.1 months.
Per the study design, if tumor progression occurred, second-line chemotherapy was offered by local investigator's practice. It is noteworthy that TTFields would continue in the treatment arm, until the second radiologically confirmed progression, or clinical deterioration, for a maximum of 24 months. Brain imaging was routinely performed, initially at baseline with contrast-enhanced magnetic resonance imaging (MRI) at 2 weeks prior to treatment initiation, then in 2-month intervals until second radiologically confirmed progression in all study participants. Two thirds of the TTFields plus TMZ group (n=141) continued treatment with TTFields beyond first tumor progression. The trial design to stop at second tumor progression may have clinical importance when considering the progression of disease and the use of TTFields as a treatment option for individuals transitioning from a new diagnosis into recurrent GBM.
The authors reported median treatment duration of 5.8 months (1–58 months) with TTFields. Three-quarters (n=157) of enrollees receiving TTFields adhered to therapy. Protocol adherence was considered wearing the device at least 18 hours per day on average during the first 3 treatment months. Further analyses in the ITT population showed the median OS was 19.6 months (95% CI, 16.6–24.4 months) in the TTF plus TMZ group compared to 16.6 months (95% CI, 13.6–19.2 months) in the TMZ alone group (HR,0.74 95% CI, 0.56–0.98; stratified log-rank P=0.03). The percentage of those affected by GBM alive at 2 years following enrollment was 43% in the TTFields plus TMZ group and 29% in the TMZ alone group (P=0.006), a 14% increase of participants alive at 2 years in the treatment arm.
The original publication (interim analysis) of the EF-14 study was limited by the investigators stopping the trial earlier and allowing participant cross over. The interim analysis was completed after the initial 315 enrollees reached 18-month follow-up. The results in the initial per-protocol population only evaluated 196, with 84 participants in the combination therapy (TTFields plus TMZ) or the TMZ-alone arms, respectively. Additionally, as an open-label trial, no sham or placebo treatment was available for the control group. Investigators deemed the use of sham to be unethical, and unpractical, and therefore the potential power of a placebo cannot be assessed. This may introduce adherence bias. The researchers acknowledge placebo bias would be unlikely to influence OS and PFS. Following the original trial, which reported results that failed to provide evidence of statistically significant improvements in median OS, the primary study outcome shifted between the two seminal trials. In the original EF-11 trial, the primary endpoint was OS, and in this trial researchers adjusted the primary outcome to PFS. The results of this study on newly diagnosed GBM showed that the addition of TTFields to maintenance TMZ chemotherapy significantly prolonged progression-free and improved OS.
Stupp et al. (2017) reported on the final analysis inclusive of the entire trial population (n=695) from the open-label, randomized phase III trial designed to evaluate the effect of TTFields plus TMZ versus maintenance TMZ alone on survival for individuals with glioblastoma. Stupp et al. previously published the results from an interim analysis on the first 395 participants of the same study. The primary outcomes were consistent to the interim analysis.
The data set was locked on December 28, 2016, and the authors reported median treatment duration of 8.2 months (1–82 months) with TTFields. After a medium follow-up of 40 months (34–66 months), the median PFS was 6.7 months (95% CI, 6.1–8.1 months) for individuals treated with combination therapy versus 4.0 months (95% CI, 3.8–4.4 months) for those treated with TMZ alone (HR, 0.63; 95% CI, 0.52–0.76; P<0.001). The secondary outcome reported median OS duration of 20.9 months from randomization (95% CI, 19.3–22.7 months) in the TTFields plus TMZ group versus 16.0 months (95% CI, 14.0–18.4 months) for TMZ only (HR, 0.63; 95% CI, 0.53–0.76; P<0.001). Both were found to be statistically and clinically significant. Analyzing the percentage of living participants over selected time periods from randomization resulted in 46% alive at 2 years, 26% alive at 3 years, and 13% alive at 5 years in the combination therapy arm, compared to the TMZ only arm reporting 31% alive at 2 years (P<0.001); 16% at 3 years (P=0.009); and 5% at 5 years (P=0.004). Significant percentage increases across each selected time period favoring adjuvant TTFields therapy.
The median time to randomization was equal among the treatment arms with 3.8 months (range, 1.7–6.2) and 3.7 months (range, 1.4–6.3) in the combination therapy, and the TMZ-alone treatment groups, respectively. Kaplan–Meier estimates for survival were accessed at 6 months for the rate of PFS between the two treatment groups. The authors reported on PFS at 6 months as 56% (95% CI, 51%–61%) for the TTFields group and 37% (30%–44%) with TMZ only (P<0.001). Cox proportional hazards analyzed both OS and PFS across factors: trial arms, age, sex, MGMT status, location, and county of residence. Results using Cox proportional hazards with 95% CIs demonstrated several prognostic factors significantly improved OS; these prognostic factors include TTFields treatment group (HR, 0.63; 95% CI, 0.53–0.76; P<0.001), female sex (HR, 0.76; 95% CI, 0.63–0.92, P=0.005), MGMT status (HR, 0.50; 95% CI, 0.41–0.62; P<0.001), younger age (measured continuously; HR, 0.978 per year; 95% CI, 0.969–0.985; P<0.001), and higher KPS (as a categorical variable in 10-point increments P<0.001).
Fifty-five percent of participants had a gross tumor resection (95% of tumor removed) and 13% had only a biopsy performed, results indicating the extent of excision was not statistically significant when investigating OS (P=0.183). The addition of TTFields was not associated with an increase in systemic adverse events (AE) (48% vs. 44%; P=0.58). Higher rates of AE found in the TTFields-treated group were attributed to longer duration of TMZ treatment in the experimental group as a result of delayed disease progression. Investigators report inclusive criteria for TTF treatment utilizing KPS. KPS is a scale measuring the ability of individuals to perform ordinary tasks. KPS scores range from 0 to 100; a higher score means a person is better able to carry out daily activities. The author reported time to sustain 10-point reduction in KPS significantly longer for the combination group versus the group treated with only TMZ (5.5 months; 95% CI, 5.0–6.3 months vs. 3.9 months; 95% CI, 3.1–5.2 months, respectively; HR, 0.80; 95% CI, 0.67–0.95; P=0.009).
Potentially important for future studies, a small majority of the experimental population (51%; n=237) continued TTFields treatment beyond first treatment progression. The investigators may want to evaluate, in the newly diagnosed population who elect to continue TTFields as a combination therapy beyond first progression, whether significant improvements are observed in PFS and OS compared to the outcomes of the historical recurrent population. The recurrent population only has the option to utilize TTFields as a monotherapy. The largest study to date utilizing the TTFields technology presented with similar limitations as observed in the interim analysis (no sham, burden of use when utilizing the device). Another limitation in the final analysis was that quality of life data points were not recorded. Also, participant heterogeneity limitations exist since nearly 70% of the study participants were male and 89% were white.
The final analysis for the treatment of glioblastoma utilizing the TTFields technology demonstrated that the combination therapy of TTFields and TMZ chemotherapy following standard concomitant TMZ and radiotherapy has shown to significantly improve PFS and OS in the newly diagnosed population.
NovoCure Inc. of Portsmouth, New Hampshire (subsidiary of NovoCure Ltd., Haifa, Israel) was granted approval for the NovoTTF-100A system. The NovoTTF-100A Treatment Kit received FDA Premarket Approval on April 8, 2011 (P100034). The current supplement Optune™ System, which received FDA Premarket Approval on October 5, 2015 (P1000034/S013), was submitted to expand the indications for use: Optune™ System with TMZ is indicated for the treatment of adult individuals with newly diagnosed, supratentorial glioblastoma following maximal debulking surgery and completion of radiation therapy together with concomitant standard of care chemotherapy.
In summary, the use of TTFields has been demonstrated to be a safe and effective alternative treatment, and may be considered for individuals with either recurrent or newly diagnosed glioblastoma. In 2015, the National Comprehensive Cancer Network (NCCN) clinical practice guidelines appropriateness in the treatment of central nervous system cancer for use of TTFields has shifted to consider category 3 in the recurrent population as a category 2B. A 2B category allows providers to consider the use of TTFields in treatment of recurrent disease. The NCCN 2019 guidelines classifies alternating electronic fields therapy as a grade 1 for newly diagnosed glioblastoma individuals. NCCN guidelines demonstrate TTFields used in concomitant treatment with adjuvant TMZ following radiotherapy and concomitant TMZ for the newly diagnosed, thus indicating that use of TTFields could be used an initial treatment therapy, when prescribed with adjuvant TMZ.
TUMOR TREATING FIELDS IN OTHER INDICATIONS
Researchers have initiated evaluations utilizing NovoCure’s TTFields technology in the treatment of other solid tumor indications. The various populations actively being investigated include individuals with cancers such as non-small cell lung (NSCLC), brain metastases (1-5; 1-10) from NSCLC, pancreatic, ovarian, mesothelioma, hepatocellular cancer, and high-grade glioma and ependymoma in children. Each of these separate indications has been either recently completed or is actively being studied to determine safety and efficacy. OS was the primary outcome in majority of clinical trials. Time to progression and PFS were often used as secondary endpoints.
Malignant Pleural Mesothelioma
Malignant pleural mesothelioma (MPM) is an aggressive tumor that has been associated with significant reductions in net health outcomes, for both morbidity and mortality. MPM is attributed to asbestos exposure and the disease has a latency period of about 40 years. TTFields therapy has been investigated for individuals with MPM in a prospective, single-arm, unblinded study (STELLAR; Ceresoli et al., 2019). The study is described in the FDA Summary of Safety and Probable Benefit associated with its Humanitarian Device Exemption designation. The STELLAR study enrolled 80 participants at 13 sites outside of the United States. Participants had inoperable, and previously untreated MPM. Participants were treated with chemotherapy in combination with TTFields delivered by the NovoTTF-100L System. The primary outcome was OS; secondary outcomes were PFS based on investigator assessment of CT scan imaging, radiological response rate, 1- and 2-year survival rates, and safety.
Median OS was 18.2 months and median PFS was 7.6 months. Nearly 90% of participants enrolled had at least one follow-up CT scan. Of those (n=70), 40% had a partial response, 57% had stable disease, and 3% progressed. The limitations of the STELLAR trial were that the study had no control group, was unblinded, small sample size, and failed to report quality of life measures. Based on the limitations of the one single study, it is not possible to draw firm conclusions about the effectiveness of TTFields therapy. To establish the clinical value TTFields adds to current treatment regimens, future studies may benefit from incorporating a cohort consisting of a sham device concurrently with the standard care.
Non-Small-Cell Lung Cancer
Metastatic non-small-cell lung cancer (NSCLC) remains incurable despite the development of new and effective therapies. Platinum agents are considered standard of care; however, once an individual's disease has progressed, treatment options to prolong survival are limited to alternative chemotherapies or an immune checkpoint inhibitor. To further extend survival in this population, TTFields therapy is being investigated as an adjunct treatment to the established care regimen. Leal et al. (2023) performed a randomized, open-label phase III clinical trial (LUNAR Trial) evaluating TTFields for the treatment of stage 4, metastatic NSCLC in adjunct to or following platinum-based systemic therapy with the aim of increasing OS without contributing to disease or treatment burden. TTFields was delivered via the thorax concomitant with standard therapy (e.g., docetaxel with or without ramucirumab, immune checkpoint inhibitor) in the treatment group, or standard therapy alone in the comparator group. The primary outcome of interest was OS. Secondary endpoints include PFS and response rate among all subgroups (e.g., docetaxel or immune checkpoint inhibitor, between three chemotherapies, and among average monthly device compliance of >75% or ≤75%). Patient-reported outcomes, adverse events, and OS in various TTFields subgroups were also measured.
OS was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median, 13.2 months [95% CI, 10.3–15.5] vs 9.9 months [8.1–11.5]; HR, 0.74 [95% CI, 0.56–0.98]; P=0.035). Among those who received TTFields and an immune checkpoint inhibitor (ICI) versus those who received ICI alone, the addition of TTFields demonstrated less risk of mortality and a greater median OS (18.5 months [95% CI, 10.6–30.3] versus 10.8 months [95% CI, 8.2–18.4; HR, 0.63 [95% CI, 0.41–0.96]; P = 0.030). When comparing the standard treatments without TTFields, ICI was associated with lower risk of death than docetaxel (HR, 0.64 [95% CI, 0.48–0.85]; P=0.002). Individuals with squamous NSCLC showed a modest lower risk of death when TTFields was given in adjunct to standard therapy than standard therapy alone (13.9 months [95% CI, 9.7–17.1] vs. 10.1 months [95% CI, 8.3–14.3]; HR, 0.67 [95% CI, 0.44–1.01]; P=0.050). Average monthly TTFields device usage of more than 75% was achieved in 22.5% (30 of 133); however, OS stratified by usage was not documented. PFS (HR, 0.85, 95% CI, 0.67–1.11; P=0.23)
and overall response rate (ORR; 20.4% vs. 17.3%) were not significantly impacted by
the addition of TTFields. Interestingly, patient-reported outcomes measured using the European
Organisation for Research and Treatment of Cancer Quality of Life Questionnaire
(EORTC QLQ-C30) to assess quality of life of individuals living with cancer saw no significant change in either group even though the study was open label. TTFields
therapy-related adverse events occurred in 71% (95 of 133) of individuals,
largely due to grade 1-2 subcutaneous tissue disorders (e.g., dermatitis, rash,
skin ulcer) that is consistent with past TTFields trials.
Despite a low percentage of individuals achieving the recommended daily device usage (≥18 hours), TTFields therapy demonstrated meaningfully clinical outcomes in adjunct to standard therapy—in particular with immune checkpoint inhibitors—over standard of care alone for those with metastatic NSCLC. The consistent quality of life outcomes and mild adverse events suggests the open-label TTFields did not exacerbate the toxicities associated with systemic therapies nor influence the individual's experience. Given the advancement of genotyping for NSCLC after the LUNAR trial was initiated, treatment management has drastically shifted in favor of immune checkpoints; therefore, as noted by Fennel (2023) responding to the study, "...the results of LUNAR are unlikely to be practice-changing in the current treatment paradigm." Future studies would need to incorporate current standard of care and a sham control with participant blinding. Overall, the LUNAR trial showed promising results using TTFields as an adjunct treatment for metastatic NSCLC.
Several clinical trials of interest are being researched. LUNAR-2 (NCT06216301) is a randomized controlled trial (RCT) evaluating the efficacy of TTFields during the initiation of platinum-based therapies and chemotherapies (P/C) compared to P/C alone prior to disease progression in the advanced/metastatic NSCLC population who have not received prior systemic treatment. The study has an expected completion date of October 2028. Another LUNAR trial (i.e., LUNAR-4 NCT06558799) is a pilot, single-arm, open-label study to test TTFields concurrently with pembrolizumab in those who have previously received a checkpoint inhibitor and platinum-based therapies. Other studies are investigating the technology with standard of care before metastatic disease. In aggregate, these trials may address previously mentioned limitations from the LUNAR study as well as provide insight into early TTFields initiation for this population.
Pancreatic Adenocarcinoma
Babiker et al. (2025) performed an RCT in treatment-naïve adults with unresectable, localized pancreatic adenocarcinoma (PAC) comparing TTFields in adjunct to gemcitabine plus nanoparticle albumin-bound paclitaxel (GnP; n=285) versus GnP alone (n=286). The primary endpoint was OS, with secondary outcomes including PFS, pain-free survival, ORR, safety, and resectability rate. All endpoints were analyzed in both ITT and modified ITT (mITT) populations.
In the ITT analysis, OS was modest, but significantly longer among the TTFields plus gemcitabine/nab-paclitaxel (GNP) cohort (16.2 months; 95% CI, 15–18) versus GNP alone (14.2 months; 95% CI, 12.8–15.4) (HR, 0.82 [95% CI, 0.68– 0.99]; P=0.039). In the mITT analysis, reflecting only individuals who were able to complete at least one full cycle of treatment, the benefit was more pronounced, with survival of 18.3 months vs 15.1 months (HR, 0.77 [95% CI 0.62–0.97]; P=0.023). Similar significance was seen among 1-year survival rates favoring TTFields (68.1% vs 60.2%; P=0.029). While TTFields therapy was unable to show improvement in planned secondary endpoints (i.e., overall PFS or ORR) over GnP alone, it did increase the proportion of individuals who remained progression free at 1 year (43.9% vs 34.1%; P=0.026). The rate of resectability remained comparable among groups (7% vs 10.1%), consistent with the general locally advanced PAC population after receiving chemotherapy.
TTFields also demonstrated benefits in two notable measures. Individuals using the device experienced a longer time before significant pain worsening or the need for pain related interventions (median 15.2 vs 9.1 months; HR 0.74 [95% CI, 0.56–0.97]; P=0.027). In a post hoc analysis of distant disease spread, TTFields likewise performed better, extending the time to distant progression to 13.9 months compared with 11.5 months (HR, 0.74 [95% CI, 0.57–0.96]; P=0.022).
In terms of safety, nearly all individuals in both groups experienced at least one side effect, which is expected with chemotherapy. Importantly, TTFields did not add extra systemic toxicity. The main device-related side effects were skin reactions—such as rash, redness, or itching—which occurred in about 76% of individuals and presented as mild to moderate in nature. Only about 8% of individuals stopped TTFields because of skin issues. Serious side effects related to chemotherapy or the cancer itself—such as infection, anemia, or neutropenia—were similar between both groups. No deaths were directly caused by TTFields.
Some limitations include unblinded study evaluators and lack of sham control, although these biases are lessened by an objective primary endpoint. Furthermore, it is important to note that treatment management for unresectable PAC is evolving. Immune checkpoint inhibitors (i.e., pamrevlumab) and NALIRIFOX (liposomal irinotecan + 5-FU + leucovorin + oxaliplatin) have been explored as a first-line option in metastatic PAC populations. NALIRIFOX in particular has shown survival superiority over GnP (Wainberg et al., 2023). Like preceding treatments, the National Comprehensive Care Network (NCCN) has extrapolated its use—initially studied among the metastatic population—to locally advanced PAC and given it a category 2A recommendation. Although the NCCN recognizes the advantage of NALIRIFOX and FOLFIRINOX over GnP, no one treatment is preferred over another.
Overall, the study showed that TTFields, when added to standard GnP chemotherapy, helped individuals live slightly longer and delayed both pain worsening and may reduce the risk of cancer spreading to distant organs, without increasing serious side effects. Given the previously mentioned limitations, such as lack of concordant superiority among crucial secondary endpoints (i.e., PFS, ORR) and the lack of blinding and sham controls, preclude the ability to make concrete determinations regarding the added value of TTFields to GnP regimen for locally advanced PAC populations compared with chemotherapy alone. Although TTFields shows promising preliminary evidence for survival, future trials would benefit from incorporating a sham control, blinding evaluators, and potentially evaluating TTFields with superior chemotherapy regimens.
Pediatric Glioma and Ependymoma Cancers
Evaluation of a trial on the feasibility of Optune for children with recurrent or progressive supratentorial high-grade glioma and ependymoma cancers was initiated in early 2017 and is projected to be completed in August 2029. This trial aims to demonstrate use of the Optune device as a feasible treatment option in the pediatric population and report treatment related toxicities assessed by Common Terminology Criteria for Adverse Events v4.0. Twenty-five children are expected to participate in this trial. This study was the first trial, inclusive of the pivotal trials, that utilizes the TTFields technology that was not funded or sponsored by the device manufacture, NovoCure, Ltd. The pediatric study is sponsored by Pediatric Brain Tumor Consortium, with support from the National Cancer Institute (NCI).
