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Cited by 177Glioma Diagnosis and TreatmentElectromagnetic Fields and Biological EffectsUltrasound and Hyperthermia Applications

Tumor treating fields: A novel treatment modality and its use in brain tumors

Open access
Hottinger, Andreas F., Pacheco, Patricia, Stupp, Roger·2016·Neuro-Oncology
DOI 10.1093/neuonc/now182PMC PMC5035531
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Abstract

Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly. This novel treatment modality has shown promise in a variety of tumor types. It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM. TTFields are continuously delivered by 4 transducer arrays consisting each of 9 insulated electrodes that are placed on the patient's shaved scalp and connected to a portable device. Here we summarize the preclinical data and mechanism of action, the available clinical data, and further outlook of this treatment modality in brain tumors and other cancer indications.

AI snapshot

Written from the paper’s full text.

TL;DR

Tumor treating fields (TTFields) are low-intensity, intermediate-frequency (200 kHz) alternating electric fields that disrupt mitosis and were tested in glioblastoma. In newly diagnosed GBM, adding TTFields to maintenance temozolomide prolonged PFS and OS, while in recurrent GBM TTFields did not significantly improve survival over physician’s-choice chemotherapy.

Key findings

  • TTFields block cell division by interfering with the mitotic spindle, septins, and cytokinesis, leading to mitotic arrest, abnormal chromosome segregation, and apoptosis; effects require continuous exposure and are frequency- and intensity-dependent.
  • In newly diagnosed GBM (EF-14 interim ITT), TTFields plus TMZ vs TMZ alone: median PFS 7.1 vs 4.0 months (HR 0.63, 95% CI 0.43–0.89; P<0.01), median OS 19.6 vs 16.6 months (HR 0.74, 95% CI 0.56–0.98; P=0.0004), and 2-year survival 43% vs 29%.
  • In recurrent GBM (EF-11), TTFields vs best physician’s-choice chemotherapy: median OS 6.6 vs 6.0 months (HR 0.86, 95% CI 0.66–1.22; P=0.27), with objective responses in 14% vs 9.6%; the trial did not demonstrate superiority.
  • In the PRiDe routine-practice dataset of 457 patients, median survival was 9.6 months overall and 20 months for patients treated at first recurrence (n=152). Skin toxicity was mainly grade 1–2 (43% in EF-14) and grade 3 in 2%.

Methods

  • Narrative review summarizing preclinical mechanism-of-action data and clinical experience with TTFields in brain tumors and other cancers.
  • Key clinical evidence reviewed: EF-11 in recurrent GBM (237 patients randomized 1:1 to TTFields [120] or best available chemotherapy [117]); EF-14 in newly diagnosed GBM (695 patients randomized 2:1, interim ITT dataset 210 TTFields/TMZ vs 105 TMZ); and PRiDe, a registry of 457 patients treated at 91 US institutions.
  • Main analysis is descriptive synthesis of intent-to-treat survival outcomes, hazard ratios, toxicity, quality of life, and ongoing trials; no new primary statistical analysis is reported.

Limitations

  • The paper states EF-11 had a heterogeneous, heavily pretreated population, allowed numerous prior lines, included many patients after third recurrence or prior bevacizumab failure, and had early TTFields discontinuations that may have reflected investigator skepticism rather than true progression.
  • The paper states EF-14 was open-label without a sham control, and the interim dataset’s subgroup analyses were limited by small sample size, especially the 105-patient control arm; PRiDe was uncontrolled and could not rule out strong selection bias or pseudoprogression.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and several cited ongoing trials had not yet reported results.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1093/neuonc/now182

Cites

32 of 32 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 64 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    TTFields have been demonstrated to prolong progression-free survival and overall survival when administered together with standard maintenance temozolomide chemotherapy in patients with newly diagnosed glioblastoma.

    “It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Findingcitation

    In the EF-14 trial, the intent-to-treat median progression-free survival was increased by 3.1 months in the TTFields group with a median PFS of 7.1 months (95% CI 5.9-8.2) compared with 4.0 months (95% CI 3.3-5.2) in the control group (HR 0.62 [98.7% CI 0.43-0.89]; P=.001).

    “In the interim analysis, the ITT median PFS was increased by 3.1 months in the TTFields group with a median PFS of 7.1 months (95% CI, 5.9–8.2 mo) compared with 4.0 months (95% CI, 3.3–5.2 mo) in the control group (HR, 0.62 [98.7% CI, 0.43–0.89]; P=.001).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Findingcitation

    In the EF-14 trial, the percentage of patients alive at 2 years following enrollment was 43% in the TTFields/TMZ group and 29% in the TMZ alone group (P=.006).

    “The percentage of patients alive at 2 years following enrollment was 43% in the TTFields/TMZ group and 29% in the TMZ alone group (P=.006)17”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Findingcitation

    The EF-11 trial showed objective responses with TTFields alone in 14% of patients compared with 9.6% in the control arm.

    “Still it showed objective responses with TTFields alone in 14% of patients compared with 9.6% in the control arm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • Findingown data

    Patients receiving TTFields therapy received additional assistance from the technical support team, limited on average to 1 visit per month and 1-2 extra visits or contacts at treatment initiation.

    “Indeed, patients receiving TTField therapy received some additional assistance by the technical support team providing the TTFields device and arrays. However, this support was on average limited to 1 visit per month, and 1–2 extra visits or contacts at the initiation of treatment.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 42
  • Classified as probably not a substantial claim. 7
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingcitation

    In the EF-14 trial, median overall survival from randomization (intent-to-treat) was 19.6 months (95% CI 16.6-24.4) in the TTFields plus TMZ group compared with 16.6 months (95% CI 13.6-19.2) in the TMZ control group (HR 0.74 [95% CI 0.56-0.98]; P=.03).

    “Median OS from randomization (ITT) was 19.6 months (95% CI, 16.6–24.4 mo) in the TTFields plus TMZ group compared with 16.6 months (95% CI, 13.6–19.2 mo) in the TMZ control group (HR: 0.74 [95% CI, 0.56–0.98]; P =.03).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In the EF-11 trial, with a median survival of 6.6 and 6.0 months in the TTFields and control arms, respectively (HR 0.86 [95% CI 0.66-1.12], P=0.27) and a 1-year survival rate of 20% in both groups, the trial failed to demonstrate superiority over established or commonly used chemotherapy regimens.

    “With a median survival of only 6.6 and 6.0 months in the TTFields and the control arm, respectively (hazard ratio: 0.86 [95% CI, 0.66–1.12), P=0.27) and a 1-year survival rate of only 20% in both groups, the trial failed to demonstrate superiority over “established” or commonly used chemotherapy regimens.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Preliminary subgroup analyses in EF-14 showed that the positive effect on progression-free and overall survival by the addition of TTFields was not restricted to any subgroup: neither age, performance status, MGMT methylation status nor extent of resection was predictive for a better treatment effect.

    “Preliminary subgroup analyses showed that the positive effect observed on PFS and OS by the addition of TTFields was not restricted to any subgroup of patients: in particular neither age, performance status, MGMT methylation status nor extent of resection was predictive for a better treatment effect.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The EF-11 study demonstrated safety and feasibility of TTFields in a large multicenter setting.

    “The study demonstrated safety and feasibility of TTFields in a large multicenter setting.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the PRiDe dataset, overall median survival was 9.6 months, and the subgroup of patients treated at first recurrence (n=152) had a median survival of 20 months.

    “Overall, median survival was 9.6 months, and the subgroup of patients who were treated at first recurrence (n=152) had a median survival of 20 months.18”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the EF-14 trial, grades 1 and 2 skin reactions were reported in 43% of patients, and severe (grade 3) reactions were seen in only 2% of patients.

    “In the EF-14 trial for newly diagnosed GBM patients, where the treatment exposure was longer than that for recurrent disease, grades 1 and 2 skin reactions were reported in 43% of patients. Severe (grade 3) reactions were again seen in only 2% of patients.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Most patients became rapidly independent and self-proficient with the device; on average, there was a median of 1.12 visits per patient and month of treatment (range, 0.5-4 visits per month).

    “Most patients became rapidly independent and self-proficient with the device; on average, there was a median of 1.12 visits per patient and month of treatment (range, 0.5–4 visits per month).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingnone given

    In the authors' experience, patients and families rapidly adapt to wearing the device and are able to continue their regular activities including work and sports.

    “In our experience, patients and families rapidly adapt to wearing the device and are able to continue their regular activities including work and even sports.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In newly diagnosed glioblastoma, TTFields administered as part of initial treatment showed a consistent prolongation of both progression-free survival and overall survival, with a hazard ratio for death of 0.74 (95% CI 0.56-0.98).

    “However, TTFields when administered as part of the initial treatment in newly diagnosed patients showed a consistent prolongation of both PFS and OS (hazard ratio for death HR: 0.74 (95% CI, 0.56–0.98).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Findingnone given

    In the EF-14 trial, patients were randomized only after the end of chemoradiotherapy, and for most patients the first cycle of maintenance TMZ had already been started at the time of randomization.

    “One important difference in the EF-14 trial compared with many other reports is that patients were randomized only after the end of chemoradiotherapy, and for most patients the first cycle of maintenance TMZ had already been started at time of randomization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    In the EF-11 trial, skin toxicity was reported in 16% of patients, with grade 3 toxicity in only 2%.

    “In the EF-11 trial, skin toxicity was reported in 16% of patients (grade 3 in only 2%).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Toxicity related to TTFields therapy consisted mainly of local skin irritation, which is usually mild, self-limiting, easily manageable with local application of steroid-containing ointments, and may require an occasional treatment break for a few days.

    “Toxicity related to TTFields therapy consisted, by the nature of this treatment, mainly of local skin irritation. This is usually mild, self-limiting, easily manageable with local application of steroid-containing ointments, and may require an occasional treatment break for a few days.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Lacouture, 2014, Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma, Semin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In the PriDE dataset, patients who received TTFields at first recurrence were treated for a median of 6.2 months and had a median survival of 20 months.

    “In the PriDE dataset reflecting routine clinical use of the device, patients who received TTFields at first recurrence were treated for a median of 6.2 months and had a median survival of 20 months, comparing favorably with recent trial results investigating other novel agents.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    A second generation of the TTFields device with a reduction in size and weight by about 50% compared with the device used in the EF-11 and EF-14 trials has been developed.

    “To reduce some of the burden of therapy, a second generation of the TTFields device with a reduction in size and weight by about 50% compared with the device used in the EF-11 and EF-14 devices has been developed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In the EF-14 trial, global health status improved at 3 and 6 months compared with baseline for patients treated with TTFields and TMZ, whereas patients in the control group showed a decrease in global health status over the same period.

    “Moreover, the global health status showed an improvement at 3 and 6 months in comparison with baseline for patients treated with TTFields and TMZ, whereas patients in the control group showed a decrease in global health status over the same time period.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Zhu, 2015, ACTC-35, Quality of life, cognitive function and functional status in the EF-14 trial, Neuro Oncol

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Nonspecific adverse effects including mild anxiety, confusion, insomnia, and headaches were reported more frequently in patients treated with TTFields plus TMZ and occurred mainly at therapy initiation.

    “Some nonspecific adverse effects including nervous system disorders such as grade 1–2 headache (21% in the experimental group vs 14% in patients with TMZ alone), mild anxiety, confusion, insomnia, and headaches were reported more frequently in the patients treated with TTFields plus TMZ and occurred mainly at the time of therapy initiation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The progression-free survival of 4.0 months from randomization observed in the control group of the EF-14 trial was numerically shorter but overall comparable to the observed progression-free survival of 5.5 months in the RTOG 0525 trial.

    “The PFS of 4.0 months (from randomization) observed in the control group of the EF14 trial is numerically shorter (likely due to the independent imaging review and assessment of progression) but overall comparable to the observed PFS of 5.5 months observed in the RTOG 0525 trial,29 a trial that also randomized patients only after completion of the concomitant radiochemotherapy part of treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In pancreatic cancer, the partial response rate was 30% and another 30% had stable disease.

    “The partial response rate was 30% and another 30% stable disease.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Rivera F Gallego J Guillen C . PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma. J Clin Oncol. 2016;34(suppl; abstr 4125). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In pancreatic cancer, median overall survival was not reached in patients with locally advanced disease and was 8.3 months (CI 4.3-14.9 months) for patients with metastatic disease.

    “It was not reached in patients with locally advanced disease, and 8.3 months (CI, 4.3–14.9 mo) for patients with metastatic disease with 1-year survival rates of 86% in locally advanced patients and 40% in patients with metastatic disease32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Rivera F Gallego J Guillen C . PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma. J Clin Oncol. 2016;34(suppl; abstr 4125). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Findingcitation

    In pancreatic cancer, the median overall survival for all patients was 14.9 months.

    “The median OS for all patients was promising for this disease at 14.9 months.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Rivera F Gallego J Guillen C . PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma. J Clin Oncol. 2016;34(suppl; abstr 4125). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    In pancreatic cancer, 1-year survival rates were 86% in locally advanced patients and 40% in patients with metastatic disease.

    “It was not reached in patients with locally advanced disease, and 8.3 months (CI, 4.3–14.9 mo) for patients with metastatic disease with 1-year survival rates of 86% in locally advanced patients and 40% in patients with metastatic disease32”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Rivera F Gallego J Guillen C . PANOVA: A pilot study of TTFields concomitant with gemcitabine for front-line therapy of advanced pancreatic adenocarcinoma. J Clin Oncol. 2016;34(suppl; abstr 4125). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    The excellent compatibility between TTFields and various chemotherapeutic agents has been demonstrated in glioblastoma patients in the EF-14 trial and in lung cancer patients.

    “The excellent compatibility between TTFields and various chemotherapeutic agents has already been demonstrated, not only in GBM patients in the EF-14 trial but also in lung cancer patients.30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200 kHz) that block cell division and interfere with organelle assembly.

    “Tumor treating fields (TTFields) are low-intensity electric fields alternating at an intermediate frequency (200kHz), which have been demonstrated to block cell division and interfere with organelle assembly.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] source

      Not checked in the free run.

    • cites [9] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In initial experiments, exposure of a variety of tumor cell lines to TTFields exerted a profound growth inhibitory effect by inducing cell cycle arrest and apoptosis, while no effect was induced on non-dividing cells.

    “In initial experiments, exposure of a variety of tumor cell lines to TTFields was shown to exert a profound growth inhibitory effect by inducing cell cycle arrest and apoptosis, while no effect was induced on non-dividing cells.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The consequences of TTFields are inadequate cell division and unequal chromosome distribution, ultimately leading to cell death by apoptosis.

    “The consequences are inadequate cell division and unequal chromosome distribution. Ultimately, cells will die in apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    In summary, TTFields block the mitotic cell cycle, particularly during metaphase, anaphase, and telophase, resulting in cell cycle arrest or delay in cell division and interference with organelle assembly, particularly the spindle apparatus.

    “In summary, TTFields will block the mitotic cell cycle, in particular during metaphase, anaphase, and telophase. This will result in cell cycle arrest or delay in cell division and interfere with organelle assembly, particularly the spindle apparatus (fig. 1 C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In telophase, the hourglass shape of daughter cells induces a nonuniform electric field enhanced at the furrow region, resulting in dielectrophoretic forces that may attract charged molecules from the cytosol and compromise normal cytokinesis.

    “In telophase, during cytokinesis the hourglass shape taken by the daughter cells that are about to separate induces a nonuniform electric field that is strongly enhanced at the level of the furrow region (→ fig. 1). This results in dielectrophoretic forces that may attract charged molecules from the cytosol and compromise normal cytokinesis.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The design and conduct of the EF-11 trial had inherent limitations: numerous prior treatment lines were allowed and led to a heterogeneous patient population, with more than 40% of patients included after the third recurrence, including many who had failed prior bevacizumab therapy.

    “The design and conduct of the EF-11 trial had some inherent limitations: numerous prior treatment lines were allowed and led to a heterogeneous patient population. More than 40% of patients were included after the third recurrence, including many patients who had failed prior bevacizumab therapy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of TTFields also results in abnormal chromosomal segregation and reduced clonogenic potential of the cell's progeny.

    “This effect also results in abnormal chromosomal segregation and reduced clonogenic potential of the cell’s progeny.10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The computational model revealed inhomogeneous fields with intensification of field strength near the ventricles due to high conductivity of cerebrospinal fluid; necrotic and edematous regions also showed high conductivity, while areas with high cellularity showed lower conductivity.

    “The computational model also revealed inhomogeneous fields with intensification of the field strength near the ventricles as a result of the high conductivity of the cerebrospinal fluid. Necrotic areas and edematous regions also showed high conductivity of the TTFields. In contrast, areas with high cellularity showed lower conductivity.15”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a computational model, the optimal frequency of TTFields for glioblastoma was found to be in the range of 200 kHz, and the field strength should be at least 1 V/cm.

    “In a computational model, the optimal frequency of TTFields for GBM was found to be in the range of 200kHz. The field strength should be ≥ 1V/cm.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Metastatic cancer is a systemic disease, so most effects of TTFields would be expected to be seen in diseases or situations where primarily locoregional control is warranted.

    “However, metastatic cancer is a systemic disease, thus most effects of application of TTFields would be expected to be seen in diseases or situations where primarily locoregional control is warranted.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    TTFields target proteins with large dipole moments, namely septins and spindle microtubules, which are essential in metaphase and anaphase for separation and equal distribution of chromosomes.

    “TTFields will target proteins with large dipole moments (ie, septins and the spindle microtubules, components essential in the metaphase and anaphase stages of the mitotic cycle for separation and equal distribution of chromosomes).9,10”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The optimal frequency to maximize the antitumor effect of TTFields is inversely correlated with cell size and when the incident angle of the electrical field is perpendicular to the mitotic plate.

    “The optimal frequency to maximize the antitumor effect is inversely correlated with cell size and when the incident angle of the electrical field is perpendicular to the mitotic plate.7”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the very first clinical application, TTFields treatment was applied to patients with cutaneous metastases of melanoma or breast cancer, and tumor shrinkage or even complete disappearance was demonstrated.

    “In the very first clinical application, TTFields treatment was applied to patients with cutaneous metastases of melanoma or breast cancer. Tumor shrinkage or even complete disappearance was demonstrated.12,14”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] source

      Not checked in the free run.

    • cites [14] Kirson ED Schneiderman RS Dbaly V . Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys. 2009;9:1. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    TTFields take a prolonged period until their effects can be clinically demonstrated, and delayed responses may occur after initial radiological tumor growth; thus, some patients in EF-11 may have discontinued TTFields treatment prematurely.

    “It is known that TTFields take a prolonged period of time until its effects can be clinically demonstrated or that delayed responses may occur after initial radiological tumor growth; thus, some patients may have discontinued TTFields treatment prematurely.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: TTFields take a prolonged period until their effects can be clinically demonstrated, and delayed responses may occur after initial radiological tumor growth.

  • May combine two claims.

    Premisereasoning

    Primary brain tumors, notably glioma, rarely metastasize; recurrence in the brain is the predominant cause of treatment failure and was chosen as the first disease in which the effect of TTFields could be investigated prospectively.

    “Primary brain tumors—and notably glioma—rarely metastasize; recurrence in the brain is the predominant cause of treatment failure and was chosen as the first disease in which the effect of TTFields could be investigated prospectively.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Primary brain tumors, notably glioma, rarely metastasize, and recurrence in the brain is the predominant cause of treatment failure.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    In the EF-14 trial, a blinded central imaging and disease assessment review determined the date of progression.

    “All treatment-related clinical decisions were based on local interpretation of imaging; however, a blinded central imaging and disease assessment review determined the date of progression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Alternating electric fields arrest dividing cells in metaphase and anaphase, perturb assembly and function of the mitotic spindle, and cause cells to undergo apoptosis.

    “Dividing cells are arrested in metaphase and anaphase, assembly and function of the mitotic spindle are perturbed, and cells ultimately undergo apoptosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The results of the randomized phase III EF-14 trial provide level 1 evidence that alternating electric fields are able to positively impact tumor growth and significantly extend survival in glioblastoma.

    “The results of the randomized phase III EF-14 trial provide level 1 evidence that alternating electric fields are able to positively impact tumor growth and significantly extend survival in GBM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    A placebo effect might be expected on subjective endpoints such as quality of life or cognitive function, but it is difficult to envision an effect on objective endpoints such as overall survival or progression-free survival, especially when progression was determined by blinded central radiologists.

    “Whereas some placebo effect might be expected on subjective endpoints, such as quality of life or cognitive function, it is difficult to envision an effect on objective endpoints such as OS or PFS (especially when progression was determined by blinded central radiologists).27”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    In the PriDE uncontrolled routine practice patient population, strong selection bias and inclusion of patients with pseudoprogression after initial TMZ chemoradiotherapy cannot be ruled out.

    “However, a strong selection bias and inclusion of patients with pseudoprogression after initial TMZ chemoradiotherapy cannot be ruled out in this uncontrolled routine practice patient population.26”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    A sham device would not be practically feasible or acceptable for patients, caregivers, and ethics committees.

    “However, a sham device would neither be practically feasible (some heating of the electrodes is inevitable; technically savvy patients would rapidly figure out whether there is any current flowing), nor acceptable for patients, caregivers, and ethics committees given the perceived burden of shaving the scalp and replacing transducer arrays every 3 days.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In October 2015, the FDA approved TTFields for use in newly diagnosed glioblastoma patients.

    “In October 2015, the FDA approved TTFields for use in newly diagnosed GBM patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Having to shave the scalp is a psychological barrier.

    “Having to shave the scalp is indeed a psychological barrier, although in oncology, for decades we have been using cytotoxic agents that are inducing complete hair loss of all body hair and not only the scalp.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Giving TTFields early in the disease course allows for prolonged exposure, and the in vitro observed synergy with TMZ may further enhance its efficacy.

    “Giving TTFields early in the disease course allows for prolonged exposure, and the in vitro observed synergy with TMZ may further enhance its efficacy.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Glioblastoma appeared to be the ideal candidate to serve as a proof of concept demonstration of TTFields.

    “As GBM is a disease that remains confined to the CNS and the scalp offers an easy application site for long-term use of transducer arrays, it appeared to be the ideal candidate to serve as a proof of concept demonstration of TTFields.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: TTFields can only be applied to certain areas of the body.
    • Rests on an assumption: It is possible to affix a transducer array to the skin of the patient over the area of the tumor.
    • Rests on an assumption: Glioblastoma remains confined to the CNS.
    • Rests on an assumption: The scalp offers an easy application site for long-term use of transducer arrays.

  • May combine two claims.

    Study design and conductcitation

    In the EF-14 trial, at a prespecified interim and futility analysis, a significant improvement in progression-free and overall survival was seen; the independent data monitoring committee recommended early termination for success and allowed crossover to the TTFields arm.

    “At a prespecified interim and futility analysis to be performed once the first 315 randomized patients reached a minimum follow-up of 18 months, a significant improvement in progression-free and overall survival was seen; consequently the independent data monitoring committee recommended that the trial be terminated early for success and that patients be allowed to cross over to the TTFields arm.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisenone given

    TTFields is a locoregional treatment.

    “TTFields is a locoregional treatment, and extending its use to other tumor types and metastatic disease is most promising in clinical situations where locoregional disease control is key for quality of life.”
    Quote in the paperSubstantial claim
49 of 49

  • The paper relies on this without support.

    TTFields take a prolonged period until their effects can be clinically demonstrated, and delayed responses may occur after initial radiological tumor growth.

    “It is known that TTFields take a prolonged period of time until its effects can be clinically demonstrated or that delayed responses may occur after initial radiological tumor growth; thus, some patients may have discontinued TTFields treatment prematurely.”

  • The paper relies on this without support.

    Primary brain tumors, notably glioma, rarely metastasize, and recurrence in the brain is the predominant cause of treatment failure.

    “Primary brain tumors—and notably glioma—rarely metastasize; recurrence in the brain is the predominant cause of treatment failure and was chosen as the first disease in which the effect of TTFields could be investigated prospectively.”

  • The paper relies on this without support.

    There is no commonly accepted standard treatment for recurrent glioblastoma.

    “In the absence of a commonly accepted standard treatment for recurrent GBM, the control patients were to receive the best available systemic therapy according to the current local practice.”

  • The paper relies on this without support.

    TTFields need to be delivered continuously to achieve the expected cytotoxic effect.

    “(1) TTFields need to be delivered in a continuous manner to achieve the expected cytotoxic effect”

  • The paper relies on this without support.

    TTFields can only be applied to certain areas of the body.

    “(2) TTFields can only be applied to certain areas of the body”

  • The paper relies on this without support.

    It is possible to affix a transducer array to the skin of the patient over the area of the tumor.

    “this (3) requires the possibility to affix transducer array to the skin of the patient over the area of the tumor.”

  • The paper relies on this without support.

    Glioblastoma remains confined to the CNS.

    “As GBM is a disease that remains confined to the CNS”

  • The paper relies on this without support.

    The scalp offers an easy application site for long-term use of transducer arrays.

    “the scalp offers an easy application site for long-term use of transducer arrays”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • TTFields force microtubular filaments to align along electric field lines, interrupting the functionality of the mitotic spindle in actively dividing cells.

    “By forcing microtubular filaments to align along electric field lines through the exogenous imposition of TTFields, the functionality of the mitotic spindle is interrupted in actively dividing cells [18] thereby disrupting replication [8,9,19]”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [18]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • EF-14 overall-survival P values disagree

    Major

    Table 1 reports P=0.0004 for EF-14 overall survival, while the results text reports P=.03 for the same overall-survival comparison.

  • EF-11 overall-survival P values disagree

    Minor

    The Figure 4 caption gives P=0.66 for EF-11 overall survival, whereas the results text gives P=0.27 for the same comparison.

  • EF-11 overall-survival confidence-interval limits disagree

    Minor

    Table 1 gives 1.22 as the upper limit of the EF-11 overall-survival hazard ratio confidence interval; the results text gives 1.12.

  • EF-14 progression confidence level disagrees

    Minor

    The results text labels the 0.43-0.89 interval for the EF-14 progression hazard ratio as a 98.7% CI, while the Figure 4 caption labels the same interval as a 95% CI.

4 of 4

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Zhu, 2015, ACTC-35, Quality of life, cognitive function and functional status in the EF-14 trial, Neuro Oncol, 17, v1

Cited by

Sorted by citations

Related

Authors
Hottinger, A. F., Pacheco, P., & Stupp, R.
Affiliations
University of Zurich (CH)
Corresponding author
  • Hottinger, Andreas F.
  • Stupp, Roger
ORCID
Venue
Neuro-Oncology
Publisher
Oxford University Press (OUP)
Published
2016-09-24
Volume
18
Issue
10
Pages
1338-1349
ISSN
  • 1522-8517 (ISSN-L)
  • 1523-5866
DOI
10.1093/neuonc/now182
PMC
PMC5035531
OpenAlex
W2523123787
Semantic Scholar
1388d2a7de8ea992c4c9bfb0addf8ec4c790b64c
Cited by
177
References
32
Citations by year
2026: 9 · 2025: 13 · 2024: 15 · 2023: 18 · 2022: 22 · 2021: 24 · 2020: 17 · 2019: 16 · 2018: 28 · 2017: 15
FWCI
2.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuro-Oncology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by-nc)
  • IRIS (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by-nc)
  • Zurich Open Repository and Archive (University of Zurich)
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
Keywords
tumor treating fields, glioblastoma, brain tumors, cell division inhibition, organelle assembly, progression-free survival, overall survival, transducer array, mechanism of action, preclinical evidence
MeSH terms
Animals, Brain Neoplasms, Electric Stimulation Therapy, Glioblastoma, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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