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Cited by 894Electromagnetic Fields and Biological EffectsGlioma Diagnosis and TreatmentMicrobial Inactivation Methods

Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors

Open access
Kirson, Eilon D., Dbalý, Vladimír, Tovaryš, František, Vymazal, Josef, Soustiel, Jean F., Itzhaki, Aviran, Mordechovich, Daniel, Steinberg-Shapira, Shirley +8 more·2007·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0702916104PMC PMC1886002
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Abstract

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro . Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro , in vivo and, as demonstrated here, in human cancer patients.

AI snapshot

Written from the paper’s full text.

TL;DR

Tumor treating fields (TTFields), low-intensity intermediate-frequency alternating electric fields, inhibited proliferation of multiple cancer cell lines and animal tumors and showed promising safety/efficacy in a 10-patient pilot trial of recurrent glioblastoma. Median time to progression was 26.1 weeks and median overall survival was 62.2 weeks, with contact dermatitis as the only device-related side effect.

Key findings

  • In culture, 24-h TTFields exposure slowed proliferation; optimal frequencies were 100 kHz for mouse melanoma B16F1, 150 kHz for human breast carcinoma MDA-MB-231, and 200 kHz for rat glioma F-98 and human glioma U-118/U-87. Two perpendicular fields were ≈20% more effective than a single direction for B16F1 and F-98 cells.
  • In rats with intracranial F-98 glioma, unidirectional TTFields reduced tumor volume by 19.8% versus sham controls (n = 26; P = 0.19), while two and three field directions inhibited growth by 42.6% (n = 42; P < 0.01) and 53.4% (n = 10; P < 0.01), respectively.
  • In mice with B16F1 melanoma, maximal growth inhibition occurred at 100 kHz, with treated tumor size 62.7 ± 8.9% of control tumors (n = 26; single-factor ANOVA P = 0.11).
  • In 10 recurrent GBM patients, median TTP was 26.1 weeks (range 3–124 weeks), PFS6 was 50% (23–77% 95% CI), and median OS was 62.2 weeks (range 20.3–124.0 weeks); after >70 months cumulative treatment, no device-related serious adverse events occurred, and 9 of 10 patients had mild to moderate contact dermatitis beneath the electrodes.

Methods

  • In vitro: cancer cell lines were grown in DMEM plus 10% FCS, exposed to TTFields via insulated PMN-PT electrodes, and proliferation was measured by XTT as the OD1/OD0 ratio after 24 h; two perpendicular field directions were switched every 0.25–1 sec.
  • Animal models: Fischer rats were inoculated intracranially with F-98 glioma cells and treated with external insulated electrodes at 200 kHz and 2 V/cm for 6 days, with tumor volume assessed by serial T1-weighted MRI; B16F1 melanoma-bearing mice were used for frequency-dependence studies, and rabbits were used for safety testing.
  • Clinical trial: a single-arm pilot trial treated 10 recurrent GBM patients with the NovoTTF-100A device at 200 kHz and 1–2 V/cm, switching between two perpendicular directions every 1 sec for an average of 18 h/day until progression; TTP, PFS6, and OS were compared with literature-based historical controls, with 95% CIs calculated from Kaplan–Meier curves.

Limitations

  • The paper states that this was a pilot trial with no randomized control group, that results were evaluated by comparison to historical control data, and that no statistical hypothesis testing was planned because of the small sample size.
  • The paper states that efficacy analysis was performed in 10 recurrent GBM patients, with historical controls drawn from a meta-analysis and four prospective trials; this single-arm design limits direct causal inference.
  • Evident from the text: several authors are employed by, consult for, or hold equity in NovoCure Ltd., and the work was supported by NovoCure Ltd.; additionally, the in vivo B16F1 frequency dependence did not reach statistical significance (P = 0.11), and the unidirectional rat glioma effect was not statistically significant (P = 0.19).

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

Integrity signals

Registry

Crossref · 10.1073/pnas.0702916104

Cites

36 of 36 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 45 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    In 10 patients with recurrent glioblastoma, median time to disease progression was 26.1 weeks.

    “Median time to disease progression in these patients was 26.1 weeks”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes.

    “The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    No device-related serious adverse events were seen after more than 70 months of cumulative treatment in all patients.

    “No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    In 10 patients with recurrent glioblastoma, median overall survival was 62.2 weeks.

    “median overall survival was 62.2 weeks.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    Median time to disease progression of the 10 recurrent glioblastoma patients was 26.1 weeks (range 3-124 weeks).

    “the median time to disease progression (TTP) of the patients is 26.1 weeks (range 3–124 weeks)”
    Quote in the paperSubstantial claim
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 28
  • The quote only partly states this claim. 2

  • May combine two claims.

    Findingown data
    § Abstract

    In mice inoculated with B16F1 melanoma and treated for 5 days by single-direction TTFields, maximal growth inhibition was at 100 kHz, with treated tumor size 62.7 ± 8.9% that of control tumors.

    “The maximal growth inhibition was found at 100 kHz, with the treated tumor size 62.7 ± 8.9% that of control tumors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    In this study, the proliferation of breast carcinoma and non-small-cell lung carcinoma cells exposed to TTFields is arrested and the cells are destroyed.

    “It was found that the proliferation of these cells is arrested and the cells are destroyed (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Rats bearing intracerebral glioma were unaffected by 100 kHz TTFields, whereas 200 kHz TTFields caused significant inhibition of tumor growth.

    “In contrast, rats bearing intracerebral glioma were unaffected by 100 kHz TTFields, whereas 200 kHz TTFields caused significant inhibition of tumor growth.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    The 10 recurrent glioblastoma patients received treatment for a total of 280 weeks without a single treatment-related serious adverse event.

    “The 10 recurrent GBM Patients received treatment for a total of 280 weeks without a single treatment-related serious adverse event”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Sensitivity to TTFields is highest for mouse melanoma cells, decreasing for rat glioma and human non-small-cell lung carcinoma, and lowest for human breast carcinoma.

    “the sensitivity being highest for mouse melanoma cells, decreasing for rat glioma and for human non-small-cell lung carcinoma and lowest for human breast carcinoma.”
    Quote in the paperNot a substantial claim

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

    Findingnone given
    § Discussion

    The field intensity is 100-fold lower within the bone marrow compared with the surrounding tissues.

    “the field intensity is 100-fold lower within the bone marrow compared with the surrounding tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    Unidirectional TTFields in a temporal-temporal direction produced a small average inhibitory effect on intracranial glioma tumor volume that did not reach statistical significance, with treated tumor volume 19.8% smaller than sham control tumors (n = 26; P = 0.19).

    “The average inhibitory effect of unidirectional TTFields (in a temporal-temporal direction) was small and did not reach statistical significance (treated tumor volume 19.8% smaller than sham control tumors; n = 26; P = 0.19, Student's t test).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    In four common cancer types exposed to TTFields for 24 hours, unexposed control cells roughly double every 24 hours, whereas the proliferation rate of exposed cells is slowed during exposure and gradually recovers after treatment is terminated.

    “It is seen that the number of unexposed (control) cells roughly doubles every 24 h, whereas the proliferation rate of the exposed cells is slowed down during exposure and gradually recovers after treatment is terminated (Fig. 2A).”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Abstract

    The treatment-related contact dermatitis responded well to application of steroid creams and periodic electrode relocation.

    “This treatment-related adverse event responded well to application of steroid creams and periodic electrode relocation.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Abstract

    Increasing the number of TTFields directions caused statistically significant inhibition of intracranial glioma tumor growth, reaching 42.6% for two directions and 53.4% for three directions positioned at 45-90° to each other.

    “However, increasing the number of TTFields directions caused statistically significant inhibition of tumor growth, reaching 42.6% and 53.4% for two (n = 42; P < 0.01, Student's t test) and three (n = 10; P < 0.01, Student's t test) directions positioned at 45–90° to each other, respectively.”
    Quote in the paperSubstantial claim

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

    Findingown data
    § Abstract

    Two recurrent glioblastoma patients had partial seizures that were unrelated to treatment.

    “Two patients had partial seizures that were unrelated to treatment.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The two partial seizures observed in recurrent glioblastoma patients were unrelated to TTFields treatment.

  • May combine two claims.

    Findingown data
    § Abstract

    In human glioma cell lines U-118 and U-87, the optimal TTFields frequency was 200 kHz, identical to rat glioma cell lines.

    “In both, the optimal TTFields frequency was identical to rat glioma cell lines (i.e., 200 kHz).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    One recurrent glioblastoma patient had a minimal response and four had stable disease for over 4 months before progressing.

    “In addition one patient had minimal response and four had stable disease for over 4 months before progressing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning
    § Discussion

    No treatment-related toxicities were found in any treated patients or upon animal exposure to field intensities threefold higher than the effective anti-tumoral dose.

    “However, no treatment-related toxicities were found in any of the treated patients or upon animal exposure to field intensities threefold higher than the effective anti-tumoral dose.”
    Quote in the paperSubstantial claim

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

    Findingnone given
    § Materials and Methods

    All patients had received adjuvant Temozolomide for their primary tumor.

    “All patients had received adjuvant Temozolomide for their primary tumor.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    TTFields are effective in arresting the proliferation and inducing death in a wide range of tumor cells in culture as well as solid tumors in animals.

    “we demonstrated initially that TTFields are effective in arresting the proliferation and inducing death in a wide range of tumor cells in culture as well as solid tumors in animals.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    These results were not accompanied by hematological or gastrointestinal toxicities, epileptic seizures, cardiac arrhythmias, etc., despite >70 months of cumulative treatment.

    “These results were not accompanied by hematological or gastrointestinal toxicities, epileptic seizures, cardiac arrhythmias, etc., despite >70 months of cumulative treatment.”
    Quote in the paperSubstantial claim

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

    Findingreasoning
    § Materials and Methods

    The impedance of each electrode is 190 Ω at 100 kHz and 95 Ω at 200 kHz.

    “This translates into an impedance of 190 and 95 Ω at 100 and 200 kHz, respectively.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Materials and Methods

    Twelve patients suffering from GBM were enrolled to the study.

    “Twelve patients, suffering from the brain tumor GBM were enrolled to the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    TTFields inhibit the growth of recurrent GBM with little or no side effects.

    “It was demonstrated that the TTFields inhibit the growth of this highly treatment-resistant tumor by using special insulated electrodes, with little or no side effects.”
    Quote in the paperSubstantial claim

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

    Findingnone given
    § Materials and Methods

    On average, the capacitance of each electrode is 8 nF.

    “On average, the capacitance of each electrode is 8 nF.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    In the current pilot trial, TTP was 26.1 weeks, PFS6 was 50%, and OS was 62.2 weeks.

    “the efficacy data collected in the current pilot trial is extremely promising (TTP, 26.1 weeks; PFS6, 50%; and OS, 62.2 weeks).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data
    § Materials and Methods

    The optimal frequency of TTFields for rat and human gliomas is 200 kHz.

    “TTFields having the optimal frequency of 200 kHz for rat and human gliomas (see Fig. 2) and an intensity of 1–2 V/cm (peak) were used in the trial.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    The time to disease progression and overall survival values of TTFields-treated recurrent glioblastoma patients are more than double the reported medians of historical control patients.

    “These time to disease progression and OS values are more than double the reported medians of historical control patients.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Historical control patients with recurrent glioblastoma have median time to progression and overall survival less than half of the observed 26.1 and 62.2 weeks.

  • May combine two claims.

    Interpretationown data
    § Abstract

    TTFields effectively slow down tumor growth in vitro, in vivo, and in human cancer patients.

    “which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data
    § Abstract

    In a pilot clinical trial in recurrent glioblastoma, TTFields treatment was safe and effective in slowing tumor progression.

    “In a pilot clinical trial conducted on this extremely malignant tumor of glial cell origin (10, 11), TTFields treatment was found to be both safe and effective in slowing tumor progression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The elevated liver enzymes observed in recurrent glioblastoma patients were caused by anti-epileptic drug usage.
    • Rests on an assumption: The two partial seizures observed in recurrent glioblastoma patients were unrelated to TTFields treatment.

  • May combine two claims.

    Premisecitation
    § Abstract

    The effects of TTFields during cytokinesis are based on unidirectional forces induced by inhomogeneous fields at the bridge separating daughter cells, which interfere with spindle tubulin orientation and induce dielectrophoresis.

    “The basis of these effects during cytokinesis was shown to be the unidirectional forces induced by the inhomogeneous fields at the bridge separating the daughter cells (Fig. 1B) that interfere with spindle tubulin orientation and induce dielectrophoresis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Cancer Res. 2004;64:3288–3295. doi: 10.1158/0008-5472.can-04-0083. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Abstract

    TTFields are effective when applied by insulated external electrodes to animal cancer models and patients with recurrent glioblastoma.

    “we demonstrate here that such fields, termed tumor treating fields (TTFields), are effective when applied by insulated external electrodes to animal cancer models and patients with recurrent glioblastoma (GBM).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    Alternating electric fields of intermediate frequencies from 10 kHz to 1 MHz were considered not to have any meaningful non-thermal biological effects.

    “Alternating electric fields of intermediate frequencies (10 kHz to 1 MHz) were considered not to have any meaningful non-thermal biological effects (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Polk C, Postow E. Biological Effects of Electromagnetic Fields Handbooks, Manuals, Etc. Boca Raton, FL: CRC; 1995. p. 618. [Google Scholar]

      Not checked in the free run.

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

    Interpretationown data
    § Abstract

    The elevated liver enzymes in recurrent glioblastoma patients were attributed to anti-epileptic drug usage.

    “The only changes seen consistently were elevated liver enzymes, attributed to anti-epileptic drug usage.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The elevated liver enzymes observed in recurrent glioblastoma patients were caused by anti-epileptic drug usage.

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

    Premisecitation
    § Discussion

    At very low frequencies below 1 kHz, electric fields stimulate excitable tissues through membrane depolarization.

    “At very low frequencies (<1 KHz), electric fields stimulate excitable tissues through membrane depolarization (13)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Polk C. In: The Biomedical Engineering Handbook. Bronzino JD, editor. Hartford, CT: CRC; 1995. pp. 1404–1416. [Google Scholar]

      Not checked in the free run.

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

    Premisecitation
    § Discussion

    Electric fields have been claimed to stimulate bone growth and accelerate fracture healing.

    “and have been claimed to stimulate bone growth and accelerate fracture healing (14).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Basset CA. Clin Plast Surg. 1985;12:259–277. [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductreasoning
    § Discussion

    The pilot trial had no randomized control group and the results were evaluated by comparing to historical control data.

    “Because this was a pilot trial there was no randomized control group and the results were evaluated by comparing to historical control data.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Discussion

    The tumor inhibitory effect of TTFields has been attributed previously to two separate mechanisms: interference with the formation of the mitotic spindle microtubules and physical destruction of cells during cleavage, both of which are strongly dependant on the orientation of mitosis axis versus the field vectors.

    “The tumor inhibitory effect of TTFields has been attributed previously to two separate mechanisms (9): interference with the formation of the mitotic spindle microtubules and physical destruction of cells during cleavage, both of which are strongly dependant on the orientation of mitosis axis versus the field vectors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Cancer Res. 2004;64:3288–3295. doi: 10.1158/0008-5472.can-04-0083. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    Most historically controlled pilot studies in recurrent GBM are compared with a large metaanalysis performed by Wong et al. in 1999 and to this data we added the four prospective trials, which included >50 GBM patients, performed since that date.

    “Most historically controlled pilot studies in recurrent GBM are compared with a large metaanalysis performed by Wong et al. in 1999 (10) and to this data we added the four prospective trials (25–28), which included >50 GBM patients, performed since that date.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [10] Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK. J Clin Oncol. 1999;17:2572–2578. doi: 10.1200/JCO.1999.17.8.2572. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [25] Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, et al. Br J Cancer. 2000;83:588–593. doi: 10.1054/bjoc.2000.1316. [DOI] [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [26] Brada M, Hoang-Xuan K, Rampling R, Dietrich PY, Dirix LY, Macdonald D, Heimans JJ, Zonnenberg BA, Bravo-Marques JM, Henriksson R, et al. Ann Oncol. 2001;12:259–266. doi: 10.1023/a:1008382516636. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [27] Chang SM, Theodosopoulos P, Lamborn K, Malec M, Rabbitt J, Page M, Prados MD. Cancer. 2004;100:605–611. doi: 10.1002/cncr.11949. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [28] Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, et al. J Clin Oncol. 2004;22:133–142. doi: 10.1200/JCO.2004.08.110. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation
    § Abstract

    The in vivo frequency dependence of B16F1 melanoma shows the same frequency dependency as cultured B16F1 cells, supporting the conclusion that 100 kHz is the optimum frequency.

    “it shows the same frequency dependency as the dependence of cultured B16F1 cells reported in ref. 9, which supports the conclusion that this is the optimum frequency.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Cancer Res. 2004;64:3288–3295. doi: 10.1158/0008-5472.can-04-0083. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    The results reported here are the first evidence of the safety and efficacy of TTFields used to treat cancer in patients.

    “The results reported here are the first evidence of the safety and efficacy of TTFields used to treat cancer in patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    As the frequency of an electric field increases, its stimulatory effect diminishes, whereas above MHz tissue heating becomes dominant.

    “However, as the frequency of the electric field increases the stimulatory effect diminishes, whereas above MHz a completely different biological effect, tissue heating, becomes dominant (15, 16).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Elson E. In: The Biomedical Engineering Handbook. Bronzino JD, editor. Hartford, CT: CRC; 1995. pp. 1417–1423. [Google Scholar]

      Not checked in the free run.

    • cites [16] Chou CK. In: The Biomedical Engineering Handbook. Bronzino JD, editor. Hartford, CT: CRC; 1995. pp. 1424–1430. [Google Scholar]

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationcitation
    § Abstract

    The finding that two perpendicular fields are more effective is consistent with previously reported effects on malignant melanoma cells.

    “This result is consistent with the previously reported effects on malignant melanoma cells (9).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [9] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y. Cancer Res. 2004;64:3288–3295. doi: 10.1158/0008-5472.can-04-0083. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Abstract

    TTFields efficacy is a function of the angle between the field and the axis of division, being maximal when they are parallel and minimal when they are perpendicular.

    “From the mechanism of action of TTFields, as illustrated in Fig. 1, it can be deduced that their efficacy must be a function of the angle between the field and axis of division; when the two are parallel its maximal and when one is perpendicular to the other, it must be minimal.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Materials and Methods

    The lowest prolonged temperature that can cause thermal injury is 44°C.

    “This value is well below the threshold of 44°C, i.e., the lowest prolonged temperature that can cause thermal injury (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Moritz AR, Henriques FCJ. Am J Pathol. 1947;23:695–720. [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Study design and conductnone given
    § Materials and Methods

    The study was performed according to an experimental protocol approved by the Rambam Medical Center ethics committee.

    “The study was performed according to an experimental protocol approved by the Rambam Medical Center ethics committee.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Materials and Methods

    The level generally recognized to present a risk of skin injury is 100 mA/cm2.

    “approximately one-third of the level that is generally recognized to present a risk of skin injury (100 mA/cm2) (34).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Moritz AR, Henriques FCJ. Am J Pathol. 1947;23:695–720. [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    TTFields treatment was well tolerated and caused almost no toxicity at all.

    “Thus, in conclusion, this treatment modality was well tolerated and caused almost no toxicity at all.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Animal experiments were conducted after approval by the Technion-Israel Institute of Technology committee for the care of laboratory animals.

    “Animal experiments were conducted after approval by the Technion–Israel Institute of Technology committee for the care of laboratory animals.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning
    § Discussion

    There is a high probability that TTFields may prove to be an effective and safe therapeutic modality to a large number of human cancers.

    “Therefore, we believe that there is a high probability that TTFields may prove to be an effective and safe therapeutic modality to a large number of human cancers.”
    Quote in the paperNot a substantial claim

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

    Premisecitation
    § Materials and Methods

    The level associated with thermal skin injury is above 0.22 W/cm2.

    “the maximal power density beneath the electrodes was kept beneath 0.22 W/cm2, i.e., below the level associated with thermal skin injury (35).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Becker CM, Malhotra IV, Hedley-Whyte J. Anesthesiology. 1973;38:106–122. doi: 10.1097/00000542-197302000-00002. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Premisenone given
    § Materials and Methods

    The field distributions are determined by the geometry and electrical properties of the electrodes and tissues.

    “These field distributions are determined by the geometry and electrical properties of the electrodes and tissues.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Written informed consent was obtained from each subject.

    “Written informed consent was obtained from each subject.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    All scans were reviewed by a board certified radiologist.

    “All scans were reviewed by a board certified radiologist (J.V.).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Materials and Methods

    An additional patient dropped out of the trial immediately following the baseline visit because of withdrawal of consent.

    “An additional patient dropped out of the trial immediately following the baseline visit because of withdrawal of consent.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data
    § Materials and Methods

    One patient was excluded from efficacy analysis because of failure to meet histological criteria for grade IV glioma.

    “During review of the histology from postprogression debulking surgery, one patient was excluded from efficacy analysis because of failure to meet histological criteria for grade IV glioma.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation
    § Discussion

    The contact dermatitis reaction is most likely the result of a combination of factors, including chronic moisture, heat, and occlusion of the skin; chemical irritation by constituents of the hydrogel and medical tape; and possibly inhibition of cellular replication in the skin by the TTFields.

    “This reaction is most likely the result of a combination of factors, including chronic moisture, heat, and occlusion of the skin; chemical irritation by constituents of the hydrogel and medical tape (29); and possibly inhibition of cellular replication in the skin by the TTFields.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Ancona A, Arevalo A, Macotela E. Dermatol Clin. 1990;8:95–105. [PubMed] [Google Scholar]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning
    § Materials and Methods

    No statistical hypothesis testing was planned because of the small sample size.

    “No statistical hypothesis testing was planned because of the small sample size.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation
    § Materials and Methods

    The assessment of tumor response was based on criteria defined by Macdonald et al.

    “The assessment of tumor response was based on criteria defined by Macdonald et al. (32).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Macdonald DR, Cascino TL, Schold SC, Jr, Cairncross JG. J Clin Oncol. 1990;8:1277–1280. doi: 10.1200/JCO.1990.8.7.1277. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

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

    Study design and conductreasoning
    § Materials and Methods

    Only three electrodes could be positioned on the rat head, generating one to three different field directions.

    “In view of the small size of the head of the rat, only three electrodes could be positioned on it, generating one to three different field directions.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    Adverse events were scored according to the common toxicity criteria scale (version 3).

    “Adverse events occurring during treatment or up to 60 days after termination of therapy were scored according to the common toxicity criteria scale (version 3).”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given
    § Materials and Methods

    The trial was performed after approval by the Na Homolce Institutional Review Board and the Czech Ministry of Health.

    “The trial was performed after approval by the Na Homolce Institutional Review Board and the Czech Ministry of Health.”
    Quote in the paperNot a substantial claim
58 of 58

  • The paper relies on this without support.

    Historical control patients with recurrent glioblastoma have median time to progression and overall survival less than half of the observed 26.1 and 62.2 weeks.

    “These TTP and OS values are more than double the reported medians of historical control patients.”

  • The paper relies on this without support.

    The elevated liver enzymes observed in recurrent glioblastoma patients were caused by anti-epileptic drug usage.

    “The only changes seen consistently were elevated liver enzymes, attributed to anti-epileptic drug usage.”

  • The paper relies on this without support.

    The two partial seizures observed in recurrent glioblastoma patients were unrelated to TTFields treatment.

    “Two patients had partial seizures that were unrelated to treatment.”

  • The paper relies on this without support.

    The historical control group is comparable to the current trial population.

    “Efficacy analysis was performed for 10 recurrent GBM patients by comparing TTP, PFS6, and OS in recurrent GBM patients treated with the NovoTTF-100A device with the TTP, PFS6, and OS of recurrent GBM patients in a literature based historical control group (10, 25–28).”

  • The paper relies on this without support.

    TTFields are most effective when applied for >16 h continuously.

    “Because in vitro data indicate that TTFields are most effective when applied for >16 h continuously (data not shown), patients were treated daily for an average of 18 h per day until progression.”

  • The paper relies on this without support.

    The relative orientation of the mitosis axis during cytokinesis is random.

    “Because the relative orientation of the mitosis axis during cytokinesis is random, it would be expected that only a fraction of dividing cells would be affected by TTFields of any specific direction.”

  • The paper relies on this without support.

    The intestine changes its orientation relative to the applied field, often lowering the efficacy of the mitotic disruption.

    “and that the intestine changes its orientation, relative to the applied field, often lowering the efficacy of the mitotic disruption.”
7 of 7

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?

  • The low efficacy in Neuhaus et al. is probably due to the lower field strength (1 V/cm) compared to the 2-3 V/cm needed for higher efficacy, and to the use of a single-direction electric field.

    “The low efficacy is probably due to the lower field strength (1 V/cm in Neuhaus et al. [46]) compared to what Kirson et al. [47] showed is needed for higher efficacy: 2–3 V/cm [47]. The latter setting resulted in a reduction in cancer cell number [47]. Neuhaus et al. also did not change the AEF direction with respect to the cells, which significantly increases efficacy as demonstrated by Kirson et”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [47]

  • Tumor Treating Fields (TTFields) are noninvasive alternating electric fields in the intermediate frequency range (100-300 kHz) used as an antimitotic cancer treatment.

    “Tumor Treating Fields (TTFields) are noninvasive, alternating electric fields within the intermediate frequency range (100–300 kHz) that are utilized as an antimitotic cancer treatment.”

    From Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics (2020) · cites this paper as [2]

  • Induction of TTFields anti-mitotic effects requires electric field intensities above 1 V/cm RMS.

    “Noteworthy, the duration of the invasion experiments and the applied electric fields intensities were shorter and lower than the duration and the intensities (above 1 V/cm RMS) required for induction of TTFields anti-mitotic effects [1,2].”

    From Tumor Treating Fields (TTFields) Hinder Cancer Cell Motility through Regulation of Microtubule and Actin Dynamics (2020) · cites this paper as [2]

  • An experimental model of rats with intracranially inoculated glioblastoma cells treated with TTFields at 200 kHz over 6 days showed smaller tumors compared with untreated rats.

    “As an example, an experimental model of rats with intracranially inoculated GBM cells treated with TTFields at a frequency of 200kHz over 6 days showed smaller tumors compared with untreated rats.12”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [12]

  • The inhibitory effect of TTFields was significantly increased when two or more, rather than one, field directions were used.

    “The inhibitory effect was significantly increased when 2 or more, rather than 1 field directions were used.12”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [12]

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.

  • Cumulative treatment duration is reported inconsistently

    Minor

    The paper reports a total of 280 treatment weeks, which is about 64 months, but elsewhere describes the cumulative treatment as more than 70 months.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 8

  1. FJJ Keller, WE Gettys, MJ Skove Physics (McGraw–Hill, New York, 1993).
  2. C Polk, E Postow Biological Effects of Electromagnetic Fields Handbooks, Manuals, Etc (CRC, Boca Raton, FL), pp. 618 (1995).
  3. CK Chou The Biomedical Engineering Handbook, ed JD Bronzino (CRC, Hartford, CT), pp. 1424–1430 (1995).
  4. S Orrenius, MJ McCabe, P Nicotera Toxicol Lett, pp. 64–65, Spec no:357–364. (1992).
  5. Y Palti Bull Res Counc Isr Sect E Exp Med 10, 54–56 (1962).
  6. JD Bronzino The Biomedical Engineering Handbook (CRC, IEEE Press, Boca Raton, FL, 1995).
  7. KJ Langen, RP Clauss, M Holschbach, H Muhlensiepen, JC Kiwit, K Zilles, HH Coenen, HW Muller-Gartner J Nucl Med 39, 1596–1599 (1998).
  8. AR Moritz, FCJ Henriques Am J Pathol 23, 695–720 (1947).

Cited by

Sorted by citations

Related

Authors
Kirson, E. D., Dbalý, V., Tovaryš, F., Vymazal, J., Soustiel, J. F., Itzhaki, A., Mordechovich, D., Steinberg-Shapira, S., Gurvich, Z., Schneiderman, R., Wasserman, Y., Salzberg, M., Ryffel, B., Goldsher, D., Dekel, E., & Palti, Y.
Affiliations
  • *NovoCure Limited, Matam Advanced Technology Centre, Haifa 31905, Israel;
  • Na Homolce Hospital (CZ)
  • Rambam Health Care Campus (IL)
  • University Hospital of Basel (CH)
  • Centre National de la Recherche Scientifique (FR)
  • Weizmann Institute of Science (IL)
  • Technion – Israel Institute of Technology (IL)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2007-06-12
Volume
104
Issue
24
Pages
10152-10157
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0702916104
PMC
PMC1886002
OpenAlex
W2156826863
Cited by
894
References
36
Citations by year
2026: 47 · 2025: 64 · 2024: 66 · 2023: 83 · 2022: 86 · 2021: 65 · 2020: 65 · 2019: 51 · 2018: 58 · 2017: 47 · 2016: 55 · 2015: 50 · 2014: 42 · 2013: 32 · 2012: 24
FWCI
7.80
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
Keywords
AC electric field, tumor treating fields, glioblastoma, brain tumors, tumor cell growth inhibition, implanted electrodes, B16F1 melanoma cells, breast cancer, non-small cell lung cancer, recurrent glioblastoma, clinical trials, device safety, contact dermatitis
MeSH terms
Adult, Animals, Brain Neoplasms, Cell Survival, Electric Stimulation Therapy, Female, Glioblastoma, Humans, Microelectrodes, Models, Biological, Neoplasm Recurrence, Local, Neoplasms, Experimental, Pilot Projects, Rats, Inbred F344, Time Factors, Survival Rate, Treatment Outcome, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Mice, Rats

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.

What counts as a claim ›How we measure confidence ›How we check this ›

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