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Cited by 171Electromagnetic Fields and Biological EffectsMicrobial Inactivation MethodsCancer Cells and Metastasis

Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs

Open access
Kirson, Eilon D., Giladi, Moshe, Gurvich, Zoya, Itzhaki, Aviran, Mordechovich, Daniel, Schneiderman, Rosa S., Wasserman, Yoram, Ryffel, Bernhard +2 more·2009·Clinical & Experimental Metastasis
DOI 10.1007/s10585-009-9262-yPMC PMC2776150
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Abstract

Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100-200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.

AI snapshot

Written from the paper’s full text.

TL;DR

In two animal models, TTFields reduced lung metastases and prolonged survival in rabbits with VX-2 kidney tumors. The effects may involve direct inhibition of metastatic cells and/or a systemic anti-tumor immune response.

Key findings

  • In mice, 7 days of TTFields reduced surface lung metastases versus sham controls (1.5 ± 1 vs. 10.3 ± 8.4; P < 0.01) and lowered lung weight (212 ± 10 vs. 253 ± 20 mg; P < 0.01). After 1 week of recovery, total metastases were similar (18 ± 12 vs. 17 ± 15; P = 0.87), but size distribution differed significantly (P < 0.05), with more large metastases in controls and more small metastases in treated mice.
  • In rabbits, TTFields reduced primary kidney tumor volume after treatment (29.0 ± 18.5 vs. 61.1 ± 38.5 cm³; P = 0.0011) and daily growth rate (1.2 ± 1.1 vs. 3.5 ± 3.2; P = 0.003). Median survival was 70 days in treated rabbits versus 57 days in controls (Log-Rank P < 0.05).
  • Rabbit lung metastases were lower when treatment began before day 14 from implantation (n = 12; Fig. 6c; the text reports this as significant while listing P > 0.05), with a trend toward fewer large metastases >3 mm (P = 0.11); no difference was seen when treatment started later. Histology showed fewer metastases per cross-section (11.8 vs. 23.2), smaller mean diameter (1.4 mm vs. 6.2 mm), greater mononuclear infiltration (score 2.0 vs. 1.4), and increased CD4, CD8, and CD45 T-cell counts in TTFields-treated rabbits.

Methods

  • Two animal models were used: female C57BL/6 mice (n = 35) injected IV with B16F10 melanoma and treated with two-directional 100 kHz TTFields for 7 days; and New Zealand White rabbits implanted with VX-2 tumor fragments under the kidney capsule and treated with two-directional 200 kHz TTFields for 5 weeks.
  • Outcomes included mouse lung surface metastases and lung weights at 1 or 7 days after treatment; rabbit MRI tumor volume, survival, and histological/immunohistochemical analysis of lung metastases.
  • Statistical analysis used Student’s t-test, Chi-squared test, Log-Rank test, and a semi-quantitative score (0–5) for immune cell infiltration.

Limitations

  • The paper states that the immune marker profile is not sufficient to prove a tumor-antigen-specific immune reaction, and that the microtubule/migration hypothesis was not directly tested; future experiments are warranted.
  • The paper presents several possible explanations for reduced rabbit lung metastases—lower primary tumor load, inhibited migration into circulation, and systemic immune activation—without directly distinguishing among them.
  • Evident from the text: this is a preclinical animal study only, with small subgroup samples (e.g., n = 12 for early-treatment lung metastasis analysis), and one reported result is internally inconsistent (“significantly lower” with P > 0.05).

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

Integrity signals

Registry

Crossref · 10.1007/s10585-009-9262-y

Cites

23 of 23 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 15 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the lung sections, a mononuclear cell infiltration was present around and within the metastases in all preparations.

    “In the lung sections, it was noted in all preparations that a mononuclear cell infiltration was present around and within the metastases.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Mean metastasis diameter was 1.4 mm per tumor cross-section in TTFields treated groups and 6.2 mm in the control group.

    “Mean metastasis diameter was 1.4 mm per tumor cross-section in TTFields treated groups and 6.2 mm in the control group.”
    Quote in the paperSubstantial claim
  • Findingown data

    When treatment was started later than 14 days from implantation, no difference was seen in the number of lung metastases between the groups.

    “When treatment was started later than 14 days from implantation, no difference was seen in the number lung metastases between the groups.”
    Quote in the paperSubstantial claim
  • Findingown data

    The average TTFields intensities in the lung were 0.5 V/cm, a fifth of the field intensity measured in the kidney.

    “The average TTFields intensities in the lung were 0.5 V/cm which is a fifth of the field intensity measured in the kidney (see “Methods”).”
    • Also stated in: § Metastases in rabbits · hedged
      “The TTFields intensity in the lungs was about 20% of the fields’ intensity in the kidney (data not shown).”
    Quote in the paperSubstantial claim
  • Findingown data

    TTFields treated rabbits had significantly increased CD4, CD8, and CD45 T-cell counts compared to control.

    “This investigation revealed that TTFields treated rabbits had significantly increased CD4, CD8, and CD45 T-cell counts (Table 1) as compared to control.”
    Quote in the paperSubstantial claim
  • May combine two claims. 10
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    The distribution of metastasis sizes differed significantly between the groups (P < 0.05, Chi-squared test), with a higher proportion of large metastases in the control group and a higher proportion of small metastases in the TTFields treated group.

    “However, the distribution of metastasis sizes differed significantly between the groups (P < 0.05, Chi-squared test) with a higher proportion of large metastases seen in the control group, and a higher proportion of small metastases in the TTFields treated group (Fig. 3).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Microscopic scanning of histological slides showed the mean number of lung metastases per tumor cross-section was 11.8 in TTFields treated mice and 23.2 for the control group.

    “The mean number of lung metastases per tumor cross-section was 11.8 in TTFields treated mice and 23.2 for the control group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The median survival of TTFields treated animals was 70 days, significantly longer than the 57 days of control animals (Log-Rank test; P < 0.05).

    “The median survival of TTFields treated animals was 70 days which is significantly longer than the 57 days of the control animals (Log-Rank test; P < 0.05).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Among the intra-tumoral infiltrating cells, CD4 T-cells were more prevalent than CD8 T-cells.

    “Among the intra-tumoral infiltrating cells, CD4 T-cells were more prevalent than CD8 T-cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Most of the immune infiltration was seen in the peri-tumoral location, but the most significant difference was the presence of abundant intra-tumoral infiltration in TTFields treated rabbits.

    “Interestingly, though most of the immune infiltration was seen in the peri-tumoral location, the most significant difference was the presence of an abundant intra-tumoral infiltration in TTFields treated rabbits.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    A trend towards a lower number of large metastases (>3 mm in diameter) was seen in the TTFields treated group, but the difference did not reach significance (P = 0.11).

    “A trend towards a lower number of large metastases (>3 mm in diameter) was also seen in TTFields treated group, however, here the difference did not reach significance (Fig. 6d; P = 0.11).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    TTFields slow tumor progression in animal cancer models and in patients with recurrent and newly diagnosed glioblastoma.

    “TTFields are low intensity, intermediate frequency alternating electric fields that were shown to disrupt cancer cell replication in vitro and to slow tumor progression in animal cancer models and patients with recurrent and newly diagnosed glioblastoma [18–20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Kirson ED, Dbaly V, Tovarys F et al (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA 104(24):10152–10157. doi: 10.1073/pnas.0702916104 source

      Not checked in the free run.

    • cites [19] Kirson ED, Gurvich Z, Schneiderman R et al (2004) Disruption of cancer cell replication by alternating electric fields. Cancer Res 64(9):3288–3295. doi: 10.1158/0008-5472.CAN-04-0083 source

      Not checked in the free run.

    • cites [20] Kirson ED, Schneiderman RS, Dbaly V et al (2009) Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9(1):1. doi: 10.1186/1756-6649-9-1 source

      Not checked in the free run.

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

    Premisecitation

    TTFields disrupt cancer cell replication in vitro.

    “TTFields are low intensity, intermediate frequency alternating electric fields that were shown to disrupt cancer cell replication in vitro and to slow tumor progression in animal cancer models and patients with recurrent and newly diagnosed glioblastoma [18–20].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Kirson ED, Dbaly V, Tovarys F et al (2007) Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA 104(24):10152–10157. doi: 10.1073/pnas.0702916104 source

      Not checked in the free run.

    • cites [19] Kirson ED, Gurvich Z, Schneiderman R et al (2004) Disruption of cancer cell replication by alternating electric fields. Cancer Res 64(9):3288–3295. doi: 10.1158/0008-5472.CAN-04-0083 source

      Not checked in the free run.

    • cites [20] Kirson ED, Schneiderman RS, Dbaly V et al (2009) Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC Med Phys 9(1):1. doi: 10.1186/1756-6649-9-1 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Immune response can inhibit the proliferation of cancerous cells or even eliminate them.

    “It is becoming widely accepted that immune response can inhibit the proliferation of cancerous cell or even eliminate them (reviewed by Dunn et al. [23])”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998. doi: 10.1038/ni1102-991 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Migration of tumor cells into the circulation depends on the proper formation of microtubule-based processes in the migrating cells.

    “Such migration is dependant on the proper formation of a microtubule based processes in the migrating cells [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Suresh S (2007) Biomechanics and biophysics of cancer cells. Acta Biomater 3(4):413–438. doi: 10.1016/j.actbio.2007.04.002 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The different size distribution between the groups suggests that metastases progression was inhibited in the TTFields group during treatment, an effect that may have been attenuated or partially lost after 1 week recovery.

    “Furthermore, the different size distribution between the two groups suggests that the metastases progression was inhibited in the TTFields group during treatment, an effect which may have been attenuated or partially lost after 1 week recovery.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Sham electrode arrays for rabbits were provided with an electrical heating element to match the temperature generated on the skin by the TTFields treatment electrodes.

    “Each sham electrode array was provided with an electrical heating element to match the temperature generated on the skin by the TTFields treatment electrodes.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Tumor volume assessment by MRI was performed by a technician blinded to the group of each rabbit.

    “Tumor volume assessment by MRI was performed by a technician blinded to the group of each rabbit.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This milieu of immune markers indicates a T-cell mediated immune response; however, it is not yet sufficient to prove a tumor-antigen specific immune reaction.

    “This milieu of immune markers indicates a T-cell mediated immune response; however, it is not yet sufficient to prove a tumor-antigen specific immune reaction.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Control mice were treated with sham electrodes that were temperature and geometrically matched to the TTFields group.

    “Control mice were treated by means of sham electrodes which were both temperature, and geometrically matched to the TTFields group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    TTFields may be clinically useful not only in treatment of locally advanced tumors, but in prevention and treatment of metastatic disease as well.

    “Therefore, TTFields may not only be clinically useful in treatment of locally advanced tumors, but in prevention and treatment of metastatic disease as well.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    CD45 activation can induce the production of TNFα, which in turn activates a family of cell-surface receptors that can mediate cell death.

    “Interestingly, CD45 activation can induce the production of TNFα [24] which in turn activates a family of cell-surface receptors that can mediate cell death.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Hayes AL, Smith C, Foxwell BM et al (1999) CD45-induced tumor necrosis factor alpha production in monocytes is phosphatidylinositol 3-kinase-dependent and nuclear factor-kappaB-independent. J Biol Chem 274(47):33455–33461. doi: 10.1074/jbc.274.47.33455 source

      Not checked in the free run.

17 of 17

  • The paper relies on this without support.

    Little is known about the effect of TTFields on the metastatic spread of solid tumors.

    “Yet, little is know about the effect of TTFields on the metastatic spread of solid tumors.”

  • The authors state this as an assumption.

    The activation of the immune response in the rabbits' lungs was mediated by the TTFields treatment.

    “Assuming that the activation of the immune response in the rabbits’ lungs was mediated by the TTFields treatment”
2 of 2

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?

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.

  • Rabbit histology result identifies treated animals as mice

    Minor

    The histological lung comparison appears in the rabbit-results section and contrasts treated animals with rabbit controls, but identifies the treated animals as mice.

  • Reported early rabbit treatment conflicts with the treatment schedule

    Minor

    The methods place baseline MRI two weeks after implantation and treatment on the following day, yet the results describe treatment beginning before day 14.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Sardari N, Colpaert C (2007) Lung metastases: epidemiology, clinical presentation and imaging. In: Schil P (ed) Lung metastases and isolated lung perfusion. Nova Science Publishers Inc., New York, pp 3–25

Cited by

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Related

Authors
Kirson, E. D., Giladi, M., Gurvich, Z., Itzhaki, A., Mordechovich, D., Schneiderman, R. S., Wasserman, Y., Ryffel, B., Goldsher, D., & Palti, Y.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Rambam Health Care Campus (IL)
Corresponding author
Kirson, Eilon D.
ORCID
Venue
Clinical & Experimental Metastasis
Publisher
Springer Science and Business Media LLC
Published
2009-04-23
Volume
26
Issue
7
Pages
633-640
ISSN
  • 0262-0898 (ISSN-L)
  • 1573-7276
DOI
10.1007/s10585-009-9262-y
PMC
PMC2776150
OpenAlex
W2168283594
Semantic Scholar
4051989aa1fcef3c6a3dfb9e2be36c2583479e5c
Cited by
171
References
23
Citations by year
2026: 5 · 2025: 12 · 2024: 14 · 2023: 12 · 2022: 19 · 2021: 14 · 2020: 16 · 2019: 12 · 2018: 10 · 2017: 7 · 2016: 14 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 3
FWCI
2.37
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Clinical & Experimental Metastasis (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
tumor treating fields, AC electric field, lung metastasis, melanoma, tumor growth inhibition, immune cell infiltration, survival extension, cancer prevention
MeSH terms
Animals, Disease Models, Animal, Electricity, Female, Lung Neoplasms, Melanoma, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasm Transplantation, Rabbits, Mice

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