Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo
Open accessAbstract
Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.
AI snapshot
Written from the paper’s full text.
TL;DR
In NSCLC cell lines and orthotopic mouse models, tumor-treating fields (TTFields) at 150 kHz reduced viability and enhanced chemotherapy efficacy when combined with pemetrexed, cisplatin, paclitaxel, or erlotinib. The authors conclude TTFields plus chemotherapy may improve NSCLC management, while calling for prospective studies.
Key findings
- TTFields induced a frequency-dependent reduction in viability across all six tested lung cancer cell lines, with a common peak effective frequency of 150 kHz; clonogenic ability was significantly impaired after 150-kHz treatment.
- Adding TTFields (1.75 V/cm RMS, 150 kHz) to pemetrexed, cisplatin, paclitaxel, or erlotinib decreased viable cells across tested lines; KLN205 resisted high-concentration paclitaxel (IC50 >100 nmol/L) but remained sensitive to TTFields.
- In orthotopic LLC1 and KLN205-T1 mouse tumors, TTFields (150 kHz, 1.86 ± 0.67 V/cm RMS) combined with chemotherapy produced smaller tumors than chemotherapy alone; no significant tumor-volume decrease was seen below a threshold TTFields intensity.
- Finite-element simulations and pig measurements indicated 2–4 V/cm RMS TTFields can be generated throughout human lungs and mediastinum; bony elements attenuated fields more than 10-fold, and mediastinum intensity was 30% higher than lung parenchyma.
Methods
- In vitro: four human NSCLC lines (H1299, A549, HCC827, HTB-182) and two murine lines (LLC1, KLN205); TTFields applied for 72 hours at 100–240 kHz, with XTT viability and clonogenic survival assays and chemotherapy agents.
- In vivo: orthotopic LLC1 (6×10³ cells) in C57Bl/6 mice and KLN205-T1 (5×10⁴ cells) in DBA/2 mice; mice were randomized to TTFields, chemotherapy, combination, or control, treated for 6 days, and tumor volume assessed at necropsy on day 17 after implantation; one-way ANOVA with Tukey test.
- Delivery modeling: finite-element mesh simulations of the human chest and in vivo TTFields measurements in pigs.
Limitations
- The paper does not include a formal limitations section; it states that further prospective studies are warranted and reports conflicts of interest (Yoram Palti holds stock in Novocure; most other authors are Novocure employees).
- Evident from the text: findings are preclinical (cell lines, mouse models, simulations, and pig measurements), not a randomized clinical trial; animal treatment was short (6 days) and group sizes are reported as small.
- Evident from the text: in vitro combination effects are described as additive, not proven synergistic, and no dose-reduction or toxicity outcomes for the combination are reported in animals.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 20 cited sources checked · 0 supported · 0 flagged
- Findingown data
Compared with exposure to erlotinib alone, the combination of TTFields and erlotinib led to a significant reduction in HCC827 (EGFR mutant) cell viability.
“Compared with exposure to erlotinib alone, the combination of TTFields and erlotinib led to a significant reduction in HCC827 (EGFR mutant) cell viability (Figure 2D).”
Quote in the paperSubstantial claim - Findingown data
The improved antitumor activity of the combination of TTFields and chemotherapy was apparent in autologous tumor studies.
“Of note, the improved antitumor activity of the combination of TTFields and chemotherapy also was apparent in autologous tumor studies.”
Quote in the paperSubstantial claim- Rests on an assumption: The orthotopic mouse tumor models used (LLC1 and KLN205-T1) adequately represent human NSCLC for assessing TTFields plus chemotherapy.
- Findingown data
TTFields treatment significantly impaired the colony-forming ability of all tested cell lines in culture.
“TTFields treatment was found to significantly impair the colony-forming ability of all tested cell lines in culture (Figure 1B).”
Quote in the paperSubstantial claim- Rests on an assumption: The human NSCLC cell lines used are representative of NSCLC in patients.
- Findingown data
LLC1 tumors exposed to TTFields in combination with chemotherapy were smaller than tumors treated with chemotherapy alone.
“The results (Figures 3A-C) showed that LLC1 tumors exposed to TTFields (1.86Ϯ0.67V/cm RMS) in combination with chemotherapy were smaller than tumors treated with chemotherapy alone.”
Quote in the paperSubstantial claim- Rests on an assumption: The orthotopic mouse tumor models used (LLC1 and KLN205-T1) adequately represent human NSCLC for assessing TTFields plus chemotherapy.
- Findingown data
TTFields therapy induced a frequency-dependent reduction in viability in all six NSCLC cell lines tested, with a common peak effective frequency at 150 kHz.
“TTFields therapy was found to induce a frequency-dependent reduction in viability in all six cell lines, with a common peak effective frequency at 150 kHz (Figure 1A).”
- Also stated in: § Abstract · boosted
“Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested”
Quote in the paperSubstantial claim- Rests on an assumption: The human NSCLC cell lines used are representative of NSCLC in patients.
- Also stated in: § Abstract · boosted
- Findingown data
Similar efficacy was observed for cultures of both adenocarcinoma and SCC histologies.
“Interestingly, similar efficacy was observed for cultures of both adenocarcinoma and SCC histologies.”
Quote in the paperNot a substantial claim- Rests on an assumption: The human NSCLC cell lines used are representative of NSCLC in patients.
- Findingown data
Similar results were observed for KLN205-T1 tumors.
“Similar results were observed for KLN205-T1 tumors (Figure 3D).”
Quote in the paperSubstantial claim- Rests on an assumption: The orthotopic mouse tumor models used (LLC1 and KLN205-T1) adequately represent human NSCLC for assessing TTFields plus chemotherapy.
- Findingown data
Adding TTFields to pemetrexed led to a decrease in the number of viable cells for all tested concentrations in both H1299 and LLC1 cultures.
“The results (Figure 2A) showed that adding TTFields to pemetrexed led to a decrease in the number of viable cells for all tested concentrations in both H1299 and LLC1 cultures.”
Quote in the paperSubstantial claim - Findingown data
The KLN205 cell line resisted high-concentration paclitaxel (IC50 >100 nmol/L).
“Interestingly, the KLN205 cell line, though resisting high-concentration paclitaxel (inhibitory concentration 50 [IC 50 ] 4100 nmol/L) (data not shown)”
Quote in the paperSubstantial claim - Findingcitation
Treatment efficacy was positively correlated with TTFields intensities.
“Treatment efficacy was found to be positively correlated with TTFields intensities, as previously described (data not shown).6,7”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res source
Not checked in the free run.
- cites [7] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Findingown data
KLN205 was sensitive to TTFields.
“was sensitive to TTFields (Figures 1A, 2B)”
Quote in the paperSubstantial claim - Findingown data
The combination of cisplatin and TTFields showed an augmented effect against NSCLC cell viability, including in the SCC cell lines HTB-182 and KLN205.
“The combination of cisplatin, a commonly used first-line NSCLC treatment, and TTFields showed a similar pattern of augmented effect against NSCLC cell viability, including in the SCC cell lines HTB-182 and KLN205 (Figure 2B).”
Quote in the paperSubstantial claim - Findingown data
Simulations demonstrated protection of hematopoietic tissue through strong attenuation of TTFields by vertebral and costal bony elements.
“The simulations also demonstrated protection of hematopoietic tissue through strong attenuation of TTFields by vertebral and costal bony elements.”
Quote in the paperSubstantial claim - Findingown data
Mouse left lung lobes injected with 5×10^4 KLN205-T1 cells in 50% Matrigel demonstrated rapid tumor growth, with a mean volume of 51±13 mm3 13 days after injection.
“Mouse left lung lobes injected with 5Â10 4 KLN205-T1 cells in 50% Matrigel demonstrated rapid tumor growth, with a mean volume of 51Ϯ13 mm 3 13 days after injection.”
Quote in the paperSubstantial claim - Findingown data
In vivo field measurements in pigs showed significant correlation with the simulations, indicating that TTFields intensities can be effectively generated within the lungs, liver, and mediastinum.
“The measurements showed significant correlation with the simulations, indicating that TTFields intensities can be effectively generated within the lungs, liver, and mediastinum (data not shown).”
Quote in the paperSubstantial claim - Findingown data
Field intensity was more than 10-fold lower in vertebral and costal bony regions than in the lung parenchyma.
“Field intensity was more than 10-fold lower in these regions than in the lung parenchyma.”
Quote in the paperSubstantial claim - Findingown data
FEM simulations demonstrated that TTFields of sufficient intensity (2-4 V/cm RMS) can be generated throughout the lungs and mediastinum by applying 150-kHz alternating fields through noninvasive transducer arrays.
“the simulations demonstrated that TTFields of sufficient intensity (2-4 V/ cm RMS) can be generated throughout the lungs and mediastinum by applying 150-kHz alternating fields through noninvasive transducer arrays.”
Quote in the paperSubstantial claim - Findingown data
Field intensity was 30% higher in the mediastinum than in the lung parenchyma.
“In addition, field intensity was 30% higher in the mediastinum than in the lung parenchyma.”
Quote in the paperNot a substantial claim - Premisecitation
In that phase I/II trial, median overall survival was 13.8 months.
“Median overall survival was 13.8 months”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Premisecitation
A phase I/II trial showed preliminary efficacy and safety of combining TTFields therapy with pemetrexed in patients with stage IIIB/IV NSCLC following failure of standard first-line therapy.
“recent phase I/II trial showed, for the first time, preliminary efficacy and safety of combining TTFields therapy with pemetrexed in patients with stage IIIB/IV NSCLC following failure of standard first-line therapy.11”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Premisecitation
In that phase I/II trial, in-field progression-free survival was 28 weeks.
“and an encouraging in-field PFS (measured at the site where TTFields were delivered to the lungs and liver) of 28 weeks.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Premisecitation
In the phase I/II trial of TTFields plus pemetrexed in stage IIIB/IV NSCLC after first-line failure, median progression-free survival was 22 weeks.
“This study demonstrated a median progression-free survival (PFS) of 22 weeks”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Premisecitation
TTFields have demonstrated effectiveness in the treatment of solid tumors in vitro and in vivo.
“TTFields have demonstrated effectiveness in the treatment of solid tumors in vitro and in vivo.[6][7][8][9][10]”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res source
Not checked in the free run.
- cites [7] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [8] Kirson, 2009, Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs, Clin Exp Metast source
Not checked in the free run.
- Premisecitation
In that phase I/II trial, 1-year survival was 57%.
“and 1-year survival was 57%”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Interpretationcitation
The phase I/II trial results compared well to matched historical controls.
“both of which compared well to matched historical controls.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Rests on an assumption: Matched historical controls used in the phase I/II trial are a valid comparator for estimating TTFields plus pemetrexed efficacy.
- Interpretationcitation
The additive effect of TTFields and pemetrexed is possibly explained by pemetrexed acting on G1 and S phases and TTFields acting on M phase.
“This effect is possibly explained by the different stages of mitosis at which the two treatment modalities putatively operate: Pemetrexed inhibits three enzymes responsible for purine and pyrimidine synthesis, thereby acting on the G1 and S phases of the cell cycle, 16 and TTFields therapy predominantly acts on cells in the M phase.6,7,9”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [16] McLeod, 2000, Pharmacokinetic and pharmacodynamic evaluation of the glycinamide ribonucleotide formyltransferase inhibitor AG2034, Clin Cancer Res
Not checked in the free run.
- cites [6] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res source
Not checked in the free run.
- cites [7] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc Natl Acad Sci U S A source
Not checked in the free run.
- Interpretationown data
These in vivo results support the in vitro findings suggesting combining TTFields therapy with chemotherapy may enhance treatment efficacy.
“These results are supportive of the in vitro findings that suggest combining TTFields therapy with chemotherapy may enhance treatment efficacy.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
- Rests on an assumption: The orthotopic mouse tumor models used (LLC1 and KLN205-T1) adequately represent human NSCLC for assessing TTFields plus chemotherapy.
- Interpretationreasoning
The combined effect of TTFields and paclitaxel may be attributed to their shared cellular targets.
“The combined effect of TTFields and paclitaxel may be attributed to their shared cellular targets.”
Quote in the paperNot a substantial claim - Interpretationown data
The in vitro findings support the previous observation suggesting a cell type-specific optimal effective frequency for TTFields therapy.
“Together, these in vitro findings support our previous observation, which suggest a cell type-specific optimal effective frequency for TTFields therapy.”
Quote in the paperNot a substantial claim - Interpretationown data
TTFields may be effective against cells resistant to paclitaxel.
“suggesting TTFields also may be effective against cells resistant to paclitaxel.”
Quote in the paperSubstantial claim - Interpretationown data
Adding TTFields therapy to systemic therapies including pemetrexed, cisplatin, paclitaxel, and erlotinib may offer a viable approach for improving clinical outcomes.
“Overall, these results suggest that adding TTFields therapy to systemic therapies including pemetrexed, cisplatin, paclitaxel, and erlotinib may offer a viable approach for improving clinical outcomes.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
- Interpretationown data
Together, our results suggest TTFields therapy can be effectively delivered locally for the treatment of NSCLC.
“Together, our results suggest TTFields therapy can be effectively delivered locally for the treatment of NSCLC.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
- May combine two claims. 10
- Classified as probably not a substantial claim. 7
- The quote only partly states this claim. 1
May combine two claims.
Findingown dataA significant decrease in tumor volume was not observed in mice treated with TTFields with average intensities below the stated threshold, demonstrating TTFields are ineffective below a certain threshold.
“Interestingly, a significant decrease in tumor volume was not observed in mice treated with TTFields with average intensities below V/cm RMS, demonstrating that TTFields are ineffective below a certain threshold.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataTTFields therapy in combination with paclitaxel had an additive effect and led to a decrease in the number of viable cells in cultures of both adenocarcinoma and SCC cells.
“TTFields therapy in combination with paclitaxel had the same additive effect and led to a decrease in the number of viable cells in cultures of both adenocarcinoma and SCC cells (Figure 2C).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataDuring the same period, left lung lobe weight increased from 67±5 mg to 123±19 mg.
“During the same period, left lung lobe weight increased from 67Ϯ5 mg to 123Ϯ19 mg.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe observed tumor uptake was 80%±11%.
“The observed tumor uptake was 80%Ϯ 11%.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataTumor uptake was observed in 85%±15% of the mice 3 weeks after inoculation, but tumor progression was highly variable (average volume, 24 mm3).
“Tumor uptake was observed in 85%Ϯ15% of the mice 3 weeks after inoculation, but tumor progression was highly variable (average volume, 24 mm 3 ).”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationTTFields are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, leading to mitotic arrest and cell death.
“Tumor-treating fields (TTFields) are lowintensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death.”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [6] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res source
Not checked in the free run.
- cites [7] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc Natl Acad Sci U S A source
Not checked in the free run.
- cites [9] Kirson, 2009, Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). BMC, Med Phys
Not checked in the free run.
May combine two claims.
PremisecitationContinuous TTFields application has demonstrated feasibility, safety, and effectiveness in patients with solid tumors including glioblastoma.
“Several pilot clinical trials and larger randomized studies in patients with solid tumors including glioblastoma have demonstrated the feasibility, safety, and effectiveness of continuous TTFields application in patients.7”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Kirson, 2007, Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors, Proc Natl Acad Sci U S A source
Not checked in the free run.
May combine two claims.
InterpretationcitationThese results support the clinical activity of TTFields therapy when added to chemotherapy in advanced NSCLC, without incremental toxicity.
“These results support the clinical activity of TTFields therapy when added to chemotherapy in advanced NSCLC, without incremental toxicity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Pless, 2011, Tumor treating fields: concept, evidence and future, Expert Opin Invest Drugs source
Not checked in the free run.
- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
- Rests on an assumption: Matched historical controls used in the phase I/II trial are a valid comparator for estimating TTFields plus pemetrexed efficacy.
May combine two claims.
InterpretationreasoningTTFields forces act on the dipole moment of tubulin chains, leading to misalignment of mitotic spindle filaments, and paclitaxel stabilizes the link between individual tubulin dimers, increasing the length and average dipole moment of tubulin filaments, which could increase TTFields-induced forces and sensitize cells to TTFields.
“TTFields forces act on the dipole moment of tubulin chains, leading to misalignment of mitotic spindle filaments 6 and paclitaxel stabilizes the link between individual tubulin dimers, subsequently increasing the length and average dipole moment of the tubulin filaments.This, in turn, could increase the TTFields-induced forces and sensitize cells to TTFields.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [6] Kirson, 2004, Disruption of cancer cell replication by alternating electric fields, Cancer Res source
Not checked in the free run.
The quote only partly states this claim.
Interpretationown dataThese results suggest an additive effect for combining TTFields and pemetrexed.
“These results suggest an additive effect for combining treatments.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
Study design and conductnone givenControl and chemotherapy-treated mice had sham transducer arrays placed on their torsos, temperature-matched to the TTFields transducer arrays.
“The control and chemotherapy-treated mice had sham transducer arrays placed on their torsos; these arrays were temperature-matched to the TTFields transducer arrays.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll animal studies were approved by the Novocure Internal Animal Care committee in accordance with Technion-Israel Institute of Technology guidelines for the care of laboratory animals.
“All animal studies were approved by the Novocure Internal Animal Care committee in accordance with the Technion-Israel Institute of Technology guidelines for the care of laboratory animals.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe combination may lead to an increased response and potentially permit the use of a lower dose of chemotherapy, thereby reducing systemic toxicity.
“The combination may lead to an increased response and also potentially may permit the use of a lower dose of chemotherapy, thereby reducing systemic toxicity.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
May combine two claims.
InterpretationreasoningThe body of evidence from in vitro studies, in vivo studies, and an early phase I/II clinical trial in patients with advanced NSCLC suggests combining TTFields therapy with systemic chemotherapy may be an approach that offers enhanced efficacy, without incremental toxicity.
“In summary, the body of evidence from in vitro studies, in vivo studies, and an early phase I/II clinical trial in patients with advanced NSCLC, suggest combining TTFields therapy with systemic chemotherapy may be an approach that offers enhanced efficacy, without incremental toxicity.”
Quote in the paperSubstantial claim- Rests on an assumption: Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
- Rests on an assumption: Matched historical controls used in the phase I/II trial are a valid comparator for estimating TTFields plus pemetrexed efficacy.
Classified as probably not a substantial claim.
Study design and conductnone givenTreatment was applied for at least 90% of the duration of the experiment.
“Treatment was applied for at least 90% of the duration of the experiment.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataMice were randomly grouped before treatment.
“Mice were randomly grouped (425 per group) before treatment with TTFields, pemetrexed, cisplatin, paclitaxel, or TTFields combined with these agents.”
- Also stated in: § Efficacy of Combination Treatments in Animal Models · plain
“Eleven days after tumor inoculation, the mice were randomly grouped (412 per group) and treated with TTFields, cisplatin, or their combination, as described earlier.”
Quote in the paperNot a substantial claim- Also stated in: § Efficacy of Combination Treatments in Animal Models · plain
The paper relies on this without support.
Preclinical in vitro and mouse model results are predictive of clinical efficacy in human NSCLC patients.
“Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC.”
The paper relies on this without support.
The orthotopic mouse tumor models used (LLC1 and KLN205-T1) adequately represent human NSCLC for assessing TTFields plus chemotherapy.
“We orthotopically implanted 6Â10 3 LLC1 cells into the left lung of C57BL/6 mice and 5Â10 4 KLN205-T1 cells into the left lung of DBA/2 mice.”
The paper relies on this without support.
Matched historical controls used in the phase I/II trial are a valid comparator for estimating TTFields plus pemetrexed efficacy.
“both of which compared well to matched historical controls.”
The paper relies on this without support.
The human NSCLC cell lines used are representative of NSCLC in patients.
“We obtained four human NSCLC cell lines and two murine cell lines from ATCC (American Type Culture Collection, Rockville, MD).”
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?
Synergistic antitumor activity was demonstrated when TTFields were applied in conjunction with cytotoxic chemotherapy with paclitaxel, doxorubicin, cyclophosphamide, or dacarbazine.
“Importantly, synergistic antitumor activity was demonstrated when TTFields were applied in conjunction with cytotoxic chemotherapy with paclitaxel, doxorubicin, cyclophosphamide, or dacarbazine (DTIC).13”
From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [13]
There may be additive efficacy in combining TTFields with spindle poisons.
“These conflicting observations suggest that there may be additive efficacy in combining TTFields with spindle poisons, a notion which is supported by clinical observations in which the combination of vinorelbine with paclitaxel in metastatic breast cancer patients has been associated with superior antitumoral activity50.”
From Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells (2015) · cites this paper as [31]
Cites
Siegel, R., Ma, J., Zou, Z., & Jemal, A. (2014) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21208 · Cited by 11,499 · see citing works
Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer
Schiller, J. H., Harrington, D., Belani, C. P., Langer, C., Sandler, A., Krook, J., Zhu, J., & Johnson, D. H. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa011954 · Cited by 4,955 · see citing works
COMPARISON OF FOUR CHEMOTHERAPY REGIMENS FOR ADVANCED NON-SMALL-CELL LUNG CANCER
Chiller, J. O. H. S., Arrington, D. A. H., Elani, C. H. P. B., Anger, C., Andler, A. L. S., Rook, J. A. K., Hu, J., & Ohnson, D. A. H. J. (2002) · Cited by 3,730 · see citing works
Scagliotti, G. V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., Serwatowski, P., Gatzemeier, U., Digumarti, R., Zukin, M., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.15.0375 · Cited by 3,203 · see citing works
Hanna, N., Shepherd, F. A., Fossella, F. V., Pereira, J. R., De Marinis, F., von Pawel, J., Gatzemeier, U., Tsao, T. C. Y., Pless, M., Muller, T., et al. (2004) · Journal of Clinical Oncology · doi:10.1200/jco.2004.08.163 · Cited by 2,426 · see citing works
Ciuleanu, T., Brodowicz, T., Zielinski, C., Kim, J. H., Krzakowski, M., Laack, E., Wu, Y.-L., Bover, I., Begbie, S., Tzekova, V., et al. (2009) · The Lancet · doi:10.1016/s0140-6736(09)61497-5 · Cited by 1,111 · see citing works
Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors
Kirson, E. D., Dbalý, V., Tovaryš, F., Vymazal, J., Soustiel, J. F., Itzhaki, A., Mordechovich, D., Steinberg-Shapira, S., Gurvich, Z., Schneiderman, R., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0702916104 · Cited by 894 · see citing works
Self-citationStupp, R., Wong, E. T., Kanner, A. A., Steinberg, D., Engelhard, H., Heidecke, V., Kirson, E. D., Taillibert, S., Liebermann, F., Dbalý, V., et al. (2012) · European Journal of Cancer · doi:10.1016/j.ejca.2012.04.011 · Cited by 862 · see citing works
Self-citationDisruption of cancer cell replication by alternating electric fields
Kirson, E. D., Gurvich, Z., Schneiderman, R., Dekel, E., Itzhaki, A., Wasserman, Y., Schatzberger, R., & Palti, Y. (2004) · Cancer research · doi:10.1158/0008-5472.can-04-0083 · Cited by 827 · see citing works
Self-citationOhe, Y., Ohashi, Y., Kubota, K., Tamura, T., Nakagawa, K., Negoro, S., Nishiwaki, Y., Saijo, N., Ariyoshi, Y., & Fukuoka, M. (2006) · Annals of Oncology · doi:10.1093/annonc/mdl377 · Cited by 633 · see citing works
Morgensztern, D., Ng, S. H., Gao, F., & Govindan, R. (2010) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181c5920c · Cited by 548 · see citing works
Kirson, E. D., Schneiderman, R. S., Dbalý, V., Tovaryš, F., Vymazal, J., Itzhaki, A., Mordechovich, D., Gurvich, Z., Shmueli, E., Goldsher, D., et al. (2009) · BMC Medical Physics · doi:10.1186/1756-6649-9-1 · Cited by 224 · see citing works
Self-citationAlternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs
Kirson, E. D., Giladi, M., Gurvich, Z., Itzhaki, A., Mordechovich, D., Schneiderman, R. S., Wasserman, Y., Ryffel, B., Goldsher, D., & Palti, Y. (2009) · Clinical & Experimental Metastasis · doi:10.1007/s10585-009-9262-y · Cited by 171 · see citing works
Self-citationBepler, G., Sommers, K. E., Cantor, A. B., et al. (2008) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3181874936 · Cited by 98 · see citing works
Tumor treating fields: concept, evidence and future
Pless, M., & Weinberg, U. (2011) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2011.583236 · Cited by 78 · see citing works
Self-citationSecond-line treatment for advanced non-small cell lung cancer: A systematic review
Barlési, F., Jacot, W., Astoul, P. J., & Pujol, J.-L. (2005) · Lung Cancer · doi:10.1016/j.lungcan.2005.08.017 · Cited by 51 · see citing works
McLeod, H. L., Cassidy, J., Powrie, R. H., Priest, D. G., Zorbas, M. A., Synold, T. W., Shibata, S., SPICER, D. V., Bissett, D., Pithavala, Y. K., et al. (2000) · PubMed · Cited by 37 · see citing works
Transient cavitation in tissues during ultrasonically induced hyperthermia
Sommer, F. G., & Pounds, D. W. (1982) · Medical Physics · doi:10.1118/1.595065 · Cited by 36 · see citing works
Onn, A., Isobe, T., Wu, W., Itasaka, S., Shintani, T., Shibuya, K., Kenji, Y., O’Reilly, M. S., Fidler, I. J., & Herbst, R. S. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-1241 · Cited by 18 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Tumor-Treating Fields: A Fourth Modality in Cancer Treatment
Mun, E. J., Babiker, H. M., Weinberg, U., Kirson, E. D., & Von Hoff, D. D. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-1117 · Cited by 380 · see citing works
Self-citationGiladi, M., Schneiderman, R. S., Voloshin, T., Porat, Y., Munster, M., Blat, R., Sherbo, S., Bomzon, Z., Urman, N., Itzhaki, A., et al. (2015) · Scientific Reports · doi:10.1038/srep18046 · Cited by 327 · see citing works
Self-citationTumor treating fields: A novel treatment modality and its use in brain tumors
Hottinger, A. F., Pacheco, P., & Stupp, R. (2016) · Neuro-Oncology · doi:10.1093/neuonc/now182 · Cited by 177 · see citing works
Tumor treating fields increases membrane permeability in glioblastoma cells
Chang, E., Patel, C. B., Pohling, C., Young, C., Song, J., Flores, T. A., Zeng, Y., Joubert, L.-M., Arami, H., Natarajan, A., et al. (2018) · Cell Death Discovery · doi:10.1038/s41420-018-0130-x · Cited by 137 · see citing works
Shteingauz, A., Porat, Y., Voloshin, T., Schneiderman, R. S., Munster, M., Zeevi, E., Kaynan, N., Gotlib, K., Giladi, M., Kirson, E. D., et al. (2018) · Cell Death & Disease · doi:10.1038/s41419-018-1085-9 · Cited by 107 · see citing works
Self-citationPermeabilizing Cell Membranes with Electric Fields
Aguilar, A. A., Ho, M. C., Chang, E., Carlson, K. W., Natarajan, A., Marciano, T., Bomzon, Z., & Patel, C. B. (2021) · Cancers · doi:10.3390/cancers13092283 · Cited by 76 · see citing works
Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells
Neuhaus, E., Zirjacks, L., Ganser, K., Klumpp, L., Schüler, U., Zips, D., Eckert, F., & Huber, S. M. (2019) · Cancers · doi:10.3390/cancers11010110 · Cited by 63 · see citing works
Porat, Y., Giladi, M., Schneiderman, R. S., Blat, R., Shteingauz, A., Zeevi, E., Munster, M., Voloshin, T., Kaynan, N., Tal, O., et al. (2017) · Journal of Visualized Experiments · doi:10.3791/55820-v · Cited by 25 · see citing works
Self-citation
- Authors
- Giladi, M., Weinberg, U., Schneiderman, R. S., Porat, Y., Munster, M., Voloshin, T., Blatt, R., Cahal, S., Itzhaki, A., Onn, A., Kirson, E. D., & Palti, Y.
- Affiliations
- Sheba Medical Center (IL)
- Corresponding author
- Giladi, Moshe
- Venue
- Seminars in Oncology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 41
- Pages
- S35-S41
- ISSN
- 0093-7754 (ISSN-L)
- OpenAlex
- W2151418338
- Cited by
- 132
- References
- 19
- Citations by year
- 2026: 5 · 2025: 17 · 2024: 9 · 2023: 14 · 2022: 17 · 2021: 14 · 2020: 10 · 2019: 11 · 2018: 16 · 2017: 7 · 2016: 9 · 2015: 3
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Seminars in Oncology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- 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
- Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
- Keywords
- tumor treating fields, AC electric field, non-small cell lung cancer, combination chemotherapy, pemetrexed, cisplatin, paclitaxel, mitotic arrest, Lewis lung carcinoma, treatment efficacy
- MeSH terms
- Pemetrexed, Adenocarcinoma, Animals, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Carcinoma, Squamous Cell, Cisplatin, Combined Modality Therapy, Electric Stimulation Therapy, Glutamates, Guanine, Humans, Lung Neoplasms, Mice, Inbred C57BL, Tumor Cells, Cultured, Survival Rate, Treatment Outcome, Apoptosis, Paclitaxel, Carcinoma, Lewis Lung, Cell Proliferation, Mice, In Vitro Techniques
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 ›
Are you an author, or do you see a problem with this page? Request a review
