Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields)
Open accessAbstract
The present study explores the efficacy and toxicity of combining a new, non-toxic, cancer treatment modality, termed Tumor Treating Fields (TTFields), with chemotherapeutic treatment in-vitro, in-vivo and in a pilot clinical trial. Cell proliferation in culture was studied in human breast carcinoma (MDA-MB-231) and human glioma (U-118) cell lines, exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide and dacarbazine (DTIC) separately and in combinations. In addition, we studied the effects of combining chemotherapy with TTFields in an animal tumor model and in a pilot clinical trial in recurrent and newly diagnosed GBM patients. The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1). The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316). Similar findings were seen in an animal tumor model. Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year. No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment. In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months. These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity.
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Written from the paper’s full text.
TL;DR
Adjuvant TTFields increased chemotherapy efficacy and sensitivity in vitro and in an animal tumor model, with additive-to-synergistic interactions and dose reduction indexes of 23–1316. In a 20-patient pilot GBM trial, combining TTFields with Temozolomide was associated with median PFS of 155 weeks and OS >39 months without increased systemic toxicity, though the single-arm design cannot separate TTFields from chemotherapy effects.
Key findings
- In vitro TTFields-chemotherapy combinations were additive with a tendency toward synergism for all drugs and cell lines tested (combination index ≤1); dose reduction indexes were 1316 for paclitaxel, 23 for doxorubicin, 152 for cyclophosphamide, and 175 for DTIC.
- IC50 values decreased with combined treatment: paclitaxel 5.00 nM to 0.005 nM, doxorubicin 0.04 μM to 0.002 μM, cyclophosphamide 6.60 mM to 0.044 mM, and DTIC in U-118 glioma cells 6.4 mM to 0.023 mM.
- In VX2 rabbit kidney tumors, tumor volume grew by a factor of 22 with TTFields-paclitaxel combination versus 70 for control, 58 for paclitaxel alone, and 34 for TTFields alone; combination inhibited growth by 69% versus control, paclitaxel alone by 15%, and TTFields alone by 53% (p < 0.01; ANOVA).
- In the pilot GBM trial, newly diagnosed patients receiving TTFields plus Temozolomide had median PFS of 155 weeks versus 31 weeks for concurrent controls (P = 0.0002; hazard ratio 3.32, 95% CI 1.9–5.9) and median OS >39 months versus about 14.7 months for matched historical controls (P = 0.0018); no TTFields-related systemic toxicity was observed, and dermatitis occurred in 18 of 20 patients.
Methods
- In vitro: human breast carcinoma MDA-MB-231 and human glioma U-118 cells were exposed to TTFields, paclitaxel, doxorubicin, cyclophosphamide, and DTIC separately and in combinations; proliferation was measured by XTT, with 150 kHz for breast cancer and 200 kHz for glioma, and combination index and dose reduction index calculated using Chou-Talalay methods.
- In vivo: VX2 tumor-bearing rabbits were randomized into four groups (n = 28 total, 7 per group): control, TTFields, paclitaxel 5 mg/animal, and combined TTFields-paclitaxel; tumors were implanted beneath the kidney capsule, treated for 21 days, and tumor volume assessed by MRI, with ANOVA for group differences.
- Pilot clinical trial: single-arm trial in 20 patients with histologically proven GBM (KPS 70–100, age ≥18); 10 recurrent GBM patients received TTFields alone and 10 newly diagnosed patients received TTFields plus maintenance Temozolomide; endpoints were safety, overall survival, and progression-free survival, assessed by Macdonald criteria and Kaplan-Meier curves against concurrent and historical controls.
Limitations
- The paper states that because the newly diagnosed GBM data were obtained only with combination treatment, one cannot directly separate the TTFields effects from the chemotherapeutic effect.
- Evident from the text: the clinical trial is a single-arm pilot with 10 patients per group and non-randomized concurrent/historical controls, limiting causal inference.
- Evident from the text: the clinical efficacy comparison relies on historical/concurrent controls rather than randomization, and the in vitro and animal findings may not fully translate to clinical outcomes.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
0 of 35 cited sources checked · 0 supported · 0 flagged
- Findingown data
The differences between separate and combined effects of TTFields and chemotherapy increase with time.
“The differences between the separate and combined effects increase with time.”
Quote in the paperNot a substantial claim - Findingown data
In MDA-MB-231 cells after 72 h, adding 1.75 V/cm TTFields reduced the IC50 of doxorubicin from 0.04 μM to 0.002 μM.
“| Doxorubicin | 0.04 μM | 0.002 μM |”
Quote in the paperSubstantial claim - Findingown data
The efficacy of TTFields-chemotherapy combination in vitro was additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1).
“The efficacy of TTFields-chemotherapy combination in-vitro was found to be additive with a tendency towards synergism for all drugs and cell lines tested (combination index ≤ 1).”
Quote in the paperSubstantial claim- Rests on an assumption: TTFields intensity can validly replace drug concentration as the dose variable in the Chou and Talalay combination-index analysis.
- Findingown data
In MDA-MB-231 cells after 72 h, adding 1.75 V/cm TTFields reduced the IC50 of cyclophosphamide from 6.60 mM to 0.044 mM.
“| Cyclophosphamide | 6.60 mM | 0.044 mM |”
Quote in the paperSubstantial claim - Findingown data
Combined treatment with TTFields and each chemotherapeutic agent caused a leftward shift of the dose-response curves.
“Combined treatment with TTFields and each of the chemotherapeutic agents caused a leftward shift of the dose response curves.”
Quote in the paperSubstantial claim
- Findingown data
Addition of TTFields to any one of paclitaxel, doxorubicin, or cyclophosphamide results in irreversible and complete inhibition of cell proliferation rate, manifested as a decrease in the number of cells in culture.
“In contrast, addition of TTFields to any one of these chemotherapeutic agents results in irreversible and complete inhibition of cell proliferation rate manifested as a decrease in the number of cells in culture.”
Quote in the paperSubstantial claim - Findingown data
A 24 h exposure to individual chemotherapeutic agents induces a reduction of approximately 25% in viable cell number compared to controls.
“Figure 3 demonstrates that a 24 hour exposure to individual chemotherapeutic agents induces a reduction of approximately 25% in viable cell number compared to controls.”
Quote in the paperSubstantial claim - Findingown data
In MDA-MB-231 cells after 72 h, adding 1.75 V/cm TTFields reduced the IC50 of paclitaxel from 5.00 nM to 0.005 nM.
“| Paclitaxel | 5.00 nM | 0.005 nM |”
Quote in the paperSubstantial claim - Findingown data
For cyclophosphamide and doxorubicin, complete inhibition of proliferation was achieved at high drug concentrations.
“For cyclophosphamide and doxorubicin complete inhibition of proliferation is achieved at high drug concentrations.”
Quote in the paperNot a substantial claim - Findingown data
During continuous 72 h exposure, inhibition of proliferation was greater for combined TTFields plus chemotherapeutic agent than for the chemotherapeutic agent alone in all cases.
“It is seen that in all cases the inhibition during combined exposure is greater than for the chemotherapeutic agent alone.”
Quote in the paperSubstantial claim - Findingown data
For cyclophosphamide, there is an almost complete loss of viable cells after 72 h of combined treatment with TTFields.
“For Cyclophosphamide there is an almost complete loss of viable cells after 72 hours of combined treatment.”
Quote in the paperSubstantial claim - Findingown data
Sensitivity to chemotherapeutic treatment was increased by 1-3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 - 1316).
“The sensitivity to chemotherapeutic treatment was increased by 1–3 orders of magnitude by adjuvant TTFields therapy (dose reduction indexes 23 – 1316).”
Quote in the paperSubstantial claim - Findingnone given
Similar findings were seen in an animal tumor model.
“Similar findings were seen in an animal tumor model.”
Quote in the paperNot a substantial claim - Findingown data
For paclitaxel, the inhibitory effect saturates at about 300 nM, near the 13% level.
“For paclitaxel, the inhibitory effect of the drug saturates at about 300 nM, near the 13% level, indicating that a fraction of the cells are insensitive to the agent.”
Quote in the paperNot a substantial claim - Findingown data
The only device-related toxicity reported was dermatitis.
“The only device related toxicity reported was a dermatitis which appeared most often (18 of 20 patients) during the second month of treatment.”
Quote in the paperNot a substantial claim - Findingown data
TTFields alone inhibited VX2 tumor growth by 53% compared to control.
“Thus the TTFields-Paclitaxel combination treatment inhibited tumor growth by 69% compared to the growth of control tumors, while Paclitaxel alone inhibited tumor growth by 15% compared to the growth of control tumors, and TTFields alone by 53% compared to the growth of control tumors.”
Quote in the paperSubstantial claim - Findingown data
For TTFields with paclitaxel and cyclophosphamide in breast cancer cells, the combination indexes are <1, indicating additivity with a tendency towards synergism.
“In contrast, for TTFields with Paclitaxel and Cyclophosphamide the CIs are <1 indicating additivity with a tendency towards synergism.”
Quote in the paperSubstantial claim - Findingown data
In both groups of GBM patients, no device-related serious adverse effects were observed.
“In both groups of patients no device related serious adverse effects were observed.”
Quote in the paperNot a substantial claim - Findingown data
The dose reduction index for TTFields-paclitaxel interaction after 72 hours of combined treatment is 1316.
“The DRIs for TTFields-drug interaction after 72 hours of combined treatment was 1316 for paclitaxel, 23 for doxorubicin, 152 for cyclophosphamide and 175 for DTIC (in U-118 glioma cells).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124/pr.58.3.10. source
Not checked in the free run.
- Findingown data
Dermatitis appeared in 18 of 20 patients during the second month of treatment.
“The only device related toxicity reported was a dermatitis which appeared most often (18 of 20 patients) during the second month of treatment.”
Quote in the paperNot a substantial claim - Findingown data
The dose reduction index for TTFields-doxorubicin interaction after 72 hours of combined treatment is 23.
“The DRIs for TTFields-drug interaction after 72 hours of combined treatment was 1316 for paclitaxel, 23 for doxorubicin, 152 for cyclophosphamide and 175 for DTIC (in U-118 glioma cells).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124/pr.58.3.10. source
Not checked in the free run.
- Findingown data
In VX2 rabbit kidney tumors, TTFields-treated tumors grew by a factor of 34 from baseline.
“As seen in Figure 5, untreated tumors increased in volume by a factor of 70 from baseline, Paclitaxel treated tumors grew by a factor of 58 from baseline, TTFields treated tumors grew by a factor of 34 from baseline and tumors treated by TTFields-Paclitaxel combination grew by a factor of 22 from baseline.”
Quote in the paperSubstantial claim - Findingown data
The dose reduction index for TTFields-DTIC interaction after 72 hours of combined treatment in U-118 glioma cells is 175.
“The DRIs for TTFields-drug interaction after 72 hours of combined treatment was 1316 for paclitaxel, 23 for doxorubicin, 152 for cyclophosphamide and 175 for DTIC (in U-118 glioma cells).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124/pr.58.3.10. source
Not checked in the free run.
- Findingown data
The dose reduction index for TTFields-cyclophosphamide interaction after 72 hours of combined treatment is 152.
“The DRIs for TTFields-drug interaction after 72 hours of combined treatment was 1316 for paclitaxel, 23 for doxorubicin, 152 for cyclophosphamide and 175 for DTIC (in U-118 glioma cells).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124/pr.58.3.10. source
Not checked in the free run.
- Findingown data
The IC50 for DTIC alone in U-118 glioma cells is 6.4 mM.
“The IC50 for DTIC alone in Figure 4 is 6.4 mM, whereas the IC50 for combined DTIC-TTFields is two orders of magnitude lower (0.023 mM).”
Quote in the paperSubstantial claim - Findingown data
TTFields-paclitaxel combination treatment inhibited VX2 tumor growth by 69% compared to control.
“Thus the TTFields-Paclitaxel combination treatment inhibited tumor growth by 69% compared to the growth of control tumors, while Paclitaxel alone inhibited tumor growth by 15% compared to the growth of control tumors, and TTFields alone by 53% compared to the growth of control tumors.”
Quote in the paperSubstantial claim - Findingown data
In the newly diagnosed GBM group, no increase in Temozolomide-related adverse events was seen due to combination with TTFields.
“In the second group, no increase in Temozolomide related adverse events was seen due to the combination with TTFields (see Table 3).”
Quote in the paperSubstantial claim - Findingown data
Differences between VX2 tumor growth curves were statistically significant (p < 0.01; ANOVA).
“Differences between curves were statistically significant (p < 0.01; ANOVA).”
Quote in the paperSubstantial claim - Findingown data
In VX2 rabbit kidney tumors, untreated tumors increased in volume by a factor of 70 from baseline.
“As seen in Figure 5, untreated tumors increased in volume by a factor of 70 from baseline, Paclitaxel treated tumors grew by a factor of 58 from baseline, TTFields treated tumors grew by a factor of 34 from baseline and tumors treated by TTFields-Paclitaxel combination grew by a factor of 22 from baseline.”
Quote in the paperSubstantial claim - Findingown data
The IC50 for combined DTIC-TTFields in U-118 glioma cells is 0.023 mM.
“The IC50 for DTIC alone in Figure 4 is 6.4 mM, whereas the IC50 for combined DTIC-TTFields is two orders of magnitude lower (0.023 mM).”
Quote in the paperSubstantial claim - Findingown data
In VX2 rabbit kidney tumors, TTFields-paclitaxel combination-treated tumors grew by a factor of 22 from baseline.
“As seen in Figure 5, untreated tumors increased in volume by a factor of 70 from baseline, Paclitaxel treated tumors grew by a factor of 58 from baseline, TTFields treated tumors grew by a factor of 34 from baseline and tumors treated by TTFields-Paclitaxel combination grew by a factor of 22 from baseline.”
Quote in the paperSubstantial claim - Findingown data
In U-118 glioma cell cultures, addition of TTFields to a chemotherapeutic agent causes a leftward shift in the dose-response curve.
“As we have shown in breast cancer cultures, the addition of TTFields to a chemotherapeutic agent causes a leftward shift in the dose-response curve in glioma cells as well.”
Quote in the paperSubstantial claim - Findingown data
Paclitaxel alone inhibited VX2 tumor growth by 15% compared to control.
“Thus the TTFields-Paclitaxel combination treatment inhibited tumor growth by 69% compared to the growth of control tumors, while Paclitaxel alone inhibited tumor growth by 15% compared to the growth of control tumors, and TTFields alone by 53% compared to the growth of control tumors.”
Quote in the paperSubstantial claim - Findingown data
In VX2 rabbit kidney tumors, paclitaxel-treated tumors grew by a factor of 58 from baseline.
“As seen in Figure 5, untreated tumors increased in volume by a factor of 70 from baseline, Paclitaxel treated tumors grew by a factor of 58 from baseline, TTFields treated tumors grew by a factor of 34 from baseline and tumors treated by TTFields-Paclitaxel combination grew by a factor of 22 from baseline.”
Quote in the paperSubstantial claim - Findingown data
For breast cancer cells (MDA-MB-231), the combination index for doxorubicin is very close to 1, indicating additivity.
“Table 2 demonstrates that for breast cancer cells the CI for Doxorubicin is very close to 1, indicating additivity [10,11].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [10] Chou TC, Talalay P: Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzyme Regul. 1984, 22: 27-55. 10.1016/0065-2571(84)90007-4. source
Not checked in the free run.
- cites [11] Chou TC: Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006, 58 (3): 621-681. 10.1124/pr.58.3.10. source
Not checked in the free run.
- Findingown data
Such sensitization was not shown to be associated with any additional systemic toxicity.
“Such sensitization was not shown to be associated with any additional systemic toxicity.”
Quote in the paperSubstantial claim - Findingown data
The difference between overall survival curves for combined TTFields-Temozolomide versus Temozolomide alone is highly significant (Log-Rank P = 0.0018).
“The difference between the OS curves is highly significant – (Log-Rank Test; P = 0.0018).”
Quote in the paperSubstantial claim - Findingown data
The median progression-free survival of concurrent controls treated with maintenance Temozolomide alone is 31 weeks.
“The median PFS of the combination treated patients is 155 weeks versus 31 weeks for concurrent controls treated with maintenance Temozolomide alone.”
Quote in the paperSubstantial claim - Findingown data
Both 24 h and 72 h combination treatments in vitro result in severe irreversible cellular damage in contrast to chemotherapy alone.
“An additional important finding is that both 24 h and 72 h combination treatments in-vitro result in severe irreversible cellular damage in contrast to chemotherapy alone.”
Quote in the paperSubstantial claim - Findingown data
At the time of report, 8 of 10 patients receiving combined TTFields-Temozolomide are alive.
“It should be noted that at the time of this report 8 of 10 patients, receiving the TTFields-Temozolomide combination treatment, are alive.”
Quote in the paperNot a substantial claim - Findingown data
The median overall survival for matched historical control patients who received maintenance Temozolomide alone is about 14.7 months.
“It is seen that for the TTFields – Temozolomide combination treated patients, the Median OS > 39 months versus about 14.7 months for matched historical control patients who received maintenance Temozolomide alone.”
Quote in the paperSubstantial claim - Premisecitation
TTFields are not associated with meaningful toxicity in contrast to most anti-cancer agents currently in use.
“Thus, TTFields are not associated with meaningful toxicity in contrast to most anti-cancer agents currently in use [5].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [5] Bantinas R, Hohl R, Peterson D: Management of Drug Toxicity. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 399-559. 3
Not checked in the free run.
- Interpretationown data
A fraction of MDA-MB-231 cells are insensitive to paclitaxel.
“For paclitaxel, the inhibitory effect of the drug saturates at about 300 nM, near the 13% level, indicating that a fraction of the cells are insensitive to the agent.”
Quote in the paperNot a substantial claim - Premisecitation
In a pilot clinical trial, recurrent GBM patients treated by TTFields alone had medians of time to disease progression and overall survival more than double the reported medians of historical control patients.
“In a pilot clinical trial, the medians of time to disease progression and overall survival of recurrent GBM patients treated by TTFields alone were more than double the reported medians of historical control patients [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
- Premisecitation
TTFields are not associated with significant side effects.
“In contrast to the widely used physical treatment modality, ionizing radiation, TTFields are not associated with significant side effects.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
- Interpretationown data
A significantly reduced dose (1-3 orders of magnitude lower drug concentration) may be used in combination with TTFields to achieve the same level of efficacy.
“Thus a significantly reduced dose (1–3 orders of magnitude lower drug concentration) may be used in combination with TTFields to achieve the same level of efficacy.”
Quote in the paperSubstantial claim - Premisecitation
Both DTIC and Temozolomide act through a common degradation product (MTIC).
“Both DTIC and Temozolomide act through a common degradation product (MTIC).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [15] Lev DC, Ruiz M, Mills L, McGary EC, Price JE, Bar-Eli M: Dacarbazine causes transcriptional up-regulation of interleukin 8 and vascular endothelial growth factor in melanoma cells: a possible escape mechanism from chemotherapy. Mol Cancer Ther. 2003, 2 (8): 753-763.
Not checked in the free run.
- cites [16] Shibuya H, Kato Y, Saito M, Isobe T, Tsuboi R, Koga M, Toyota H, Mizuguchi J: Induction of apoptosis and/or necrosis following exposure to antitumour agents in a melanoma cell line, probably through modulation of Bcl-2 family proteins. Melanoma Res. 2003, 13 (5): 457-464. 10.1097/00008390-200310000-00004. source
Not checked in the free run.
- Interpretationown data
Additivity was seen between TTFields and paclitaxel at the intensity and concentration used in VX2 tumors.
“Thus, additivity was seen between TTFields and Paclitaxel at the intensity and concentration used.”
Quote in the paperSubstantial claim - Study design and conductown data
The TTFields intensity within the kidneys of rabbits using the electrode configuration was between 1-3 V/cm, based on finite element mesh simulations and direct measurements.
“The TTFields intensity within the kidneys of the rabbits, using this electrode configuration, is between 1–3 V/cm (based on both finite element mesh simulations and direct measurements using an invasive probe – data not shown).”
Quote in the paperNot a substantial claim - Premisecitation
One of the mechanisms of action of TTFields is the misalignment of mitotic spindle filaments as a result of TTFields forces on tubulin chains.
“One of the mechanisms of action of TTFields is the misalignment of mitotic spindle filaments as a result of TTFields forces on tubulin chains [2].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y: Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004, 64 (9): 3288-3295. 10.1158/0008-5472.CAN-04-0083. source
Not checked in the free run.
- Premisecitation
Taxanes act by stabilizing the link between individual tubulin dimers.
“Taxanes act by stabilizing the link between individual tubulin dimmers [21].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Abal M, Andreu JM, Barasoain I: Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets. 2003, 3 (3): 193-203. 10.2174/1568009033481967. source
Not checked in the free run.
- Premisecitation
Published Temozolomide data indicates an increase of about 20% in overall survival compared to ionizing radiation treatment alone.
“while the published Temozolomide data indicates an increase of about 20% in OS compared to ionizing radiation treatment alone [14]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Stupp R, Mason WP, Bent van den MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005, 352 (10): 987-996. 10.1056/NEJMoa043330. source
Not checked in the free run.
- Premisecitation
Cyclophosphamide inhibits DNA replication by interfering with the separation of the double stranded DNA essential for transcription.
“Cyclophosphamide (an alkylating agent) inhibits DNA replication by interfering with the separation of the double stranded DNA essential for transcription [23].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [23] Sladek NE: Influence of aldehyde dehydrogenase activity on the sensitivity of lymphocytes and other blood cells to oxazaphosphorines. Methods Find Exp Clin Pharmacol. 1987, 9 (9): 617-626.
Not checked in the free run.
- Interpretationown data
This result strengthens the assumption that combination therapy with TTFields may be much more effective than treatment by individual agents.
“This result strengthens the assumption that combination therapy with TTFields may be much more effective than treatment by individual agents.”
Quote in the paperSubstantial claim - Interpretationown data
These results raise the possibility of dose reduction of chemotherapy when used in combination with TTFields.
“In addition to this increase in efficacy, these results raise the possibility of dose reduction of chemotherapy when used in combination with TTFields.”
Quote in the paperSubstantial claim - Interpretationreasoning
The results presented in Figure 6 point towards additivity between TTFields and Temozolomide.
“However, if we assume that the TTFields therapeutic efficacy for newly diagnosed patients is similar to recurrent GBM, i.e. the median of OS is increased by 270% [1] while the published Temozolomide data indicates an increase of about 20% in OS compared to ionizing radiation treatment alone [14], the results presented in Figure 6 point towards additivity between TTFields and Temozolomide.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
- cites [14] Stupp R, Mason WP, Bent van den MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO: Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005, 352 (10): 987-996. 10.1056/NEJMoa043330. source
Not checked in the free run.
- The authors state this as an assumption: TTFields therapeutic efficacy for newly diagnosed GBM patients is similar to that in recurrent GBM.
- Interpretationreasoning
In the specific case of paclitaxel, the combined effect may be attributed to their similar site of action - the spindle microtubules.
“In the specific case of Paclitaxel, one of the most commonly used treatments for late-stage human breast cancer [20], the combined effect may be attributed to their similar site of action – the spindle microtubules [1,2,21].”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
- cites [2] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y: Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004, 64 (9): 3288-3295. 10.1158/0008-5472.CAN-04-0083. source
Not checked in the free run.
- cites [21] Abal M, Andreu JM, Barasoain I: Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets. 2003, 3 (3): 193-203. 10.2174/1568009033481967. source
Not checked in the free run.
- Premisecitation
Taxanes increase the length of tubulin filaments within the cell.
“As illustrated schematically in Figure 7A taxanes increase the length of tubulin filaments within the cell.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [21] Abal M, Andreu JM, Barasoain I: Taxanes: microtubule and centrosome targets, and cell cycle dependent mechanisms of action. Curr Cancer Drug Targets. 2003, 3 (3): 193-203. 10.2174/1568009033481967. source
Not checked in the free run.
- May combine two claims. 21
- Classified as probably not a substantial claim. 7
- The quote only partly states this claim. 3
May combine two claims.
Findingown dataNo TTFields-related systemic toxicity was observed in any of the 20 GBM patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment.
“No TTFields related systemic toxicity was observed in any of these patients, nor was an increase in Temozolomide toxicity seen in patients receiving combined treatment.”
Quote in the paperSubstantial claim- Rests on an assumption: The dividing cells of the hematopoietic system are not affected by TTFields because the muscles surrounding marrow-containing bones serve as an effective electric field shield.
May combine two claims.
Findingown dataFor each of paclitaxel, doxorubicin, and cyclophosphamide alone, cell proliferation decreased with increasing drug concentration in MDA-MB-231 cells.
“For each drug alone there is a decrease in cell proliferation with increase in concentration.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn MDA-MB-231 cells at 150 kHz, TTFields at 0.63 V/cm caused no significant change in cell proliferation, while intensities of 1.25, 1.75, and 2.95 V/cm decreased proliferation to 90 ± 3%, 74 ± 4%, and 25 ± 5% of control, respectively.
“At the lowest field intensity of 0.63 V/cm there is no significant change in cell proliferation. For TTFields intensities of 1.25, 1.75 and 2.95 V/cm cell proliferation decreases (control = 100%) to: 90 ± 3%, 74 ± 4% and 25 ± 5%, respectively.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data20 GBM patients were treated with TTFields for a median duration of 1 year.
“Finally, 20 GBM patients were treated with TTFields for a median duration of 1 year.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataIn newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months.
“In newly diagnosed GBM patients, combining TTFields with Temozolomide treatment led to a progression free survival of 155 weeks and overall survival of 39+ months.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAfter a 24 h exposure to individual chemotherapeutic agents, the proliferation rate recovers almost completely during the following 48 h, except for doxorubicin, where recovery is slower and delayed by about 24 h.
“The proliferation rate (slope of the graph) recovers almost completely during the following 48 hours, except for doxorubicin, where recovery is slower and delayed by about 24 hours.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThe severity of dermatitis decreased upon use of topical corticosteroids and periodic electrode relocation.
“The severity of the dermatitis decreased upon use of topical corticosteroids and periodic electrode relocation.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataThe dermatitis continued for the duration of treatment and resolved completely within days to weeks from treatment termination.
“The dermatitis continued for the duration of treatment and resolved completely within days to weeks from treatment termination.”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataThe median overall survival for newly diagnosed GBM patients treated with combined TTFields-Temozolomide is >39 months.
“It is seen that for the TTFields – Temozolomide combination treated patients, the Median OS > 39 months versus about 14.7 months for matched historical control patients who received maintenance Temozolomide alone.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown data5 of 10 newly diagnosed GBM patients receiving combined TTFields-Temozolomide are currently progression free.
“Note that 5 of 10 patients are currently progression free.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThe difference between progression-free survival curves for combined TTFields-Temozolomide versus Temozolomide alone is highly significant (Log-Rank P = 0.0002), with hazard ratio 3.32 (95% CI 1.9-5.9).
“The difference between the PFS curves is highly significant – Log-Rank Test (P = 0.0002), Hazard Ratio 3.32 (95%CI 1.9–5.9).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThis significant increase in efficacy was obtained without any increase in device or drug related toxicity.
“It is important to note that this significant increase in efficacy was obtained without any increase in device or drug related toxicity (see table 3).”
Quote in the paperSubstantial claimThe quote only partly states this claim.
Findingown dataThe median progression-free survival of newly diagnosed GBM patients treated with combined TTFields-Temozolomide is 155 weeks.
“The median PFS of the combination treated patients is 155 weeks versus 31 weeks for concurrent controls treated with maintenance Temozolomide alone.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationTTFields have been demonstrated to be highly effective when applied to cell cultures, animal cancer models, and patients with locally advanced and/or metastatic solid tumors.
“A new physical cancer treatment modality termed Tumor Treating Fields, or TTFields, has recently been demonstrated to be highly effective when applied to cell cultures, animal cancer models, as well as to patients suffering from locally advanced and or metastatic solid tumors [1-3].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
- cites [2] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y: Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004, 64 (9): 3288-3295. 10.1158/0008-5472.CAN-04-0083. source
Not checked in the free run.
- cites [3] Salzberg M, Kirson E, Palti Y, Rochlitz C: A pilot study with very low-intensity, intermediate-frequency electric fields in patients with locally advanced and/or metastatic solid tumors. Onkologie. 2008, 31 (7): 362-365. 10.1159/000137713. source
Not checked in the free run.
May combine two claims.
Interpretationown dataCombining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment-related toxicity.
“These results indicate that combining chemotherapeutic cancer treatment with TTFields may increase chemotherapeutic efficacy and sensitivity without increasing treatment related toxicity.”
Quote in the paperSubstantial claim- Rests on an assumption: The dividing cells of the hematopoietic system are not affected by TTFields because the muscles surrounding marrow-containing bones serve as an effective electric field shield.
Classified as probably not a substantial claim.
PremisecitationMany cancer treatment protocols require simultaneous or sequential use of a number of therapeutic agents to increase efficacy while maintaining tolerable toxicity.
“In view of the unfavorable therapeutic indexes of the available effective chemical and physical (i.e. ionizing radiation) therapeutic agents, many cancer treatment protocols require simultaneous or sequential use of a number of therapeutic agents in an attempt to increase efficacy while maintaining tolerable toxicity [5-7].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [5] Bantinas R, Hohl R, Peterson D: Management of Drug Toxicity. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 399-559. 3
Not checked in the free run.
- cites [6] Bryer M: Combined Modality Therapy. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 73-81. 3
Not checked in the free run.
- cites [7] Burris H: Combination Chemotherapy. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 69-73. 3
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAdding ionizing radiation to chemotherapy gives both the benefit of the radiation effect and sensitization leading to increased efficacy without a corresponding increase in toxicity.
“Within this framework it is generally accepted that by adding ionizing radiation [8] to chemotherapy one gets both the benefit of the radiation effect as well as sensitization leading to an increased efficacy without a corresponding increase in toxicity.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Leonard CE, Chan DC, Chou TC, Kumar R, Bunn PA: Paclitaxel enhances in vitro radiosensitivity of squamous carcinoma cell lines of the head and neck. Cancer Res. 1996, 56 (22): 5198-5204.
Not checked in the free run.
May combine two claims.
PremisecitationTTFields have no effect on quiescent cells while having an anti-mitotic effect on dividing cells.
“These specially tuned fields have no effect on quiescent cells while having an anti-mitotic effect on dividing cells.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Kirson ED, Gurvich Z, Schneiderman R, Dekel E, Itzhaki A, Wasserman Y, Schatzberger R, Palti Y: Disruption of cancer cell replication by alternating electric fields. Cancer Res. 2004, 64 (9): 3288-3295. 10.1158/0008-5472.CAN-04-0083. source
Not checked in the free run.
Classified as probably not a substantial claim.
Study design and conductcitationAssessment of tumor response was based on monthly MRIs according to the Macdonald criteria.
“Assessment of tumor response was based on monthly MRIs according to the Macdonald criteria [12].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] Macdonald DR, Cascino TL, Schold SC, Cairncross JG: Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990, 8 (7): 1277-1280. source
Not checked in the free run.
May combine two claims.
Study design and conductcitationUsing the electrode configuration, the lowest TTFields intensity at the center of the brain was 0.7 V/cm (RMS), calculated using finite element mesh simulations and verified by direct measurement in large animals and a human volunteer.
“Using this electrode configuration, the lowest TTFields intensity at the center of the brain was 0.7 V/cm (RMS). This intensity was calculated using finite element mesh simulations and verified by direct measurement in large animals and a human volunteer [1].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAnimals were assigned randomly into 4 groups before treatment start.
“The animals were assigned randomly into 4 groups before treatment start:”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe increase in filament length due to taxanes increases the dipole moment of these macromolecules, leading to an increase in TTFields-induced forces and thus to a higher sensitivity of the cell to TTFields.
“The increase in filament length due to taxanes, increases the dipole moment of these macromolecules, leading to an increase in the TTFields induced forces and thus to a higher sensitivity of the cell to TTFields (see Figure 7A).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataAs demonstrated by the high DRIs calculated in this study, chemo/TTFields combinations are expected to provide the same or even greater therapeutic efficacy with much lower drug concentrations thus lowering further the overall toxicity.
“Moreover, as demonstrated by the high DRIs calculated in this study, chemo/TTFields combinations are expected to provide the same or even greater therapeutic efficacy with much lower drug concentrations thus lowering further the overall toxicity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe results support the possibility that TTFields may be used not only as an effective stand-alone anti-proliferation agent but also as an effective adjuvant that enhances chemotherapy efficacy without an increase in toxicity.
“The results of this study support the possibility that TTFields may be used, not only as an effective stand alone anti-proliferation agent (as shown previously in [1]), but also as an effective adjuvant that enhances chemotherapy efficacy without an increase in toxicity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
May combine two claims.
Interpretationown dataThe results support the notion that TTFields may be used clinically not only as an anti-proliferation agent but also as effective sensitizers of currently used chemotherapeutic agents.
“The results of the present study support the notion that TTFields may be used clinically not only as an anti-proliferation agent as shown before [1], but also as effective sensitizers of currently used chemotherapeutic agents.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
May combine two claims.
InterpretationreasoningSince TTFields act at a completely different stage (M phase) of the cell cycle from doxorubicin and cyclophosphamide, additivity between chemotherapy and TTFields can be expected.
“As illustrated in Figure 7B, since TTFields act at a completely different stage (M phase) of the cell cycle from both these agents, additivity between chemotherapy and TTFields can be expected.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAs reported previously, both progression-free survival and overall survival in the recurrent GBM salvage therapy group were at least double that of concurrent and historical controls, respectively.
“As reported previously [1], both progression free survival (PFS) and overall survival (OS) in the recurrent GBM salvage therapy group were at least double that of concurrent and historical controls, respectively.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Kirson ED, Dbaly V, Tovarys F, Vymazal J, Soustiel JF, Itzhaki A, Mordechovich D, Steinberg-Shapira S, Gurvich Z, Schneiderman R, Wasserman Y, Salzberg M, Ryffel B, Goldsher D, Dekel E, Palti Y: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci USA. 2007, 104 (24): 10152-10157. 10.1073/pnas.0702916104. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationDoxorubicin affects both DNA and RNA synthesis.
“Doxorubicin that has a broad spectrum of activity both in experimental tumor models and in human malignancy, affects both DNA and RNA synthesis [22].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Plosker GL, Faulds D: Epirubicin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cancer chemotherapy. Drugs. 1993, 45 (5): 788-856. source
Not checked in the free run.
May combine two claims.
Study design and conductreasoningThe data for newly diagnosed GBM patients, which points to well over a 300% increase in PFS and OS, was obtained only with combination treatment, so one cannot directly separate the TTFields effects from the chemotherapeutic effect.
“Since the data for newly diagnosed GBM patients, which points to well over a 300% increase in PFS and OS, was obtained only with combination treatment, one cannot directly separate the TTFields effects from the chemotherapeutic effect.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The dividing cells of the hematopoietic system are not affected by TTFields because the muscles surrounding marrow-containing bones serve as an effective electric field shield.
“Fortunately, the dividing cells of the hematopoietic system are not affected by TTFields as the muscles surrounding the marrow containing bones serve as an effective electric field shield.”
The paper relies on this without support.
TTFields intensity can validly replace drug concentration as the dose variable in the Chou and Talalay combination-index analysis.
“TTFields intensity replaced the concentration (dose) variable in the analyses.”
The authors state this as an assumption.
TTFields therapeutic efficacy for newly diagnosed GBM patients is similar to that in recurrent GBM.
“if we assume that the TTFields therapeutic efficacy for newly diagnosed patients is similar to recurrent GBM”
The authors state this as an assumption.
Tumor cells are sensitized to TTFields by chemotherapy.
“one may assume that tumor cells are sensitized to TTFields by chemotherapy”
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?
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 [49]
TTFields application to animals and patients has almost no acute or chronic toxicity.
“The application of TTFields to animals and patients has been shown to have almost no acute or chronic toxicity [18, 20].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [20]
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].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [20]
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].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [20]
The low intensity used (single volts per cm) does not cause significant heating within the body.
“In addition, the low intensity used (single volts per cm), does not cause significant heating within the body [18, 20].”
From Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs (2009) · cites this paper as [20]
The citation lists haven’t been fetched yet
References 21 · Cited by 224
Research works printed but not linked: 3
- Bryer M: Combined Modality Therapy. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 73-81. 3
- Burris H: Combination Chemotherapy. The Chemotherapy Source Book. Edited by: Perry MC. 2001, Lippincott Williams & Wilkins, 69-73. 3
- Kirson ED, Dbalý V, Rochlitz C, Tovaryš F, Salzberg M, Palti Y: Treatment of locally advanced solid tumors using alternating electric fields (TTFields) – a translational study. Proceedings of 97th AACR Annual Meeting: 2006; Washington, DC. 2006
- Authors
- Kirson, E. D., Schneiderman, R. S., Dbalý, V., Tovaryš, F., Vymazal, J., Itzhaki, A., Mordechovich, D., Gurvich, Z., Shmueli, E., Goldsher, D., Wasserman, Y., & Palti, Y.
- Affiliations
- Na Homolce Hospital (CZ)
- Technion – Israel Institute of Technology (IL)
- Corresponding author
- Kirson, Eilon D
- Venue
- BMC Medical Physics
- Published
- 2009-01-08
- Volume
- 9
- Issue
- 1
- Pages
- 1-1
- ISSN
- 1756-6649 (ISSN-L)
- PMC
- PMC2647898
- OpenAlex
- W1968590286
- Semantic Scholar
- 7db7c14bd3d7599227c5dd294dac4d05410b9aec
- Cited by
- 224
- References
- 21
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 10 · 2023: 12 · 2022: 17 · 2021: 20 · 2020: 23 · 2019: 11 · 2018: 19 · 2017: 23 · 2016: 16 · 2015: 14 · 2014: 13 · 2013: 7 · 2012: 7
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- BMC Medical Physics (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Novocure
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
- Keywords
- tumor treating fields, AC electric field, combination chemotherapy, glioblastoma, breast cancer, paclitaxel, doxorubicin, cyclophosphamide, dacarbazine, temozolomide, drug sensitivity, combination index, treatment toxicity, progression-free survival, newly diagnosed glioblastoma
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.
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