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Cited by 1,259Glioma Diagnosis and TreatmentMathematical Biology Tumor GrowthElectromagnetic Fields and Biological Effects

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial

Open access
Stupp, Roger, Taillibert, Sophie, Kanner, Andrew A., Kesari, Santosh, Steinberg, David M., Toms, Steven A., Taylor, Lynne P., Lieberman, Frank +22 more·2015·JAMA
DOI 10.1001/jama.2015.16669
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Abstract

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

AI snapshot

Written from the paper’s full text.

TL;DR

In this prespecified interim analysis of the EF-14 trial, adding tumor-treating fields (TTFields) to maintenance temozolomide significantly prolonged progression-free and overall survival in patients with glioblastoma after chemoradiotherapy. The trial was terminated early based on these interim results.

Key findings

  • Among 315 patients in the interim analysis (210 TTFields plus temozolomide; 105 temozolomide alone), median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2) vs 4.0 months (95% CI, 3.3-5.2) (HR, 0.62 [98.7% CI, 0.43-0.89]; P = .001).
  • Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0) vs 15.6 months (95% CI, 13.3-19.1) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). In the intent-to-treat population, median overall survival was 19.6 months vs 16.6 months (HR, 0.74 [95% CI, 0.56-0.98]; P = .03), and 2-year survival was 43% vs 29% (P = .006).
  • TTFields plus temozolomide was not associated with a significant increase in systemic toxic effects; localized skin toxicity occurred in 43% (mild to moderate) and 2% (grade 3) with TTFields, and seizure incidence was 7% vs 8%.

Methods

  • Multicenter, open-label, randomized phase 3 trial; patients with newly diagnosed supratentorial glioblastoma who were progression-free after chemoradiotherapy were randomized 2:1 to TTFields plus temozolomide or temozolomide alone. The study enrolled 695 of 700 planned patients at 83 centers; this interim analysis included the first 315 patients with at least 18 months of follow-up.
  • TTFields were delivered continuously (>18 hours/day) via 4 transducer arrays on the shaved scalp; temozolomide was given at 150-200 mg/m²/d for 5 days every 28 days.
  • Primary end point was progression-free survival in the intent-to-treat population (significance threshold .01); overall survival in the per-protocol population was a powered secondary end point (significance threshold .006). Analyses used stratified log-rank tests, with central blinded MRI review.

Limitations

  • The paper states that enrollment occurred only after radiochemotherapy, leading to variation in standard treatment delivery and exclusion of patients who progressed early during radiochemotherapy; there is likely reporting bias for second-line therapies because TTFields were continued in the intervention group.
  • The paper states this is a planned interim analysis of the first 315 patients, and mature data from the full data set are needed for detailed subgroup analyses.
  • The paper states the trial was open-label and no sham or placebo control was used; it argues objective end points assessed by blinded review are independent of placebo effects, but the open-label design remains a stated limitation. Funding and author conflicts with Novocure are also evident in the text.

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

Integrity signals

Registry

Crossref · 10.1001/jama.2015.16669

Cites

28 of 28 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 22 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    A total of 12 patients died of causes considered unrelated to treatment while receiving adjuvant therapy (8 [3.9%] in the temozolomide plus TTFields group and 4 [4.0%] in the temozolomide alone group).

    “A total of 12 patients died of causes considered unrelated to treatment while receiving adjuvant therapy (8 [3.9%] in the temozolomide plus TTFields group and 4 [4.0%] in the temozolomide alone group; Table 2).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Patients who received TTFields plus temozolomide had a median overall survival of 20.5 months compared with 15.6 months in those who received temozolomide alone (per-protocol analysis; ITT analysis did not differ substantially).

    “Patients who received TTFields plus temozolomide had a median overall survival of 20.5 months compared with 15.6 months in those who received temozolomide alone (as per the prespecifed per-protocol analysis; the ITT analysis did not differ substantially).”
    Quote in the paperSubstantial claim
  • Findingown data

    In additional analyses in the ITT population, the median overall survival was 19.6 months (95% CI, 16.6-24.4 months) in the TTFields plus temozolomide group compared with 16.6 months (95% CI, 13.6-19.2 months) in the temozolomide alone group (HR, 0.74 [95% CI, 0.56-0.98]; stratified log-rank P = .03).

    “In additional analyses in the ITT population, the median overall survival was 19.6 months (95% CI, 16.6-24.4months) in the TTFields plus temozolomide group compared with 16.6 months (95% CI, 13.6-19.2months) in the temozolomide alone group (HR, 0.74 [95% CI, 0.56-0.98];stratified log-rank P = .03;Figure 2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    The incidence of seizures was almost identical in the 2 groups (15 [7%] in the TTFields plus temozolomide group vs 8 [8%] in temozolomide alone group).

    “The incidence of seizures was almost identical in the 2 groups (15 [7%] in the TTFields plus temozolomide group vs 8 [8%] in temozolomide alone group).”
    Quote in the paperSubstantial claim
  • Findingown data

    Two-thirds (n = 141) of patients in the TTFields plus temozolomide group continued treatment with TTFields after first tumor progression.

    “Two-thirds (n = 141) of patients in the TTFields plus temozolomide group continued treatment with TTFields after first tumor progression.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 26
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Findingown data

    Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (HR, 0.62 [98.7% CI, 0.43-0.89]; P = .001).

    “Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89];P = .001).”
    • Also stated in: § Efficacy End Points · plain
      “the median progressionfree survival from randomization was 7.1 months (95% CI, 5.9-8.2months) in the TTFields plus temozolomide group compared with 4.0 months (95% CI, 3.3-5.2months) in the temozolomide alone group (HR, 0.62 [98.7% CI, 0.43-0.89];stratified log-rank P = .001;Figure 2A)”
    • Also stated in: § Efficacy End Points · plain
      “Thus, adding TTFields to temozolomide treatment increased median progressionfree survival in the ITT population by 3.1 months.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No increase in seizure rate or neurological adverse events was observed.

    “No increase in seizure rate or neurological adverse events was observed.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Second-line treatments, such as nitrosoureas, temozolomide rechallenge, and bevacizumab, were received by 67% of the patients in the TTFields plus temozolomide group compared with 57% in the temozolomide alone group; about 40% of second-line therapies included bevacizumab and about 40% included nitrosoureas.

    “Second-line treatments, such as nitrosoureas, temozolomide rechallenge, and bevacizumab, were received by 67% of the patients in the TTFields plus temozolomide group compared with 57% in the temozolomide alone group; about 40% of second-line therapies included bevacizumab and about 40% included nitrosoureas.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Because TTFields were applied only to the head, an increase in systemic adverse events was neither seen nor expected.

    “Because TTFields were applied only to the head, an increase in systemic adverse events was neither seen nor expected.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In the ITT population, TTFields plus temozolomide produced a gain of 3 months in median progression-free survival (from 4.0 to 7.2 months; HR, 0.62) and median overall survival (from 16.6 to 19.6 months; HR, 0.74), and a 2-year survival gain of 14% (from 29% to 43%).

    “In the present trial, the gain of 3 months in both median progression-free survival (from 4.0 months to 7.2 months; HR, 0.62) and median overall survival (from 16.6 months to 19.6 months; HR, 0.74), translating into a survival gain at 2 years of 14% (from 29% to 43%) in the ITT population”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The independent data and safety monitoring committee met in October 2014 to review the interim analysis; the trial met the predefined boundaries for success (improvement of both progression-free and overall survival) and the committee recommended study termination, thus allowing patients in the control group to crossover and receive TTFields.

    “The independent data and safety monitoring committee met in October 2014 to review the interim analysis; the trial met the predefined boundaries for success (improvement of both progression-free and overall survival) and the committee recommended study termination, thus allowing patients in the control group to crossover and receive TTFields.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Eight patients in the TTFields plus temozolomide group (4%) compared with 6 patients in the temozolomide alone group (3%) were considered stable by blinded central review; however, treatment had been changed by the study investigator due to local interpretation of tumor progression.

    “Eight patients in the TTFields plus temozolomide group (4%) compared with 6 patients in the temozolomide alone group (3%) were considered stable by blinded central review; however, treatment had been changed by the study investigator due to local interpretation of tumor progression.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The median number of temozolomide cycles until evidence of first tumor progression was 6 cycles (range, 1-26 cycles) for patients in the TTFields plus temozolomide group and 4.0 cycles (range, 1-24 cycles) for patients in the temozolomide alone group.

    “The median number of temozolomide cycles until evidence of first tumor progression was 6 cycles (range, 1-26 cycles) for patients in the TTFields plus temozolomide group and 4.0 cycles (range, 1-24 cycles) for patients in the temozolomide alone group”
    Quote in the paperSubstantial claim

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

    Findingown data

    At the time of this report, 35 patients in the control group crossed over to receive TTFields.

    “At the time of this report, 35 patients in the control group crossed over to receive TTFields.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The median duration of treatment with TTFields was 9 months (range, 1-58 months).

    “the median duration of treatment with TTFields was 9 months (range, 1-58 months).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mild anxiety, confusion, insomnia, and headaches were reported more frequently in the patients treated with TTFields plus temozolomide and occurred mainly at the time of therapy initiation.

    “Mild anxiety, confusion, insomnia, and headaches were reported more frequently in the patients treated with TTFields plus temozolomide and occurred mainly at the time of therapy initiation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The addition of TTFields to standard maintenance temozolomide significantly improved progression-free and overall survival.

    “the addition of TTFields to standard maintenance temozolomide significantly improved progression-free and overall survival.”
    • Also stated in: § Conclusions · plain
      “adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The control groups with standard dose temozolomide only in the present study and the RTOG 0525 trial were comparable: progression-free survival from randomization of 4.0 months in the present study and 5.5 months in the RTOG 0525 trial and overall survival of 16.6 months in both trials.

    “The control groups with standard dose temozolomide only in these 2 trials were comparable: progression-free survival from randomization of 4.0 months in the present study and 5.5 months in the RTOG 0525 trial and overall survival of 16.6 months in both trials.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3]

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Mild to moderate skin irritation was observed in 43% of patients treated with TTFields plus temozolomide and severe skin reaction (grade 3) in 2%.

    “Mild to moderate skin irritation was observed in 43% of patients treated with TTFields plus temozolomide and severe skin reaction (grade 3) in 2%.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea.

    “The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.

    “This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up.”
    • Also stated in: § Statistical Considerations · plain
      “This prespecified interim analysis was to be performed after the first 315 randomized patients reached a minimum 18-month follow-up.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months).

    “The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months).”
    • Also stated in: § Study Participants · plain
      “Data for the interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 to temozolomide alone”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Tumor-treating fields (TTFields) are an antimitotic treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency (200 kHz) alternating electric fields via transducer arrays applied to the shaved scalp.

    “Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly.”
    • Also stated in: § Abstract · plain
      “Tumor-treating fields (TTFields) are an antimitotic treatment that selectively disrupts the division of cells by delivering low-intensity, intermediate-frequency (200 kHz) alternating electric fields via transducer arrays applied to the shaved scalp.[8][9][10]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8][9][10]

      Not checked in the free run.

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

    Premisecitation

    In that trial, TTFields were associated with better quality of life without the typical chemotherapy-associated toxic effects.

    “but the therapy was associated with better quality of life without the typical chemotherapy-associated toxic effects.13”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13]

      Not checked in the free run.

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

    Study design and conductown data

    The trial was terminated based on the results of this planned interim analysis.

    “The trial was terminated based on the results of this planned interim analysis.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Recent randomized studies of patients with glioblastoma, which did not use placebo controls, failed to show any increase in progression-free or overall survival despite intensive treatment regimens requiring twice weekly hospital visits.

    “Recent randomized studies of patients with glioblastoma, which did not use placebo controls, failed to show any increase in progression-free or overall survival 3,7 despite intensive treatment regimens requiring twice weekly hospital visits.7”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3]

      Not checked in the free run.

    • cites [7]

      Not checked in the free run.

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

    Study design and conductnone given

    The study was also designed to have 80% power (HR, 0.76; 2-sided α level of .05) to examine overall survival as a secondary end point.

    “The study was also designed to have 80% power (HR, 0.76; 2-sided α level of .05) to examine overall survival as a secondary end point.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The trial population and the results in the control group in this study were comparable with other glioblastoma clinical trials.

    “The trial population and the results in the control group in this study were comparable with other glioblastoma clinical trials.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    Patient characteristics of all patients randomized did not differ significantly from the interim data set, and the results for the main end points were similar in these analyses compared with the interim analysis.

    “Patient characteristics of all patients randomized did not differ significantly from the interim data set, and the results for the main end points were similar in these analyses compared with the interim analysis (eAppendix 1 in Supplement 2).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductnone given

    The support provided to patients in the TTFields plus temozolomide group by device support specialists during the trial was largely technical in nature and did not include medical supportive care.

    “In addition, the support provided to patients in the TTFields plus temozolomide group by device support specialists during the trial was largely technical in nature and did not include medical supportive care.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Evaluation of MGMT gene promoter methylation status was performed by a central laboratory blinded to treatment group.

    “evaluation of MGMT gene promoter methylation status was performed as described previously 7,15,16 by a central laboratory blinded to treatment group (MDxHealth).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7]

      Not checked in the free run.

    • cites [15]

      Not checked in the free run.

    • cites [16]

      Not checked in the free run.

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

    Study design and conductnone given

    An independent data and safety monitoring committee was chartered to stop the trial if the interim analysis of progression-free survival (ITT population) and overall survival (per-protocol population) surpassed these predetermined thresholds, as well as for futility or safety concerns.

    “An independent data and safety monitoring committee was chartered to stop the trial if the interim analysis of progression-free survival (ITT population) and overall survival (per-protocol population) surpassed these predetermined thresholds, as well as for futility or safety concerns.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    There is likely reporting bias for second-line therapies after tumor progression because in the TTFields plus temozolomide group, TTFields were to be continued, and thus, more detailed treatment information has been tracked for this group.

    “There is likely reporting bias for second-line therapies after tumor progression because in the TTFields plus temozolomide group, TTFields were to be continued, and thus, more detailed treatment information has been tracked for this group.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Multiple imputation analyses were performed for the trial's primary end point of progression-free survival in the ITT population to test the sensitivity of the results to possible bias using informative and interval censoring.

    “Multiple imputation analyses also were performed for the trial's primary end point of progression-free survival in the ITT population to test the sensitivity of the results to possible bias using informative and interval censoring.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    When the interval from diagnosis to randomization is added to the outcome results in this study, the progression-free survival of 7.8 months in the control group is comparable with most other reported studies, and supports the generalizability of these results.

    “When the interval from diagnosis to randomization is added to the outcome results in this study, the progressionfree survival of 7.8 months in the control group is comparable with most other reported studies, and supports the generalizability of these results.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most glioblastoma trials report survival from the date of initial diagnosis or study enrollment before starting radiochemotherapy, about 3 to 4 months before randomization in the current study.

  • May combine two claims.

    Interpretationown data

    In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.

    “In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The protocol prespecified that overall survival would be analyzed in an as-treated population, excluding all patients in both treatment groups who (1) never started maintenance temozolomide, (2) had major protocol violations, (3) crossed over to the other treatment group, or (4) received TTFields outside the protocol setting.

    “The protocol prespecified that overall survival would be analyzed in an as-treated population, excluding all patients in both treatment groups who (1) never started maintenance temozolomide, (2) had major protocol violations, (3) crossed over to the other treatment group, or (4) received TTFields outside the protocol setting.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductnone given

    The panel did not have information on treatment received and no stigmata of TTFields array pads were evident on MRI.

    “The panel did not have information on treatment received and no stigmata of TTFields array pads were evident on MRI.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    In cases of disagreement between central reviewers, a third blinded radiologist adjudicated.

    “In cases in which the central reviewers were not in agreement, a third blinded radiologist adjudicated between them.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    To avoid an increase in the risk of a false-positive result, overall survival was to be tested statistically only if the primary end point was met.

    “To avoid an increase in the risk of a falsepositive result, overall survival was to be tested statistically only if the primary end point was met.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The primary end point would be achieved in the interim analysis if progression-free survival in the ITT population was significantly longer in the intervention group compared with the control group using a stratified log-rank test with an α level of .01.

    “The primary end point would be achieved in the interim analysis if progression-free survival in the ITT population was significantly longer in the intervention group compared with the control group using a stratified log-rank test with an α level of .01.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Randomization was performed through a central web-based randomization system and was stratified by extent of resection and by MGMT methylation status.

    “Randomization was performed through a central web-based randomization system and was stratified by extent of resection (biopsy, partial resection, gross total resection) and by O 6 -methylguanine-DNA methyltransferase (MGMT) methylation status (methylated, unmethylated, or unknown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Patients in this trial were randomized only after the end of radiochemotherapy, and for most, the first cycle of maintenance temozolomide had been started at randomization; thus, patients with early tumor progression during radiochemotherapy were excluded.

    “Nevertheless, patients in this trial were randomized only after the end of radiochemotherapy, and for most, the first cycle of maintenance temozolomide had been started at the time of randomization; thus, patients with early tumor progression during radiochemotherapy were excluded.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    All MRIs were reviewed centrally by 2 blinded independent radiologists and evaluated for tumor response and progression using Macdonald criteria.

    “All MRIs were reviewed centrally by 2 blinded independent radiologists (BioClinica Inc) and were evaluated for tumor response and progression using the criteria developed by Macdonald et al. 19”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Macdonald et al. 19

      Not checked in the free run.

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

    Study design and conductnone given

    The results of the central review were not communicated to the study investigator, and all treatment decisions were based on local imaging interpretation.

    “The results of the central review were not communicated to the study investigator, and all treatment decisions were based on local imaging interpretation.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation

    This adverse effect could be managed using published skin care guidelines for patients receiving TTFields.

    “This adverse effect could be managed using published skin care guidelines for patients receiving TTFields.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25]

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The secondary end point would be achieved in the interim analysis if overall survival in the as-treated population (per-protocol population) was significantly longer in the TTFields plus temozolomide group using a stratified log-rank test with an α level of .006.

    “The secondary end point would be achieved in the interim analysis if overall survival in the as-treated population (per-protocol population) was significantly longer in the TTFields plus temozolomide group using a stratified log-rank test with an α level of .006.”
    Quote in the paperSubstantial claim
42 of 42

  • The paper relies on this without support.

    Most glioblastoma trials report survival from the date of initial diagnosis or study enrollment before starting radiochemotherapy, about 3 to 4 months before randomization in the current study.

    “Most glioblastoma trials have reported survival from the date of initial diagnosis or study enrollment before starting radiochemotherapy, thus 3 to 4 months before randomization of the current study.”
1 of 1

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?

  • In newly diagnosed glioblastoma, 200 kHz TTFields combined with adjuvant temozolomide prolonged median overall survival by 4.9 months and median progression-free survival by 2.7 months compared with adjuvant temozolomide alone.

    “Based on the results of a phase III clinical trial that showed 200 kHz TTFields in combination with adjuvant temozolomide chemotherapy prolonged the median overall survival (OS) in newly diagnosed GBM patients by 4.9 months (and prolonged median progression-free survival [PFS] by 2.7 months) compared to adjuvant temozolomide alone”

    From Permeabilizing Cell Membranes with Electric Fields (2021) · cites this paper as [11]

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

    “It has been evaluated in randomized phase 3 trials in glioblastoma (GBM) and demonstrated to prolong progression-free survival (PFS) and overall survival (OS) when administered together with standard maintenance temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM.”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [17]

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

    “Median OS from randomization (ITT) was 19.6 months (95% CI, 16.6–24.4 mo) in the TTFields plus TMZ group compared with 16.6 months (95% CI, 13.6–19.2 mo) in the TMZ control group (HR: 0.74 [95% CI, 0.56–0.98]; P =.03).”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [17]

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

    “All treatment-related clinical decisions were based on local interpretation of imaging; however, a blinded central imaging and disease assessment review determined the date of progression.”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [17]

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

    “Preliminary subgroup analyses showed that the positive effect observed on PFS and OS by the addition of TTFields was not restricted to any subgroup of patients: in particular neither age, performance status, MGMT methylation status nor extent of resection was predictive for a better treatment effect.”

    From Tumor treating fields: A novel treatment modality and its use in brain tumors (2016) · cites this paper as [17]

Self-check

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

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

  • MGMT invalid-test subgroup counts do not match the total

    Minor

    The treatment-group counts of invalid MGMT tests sum to 35, not the reported all-patients total of 36.

    Reported 36 · recomputed 35

  • Six control-group patients are labeled 3% rather than about 6%

    Minor

    The interim control group comprised 105 patients. Six of 105 is 5.7%, not the reported 3%.

    Reported 3 · recomputed 5.714286

  • Discussion changes the TTFields median progression-free survival

    Minor

    The efficacy results give the TTFields-group median as 7.1 months, whereas the discussion describes the same comparison as 7.2 months.

3 of 3

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Authors
Stupp, R., Taillibert, S., Kanner, A. A., Kesari, S., Steinberg, D. M., Toms, S. A., Taylor, L. P., Lieberman, F., Silvani, A., Fink, K. L., Barnett, G. H., Zhu, J.-J., Henson, J. W., Engelhard, H. H., Chen, T. C., Tran, D. D., Sroubek, J., Tran, N. D., Hottinger, A. F., Landolfi, J., Desai, R., Caroli, M., Kew, Y., Honnorat, J., Idbaih, A., Kirson, E. D., Weinberg, U., Palti, Y., Hegi, M. E., & Ram, Z.
Affiliations
  • University of Zurich (CH)
  • Assistance Publique – Hôpitaux de Paris (FR)
  • Tel Aviv University (IL)
  • University of California San Diego (US)
  • Geisinger Health System (US)
  • Tufts Medical Center (US)
  • University of Pittsburgh Medical Center (US)
  • Fondazione IRCCS Istituto Neurologico Carlo Besta (IT)
  • Baylor University Medical Center (US)
  • Cleveland Clinic (US)
  • Swedish Medical Center (US)
  • University of Illinois Chicago (US)
  • University of Southern California (US)
  • Barnes-Jewish Hospital (US)
  • Na Homolce Hospital, Prague, Czech Republic
  • Moffitt Cancer Center (US)
  • Centre Hospitalier Universitaire Vaudois (CH)
  • New Jersey Neuroscience Institute, Edison
  • Maine Medical Center (US)
  • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
  • Houston Methodist (US)
  • Hospices Civils de Lyon, University Claude Bernard Lyon 1, Lyon, France
  • Assistance Publique des Hôpitaux de Paris, La Pitié-Salpétrière-University Hospital, Pierre and Marie Curie University, Paris, France
  • Novocure, Haifa, Israel
Corresponding author
Stupp, Roger
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2015-12-15
Volume
314
Issue
23
Pages
2535
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2015.16669
OpenAlex
W2205491921
Cited by
1,259
References
28
Citations by year
2026: 75 · 2025: 111 · 2024: 102 · 2023: 99 · 2022: 136 · 2021: 114 · 2020: 130 · 2019: 117 · 2018: 156 · 2017: 141 · 2016: 76 · 2015: 1
FWCI
69.79
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed (publishedVersion)
  • SERVAL (Université de Lausanne) (publishedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
  • IRIS (submittedVersion)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
Funders
  • Merck KGaA
  • Novocure
  • Genentech
  • Mundipharma EDO
Topics
  • Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
  • Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Electromagnetic Fields and Biological Effects
Keywords
glioblastoma, tumor treating fields, temozolomide, maintenance therapy, chemoradiotherapy, progression-free survival, overall survival, antimitotic therapy, central nervous system malignancies, treatment efficacy and safety, randomized controlled trials, transducer array, treatment-related adverse events, neurocognitive function, quality of life
MeSH terms
Temozolomide, Adult, Aged, Aged, 80 and over, Brain Neoplasms, Canada, Carmustine, Combined Modality Therapy, Dacarbazine, Electric Stimulation Therapy, Europe, Female, Glioblastoma, Humans, Israel, Male, Middle Aged, United States, Disease Progression, Disease-Free Survival, Antineoplastic Agents, Alkylating, Young Adult, Republic of Korea, Early Termination of Clinical Trials, Chemoradiotherapy, Maintenance Chemotherapy

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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

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

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