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Tumor-treating fields: time for demystification

      Tumor-treating fields (TTF) represent a relatively novel treatment modality based on the delivery of low-intensity, intermediate-frequency (200 kHz) alternating electrical fields that are thought to interfere with cellular proliferation by disrupting mitotic spindle formation during metaphase [
      • Kirson E.D.
      • Gurvich Z.
      • Schneiderman R.
      • et al.
      Disruption of cancer cell replication by alternating electric fields.
      ,
      • Giladi M.
      • Schneiderman R.S.
      • Voloshin T.
      • et al.
      Mitotic spindle disruption by alternating electric fields leads to improper chromosome segregation and mitotic catastrophe in cancer cells.
      ]. Being a local treatment, glioblastoma emerged early on as a potentially paradigmatic disease to explore the potential clinical utility of TTF. For glioblastoma treatment, TTF were administered via transducer arrays attached to the scalp. Yet, the initially great expectations that were based on 10 recurrent glioblastoma patients who experienced median time to disease progression of 26.1 weeks and median overall survival of 62.2 weeks [
      • Kirson E.D.
      • Dbaly V.
      • Tovarys F.
      • et al.
      Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.
      ], were not met in a randomized trial of TTF versus best physician’s choice [
      • Stupp R.
      • Wong E.T.
      • Kanner A.A.
      • et al.
      NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.
      ], in the setting of recurrent glioblastoma where no intervention, including all ‘best physician’s choices’, has ever shown to prolong survival in an adequately powered randomized clinical trial [
      • Weller M.
      • Cloughesy T.
      • Perry J.R.
      • Wick W.
      Standards of care for treatment of recurrent glioblastoma—are we there yet?.
      ,
      • Wick W.
      • Gorlia T.
      • Bendszus M.
      • et al.
      Lomustine and bevacizumab in progressive glioblastoma.
      ]. Yet, despite a negative trial in the recurrent setting, TTF were moved forward to a reasonably sized phase III clinical trial, EF-14, which—unexpectedly for most of the neuro-oncology community—reported a small, but solid overall survival benefit [
      • Stupp R.
      • Taillibert S.
      • Kanner A.A.
      • et al.
      Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial.
      ]. Parallels to the development of temozolomide, the current standard of care for glioblastoma [
      • Weller M.
      • van den Bent M.
      • Tonn J.C.
      • for the European Association for Neuro-Oncology (EANO) Task Force on Gliomas
      • et al.
      EANO guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.
      ], have been drawn by some colleagues who support integration of TTF into current standards of care: single agent activity at recurrence was modest at best for temozolomide, too [
      • Yung W.K.
      • Albright R.E.
      • Olson J.
      • et al.
      A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse.
      ], in fact so modest that temozolomide might not be moved forward today to a fully sized phase III trial in newly diagnosed disease with similarly marginal efficacy at recurrence, yet, its efficacy in the first-line setting still changed clinical practice across the world [
      • Weller M.
      • van den Bent M.
      • Tonn J.C.
      • for the European Association for Neuro-Oncology (EANO) Task Force on Gliomas
      • et al.
      EANO guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.
      ,
      • Stupp R.
      • Mason W.P.
      • van den Bent M.J.
      • on behalf of the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor and Radiotherapy Groups and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)
      • et al.
      Radiotherapy plus concomitant and adjuvant temozolomide for patients with newly diagnosed glioblastoma.
      ].
      The final analysis of the EF-14 trial reports a median progression-free survival from randomization of 6.7 months in the TTF-plus-temozolomide group versus 4.0 months in the temozolomide-alone group (hazard ratio, HR = 0.63; 95% CI 0.52–0.76; P < 0.001) and a median overall survival of 20.9 months in the TTF-plus-temozolomide group versus 16.0 months in the temozolomide-alone group (HR 0.63; 95% CI 0.53–0.76; P < 0.001). Systemic adverse events were similar in both arms, and mild-to-moderate skin toxicity underneath the transducer arrays was reported in 52% of the patients in the experimental arm.
      The EF-14 trial represents the first positive trial of any therapeutic intervention in newly diagnosed glioblastoma since 2005. Yet, neither the trial results nor the treatment itself have been broadly embraced, neither by neuro-oncology health care professionals nor by patients and caregivers, at least in most European countries. Why is that so? The reasons are manifold and arise at multiple levels.
      There are scientific questions that have produced uncertainty. Why would a treatment in an incurable, steadily progressive disease fail to work at first recurrence after radiotherapy as defined largely by magnetic resonance imaging [
      • Stupp R.
      • Wong E.T.
      • Kanner A.A.
      • et al.
      NovoTTF-100A versus physician's choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality.
      ], but work quite impressively when given in the setting of maintenance temozolomide chemotherapy after completion of radiotherapy with concomitant temozolomide [
      • Stupp R.
      • Taillibert S.
      • Kanner A.A.
      • et al.
      Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial.
      ,
      • Stupp R.
      • Taillibert S.
      • Kanner A.
      • et al.
      Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma. A randomized clinical trial.
      ]? Do we believe that the biology of glioblastoma changes within a few months? Should we postulate that radiotherapy preceding TTF only shortly provided sensitization? Why have no specific imaging changes been observed and reported in patients treated with TTF? We await careful characterization of tissues from patients undergoing surgery at failure after TTF, but no systematic studies are available although many patients must have been operated since. No subgroup of patients defined by any known prognostic factor or biomarker has been identified to preferentially derive benefit from TTF. A substantial increase in long-term survival was not achieved.
      Could the prolongation of overall survival possibly be due to a placebo effect? While this is an interesting consideration, it seems to be somewhat far-fetched, at least to assume that the entire hazard ratio is driven by a placebo effect. A contemporary trial exploring the integrin antagonist cilengitide involved two infusions per week until progression without a placebo control, and these patients are likely to have received attention at the participating sites, too. Yet, the CENTRIC trial gave no hint of a survival effect, as documented by an HR of 1.02 [
      • Stupp R.
      • Hegi M.E.
      • Gorlia T.
      • et al.
      Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 Study): a multicentre, randomised, open-label, phase 3 trial.
      ]. Still, patients in the experimental arm of the EF-14 trial received major support and coaching by the company which continues to raise concerns because the study design could have controlled for that, but did not. Importantly, placebo effects should not be equaled with survival benefit afforded by measures other than tumor-specific therapy since early palliative care has been reported to prolong survival in patients with non-small-cell lung cancer [
      • Temel J.S.
      • Greer J.A.
      • Muzikansky A.
      • et al.
      Early palliative care for patients with metastatic non-small-cell lung cancer.
      ].
      Could we truly ask for a second clinical trial with a placebo control? In the setting of one positive trial, I do not think that it is reasonable to request from patients to have their heads shaved and to spend 85% of their life including sleep with a heavy device to help altruistically solving a controversy over a still moderate survival difference. Conversely, an alternative path forward for the neuro-oncology community would be to try to conduct clinical trials of intensive supportive care early in the disease course which may help to estimate the potential survival benefit that can be derived from such interventions.
      There has also been a lot of debate on the financial toxicity imposed by TTF [
      • Bernard-Arnoux F.
      • Lamure M.
      • Ducray F.
      • et al.
      The cost-effectiveness of tumor-treating fields therapy in patients with newly diagnosed glioblastoma.
      ]. This is a relevant issue as of today, but probably not in the long term. History tells us that prizes come down and both oncology and the neurosciences have seen other treatments that incurred or incur high cost with moderate efficacy at best.
      Colleagues in favor of TTF continue raise the question of whether not we would all embrace TTF if it was a pill, with the data as they stand? This question would appear to be futile since TTF is not a pill and since patients will in their vast majority almost certainly select a pill over a device, which remains to be stigmatizing in many ways. So what would be needed to change the overall skeptical attitude toward TTF in the future? I trust that most neuro-oncologists would be reassured if there were compelling studies on mode of action including preclinical work, studies on better understanding the treatment set-up such as electrode placement and dosing analyses and careful studies of imaging and pathology changes induced by the treatment. No therapeutic intervention will ever make it into clinical practice without sufficient trust, from health care providers, patients and caregivers, in its overall value in the setting of an incurable disease such as glioblastoma.

      Funding

      None declared.

      Disclosure

      MW has received research grants from Abbvie, Acceleron, Actelion, Bayer, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, OGD2, Piqur, Roche and Tragara, and honoraria for lectures or advisory board participation or consulting from Abbvie, BMS, Celgene, Celldex, Merck, Sharp & Dohme (MSD), Merck (EMD), Novocure, Orbus, Pfizer, Progenics, Roche, Teva and Tocagen (no grant numbers apply).

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