Tumor Treating Fields in Neuro-Oncological Practice

Transcription

1 Curr Oncol Rep (2017) 19:53 DOI /s NEURO-ONCOLOGY (S NAGPAL, SECTION EDITOR) Tumor Treating Fields in Neuro-Oncological Practice Maciej M. Mrugala 1,2,3,4 & Jacob Ruzevick 1 & Piotr Zlomanczuk 5 & Rimas V. Lukas 6 # Springer Science+Business Media New York 2017 Abstract Electric fields are known to produce biological effects. Depending on specific frequency, they can stimulate healing, directly damage tissues, or produce anti-mitotic activity. Frequencies of KHz have been shown to disrupt mitosis and lead to cellular death. Growth of cancer cell lines, both in vitro and in vivo, was shown to be inhibited by application of the electric fields. In the clinical setting, electric fields are available for treatment of brain tumors, specifically glioblastoma (GBM), through a portable device producing so-called tumor treating fields (TTF). Clinical trials conducted in patients with recurrent and newly diagnosed GBM indicated that this novel treatment modality is active and associated with minimal toxicity. This manuscript will review the available evidence supporting the use of TTF in neuro-oncologic practice. Maciej M. Mrugala and Jacob Ruzevick contributed equally to this work. This article is part of the Topical Collection on Neuro-oncology * Maciej M. Mrugala mrugala.maciej@mayo.edu Departments of Neurological Surgery, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA Departments of Neurology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA Departments of Medicine, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA, USA Department of Neurology, Mayo Clinic, 5777 East Mayo Boulevard, Phoenix, AZ 85054, USA Department of Physiology, Nicolaus Copernicus University, Collegium Medicum, Bydgoszcz, Poland Department of Neurology and Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA Keywords Tumor treating fields. NovoTTF. Bevacizumab. Glioblastoma Introduction Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is fatal in most patients. Despite treatment with maximal surgical resection, chemotherapy, and radiation, the average survival is approximately 15 months [1], with a median time to recurrence being approximately 7 months[2]. Following recurrence, the median progressionfree survival is only 9 22 weeks [3, 4]. The most recent Food and Drug Administration (FDA)-approved pharmaceutical for recurrent GBM was bevacizumab, which was approved after several studies showed significant clinical benefit [4 8]. While new chemotherapeutics including monoclonal antibodies, small molecular inhibitors, and immunotherapies are rapidly changing the landscape of GBM treatment options, GBM inevitably develops resistance to systemic therapies. A multimodality approach is critical for continued improvement of patient outcomes. The NovoTTF-100A System, now called Optune (Novocure Ltd., Haifa, Israel), was recently approved by the FDA for patients with recurrent and newly diagnosed GBM [9, 10, 11, 12 ]. The system is a portable, non-invasive device that delivers low intensity, intermittent frequency, alternating electric fields directly to the tumor bed and peri-tumoral tissues. The unit can be carried around in a compact backpack or used as a stationary unit with transducer arrays placed directly on the patient s scalp using computer-generated maps (Fig. 1a, d). Unlike chemotherapeutics, tumor treating fields (TTF) have no half-life, requiring that the device be worn continually in order to produce a beneficial anti-mitotic effect. A single cycle of TTF treatment is 4 weeks of near continuous usage. This duration of usage was

2 53 Page 2 of 8 Curr Oncol Rep (2017) 19:53 Fig. 1 a, d The NovoTTF system is comprised of transducer arrays that are placed on the scalp and connected to the electric field generator. b, c NovoTAL System allows physicians to create treatment maps and customize NovoTTF therapy. The intensity of the electric field can be modulated and optimized by changing the location of the transducer arrays on the scalp. e Clinical efficacy of NovoTTF is significantly improved when compliance exceeds 75% daily use. Shown here is an example of a patient s compliance report generated for a single cycle of NovoTTF therapy. Images courtesy of and used with kind permission from Novocure shown to be necessary for tumor treating fields to exert therapeutic effects on glioblastoma [13]. Analysis of phase III clinical data as well as patient registry data showed that median overall survival (OS) was significantly increased when compliance rates (>18 h of use per day) were greater than 75% (Fig. 1e). [14, 15]. intracellular structures necessary to the creation of the cleavage furrow formed during cytokinesis [16, 17]. The optimal frequencies needed to induce cell arrest differ between cell lines and are inversely related to cell size. For GBM cells, the optimal frequency is around 150 khz. In addition, increasing the number of TTF directions significantly increases its anti-proliferative activity, likely as a result of correct orientation of the fields and mitotic axis leading to disruption of the mitotic apparatus during cytokinesis [10, 18]. Modeling of intracranial electric fields delivered via TTF has demonstrated variability in voltage per centimeter which is dependent on non-modifiable variables intrinsic to the neuroanatomy [19 ]. Refined understanding of this could lead to optimization of electric field delivery. Whether this would influence clinically relevant outcomes is uncertain. Pre-Clinical Evidence TTF are a novel approach to GBM therapy that utilizes noninvasive electric fields to arrest actively dividing cells. Alternating electric fields with frequencies between 100 and 300 khz lead to disruption of mitosis, ultimately leading to cell apoptosis. Alternating electric fields have been shown to arrest multiple neoplastic cell lines in vitro, including glioma, melanoma, small cell lung cancer, ovarian cancer, and breast cancer, as well as prolong survival in pre-clinical animal models of glioma. It is postulated that this is most likely secondary to disruption of the polarized tubulin subunits which compose the mitotic spindle as well as membrane blebbing induced by disruption of Clinical Experience with TTF The efficacy of TTF has been shown in numerous clinical trials including four prospective studies in GBM with the most

3 Curr Oncol Rep (2017) 19:53 Page 3 of 8 53 pivotal being a phase III clinical trial in recurrent GBM comparing TTF to the physician s best choice of chemotherapy and a phase III study in newly diagnosed GBM comparing standard of care with addition of TTF. A summary of clinical studies with TTF in solid tumors and GBM is shown in Table 1. Early Studies of TTF The first clinical experience with TTF for recurrent GBM in humans was published by Kirson et al. in Ten patients were included in this study, and 70% were male. The age range was with a median age of 54.5 years. The Karnofsky performance score (KPS) for all patients was 70%. The median OS was 62.2 weeks ( ), which compared favorably to historical controls treated with systemic chemotherapy. In this study, one patient experienced a complete response and one a partial response to treatment with TTF. These patients were progression free over 2 years after introduction of TTF. A single patient had a minimal response, and four patients had stable disease prior to progression. In terms of side effects, 90% of the patients experienced mild-moderate contact dermatitis of the skin under the treatment arrays. These changes were managed with topical corticosteroids and periodic electrode relocation [10]. TTF Versus the Physician s ChoiceChemotherapy in Recurrent GBM The first phase III clinical trial (EF-11) was a multi-institutional, international trial that randomized 237 patients 1:1 with NovoTTF-100A without chemotherapy (120 patients) versus the best available physician s choice of chemotherapy (control 117 patients). Criteria for patient selection included WHO grade IV GBM located in the supratentorial compartment, age greater than 18 years, KPS >70%, and adequate hematologic, renal, and hepatic function. Patients were required to have previously undergone radiotherapy, though there were no restrictions on previous chemotherapeutics or number of recurrences. Patients with infratentorial tumors, implanted pacemakers, or ventricular shunts were excluded. Infratentorial tumors were excluded due to limitations of the current arrays to adequately provide field coverage of posterior fossa tumors. Uninterrupted usage was recommended, though two breaks lasting 1 h were allowed for hygienic reasons as well as 2 3 days off of treatment during the end of each 4-week cycle. Seventy-eight percent of patients were able to complete a 4-week cycle with a median compliance of 86%. Of the control group, 113 patients started chemotherapy with 112 patients completing at least 1 full course. Patients in the control group received a single agent or combination regiment containing bevacizumab (31%), irinotecan (31%), nitrosoureas (25%), carboplatin (13%), temozolomide (11%), or other agents (5%). It should be noted that the duration of systemic therapy was not reported whereas only patients who had completed a full cycle of TTF were included, potentially inducing a bias in favor of TTF. The median OS was 6.6 months in the TTF arm versus 6.0 months in the control arm (p =.27). The 1-year survival proportion was 20% in both treatment arms with extended survival at 2 and 3 years being 8 and 4% for TTF-treated patients versus 5 and 1% for chemotherapy-treated patients. Progression-free survival was 2.2 versus 2.1 months in patients treated with TTF versus systemic therapy, respectively. Radiographic responses (partial or complete responses) were seen in 14 patients treated with TTF versus 7 control patients, the difference of which was not statistically significant. There was no statistical difference in survival among control patients treated with various systemic therapy regimens [9 ]. The US FDA approved the use of TTF for recurrent GBM in 2011, based on efficacy comparable to chemotherapy, superior safety profile, and better quality of life. Use of TTF in clinical practice was not readily adopted after the results of EF-11 study were published. We believe that several factors were responsible. Given the fact that this was an entirely new, device-based treatment modality, and it was shown to provide limited benefit (equal to chemotherapy), many clinicians were initially skeptical. In addition, lack of familiarity with the technology resulted in low initial acceptance of this therapy. Post hoc analysis of the study also revealed that 23% of the patients in TTF arm did not receive a complete cycle of treatment, and when these subjects were removed from comparison with chemotherapy-treated patients in the modified intentto-treat analysis, TTF was found to be superior to chemotherapy [9 ]. Several additional post hoc studies have shown that TTF likely benefits diverse clinical subsets of patients. Kanner et al. demonstrated that TTF monotherapy versus chemotherapy in patients under 60 years old had a trend toward improved survival in the TTF-treated patients [22]. There was improved OS in patients who received at least one course of TTF (7.8 months) as compared to patients who completed at least one course of chemotherapy, including bevacizumab (6.0 months). Again, this may be biased by the definition of one course of treatment having different durations in the two arms. Compared to bevacizumab specifically, there was a positive trend toward improved survival in those patients treated with TTF (6.6 versus 5.0 months, p =.054) [23]. Median OS was also statistically improved in patients receiving TTF therapy versus those receiving chemotherapy who had previously failed bevacizumab (6.0 versus 3.3 months), had GBM that had transformed from a low-grade glioma (25.3 versus 7.7 months), had tumor size >18 cm 2 (5.6 versus 3.3 months), and those who had KPS >80 (7.9 versus 6.1 months). Monotherapy, with TTF versus bevacizumab, showed an improvement in median OS in favor of TTF (6.6

4 53 Page 4 of 8 Curr Oncol Rep (2017) 19:53 Table 1 Summary of clinical trials in GBM and solid tumors involving TTF Trials involving GBM OS OS PFS PFS Study N Pathology Study design NovoTTF Chemotherapy NovoTTF Chemotherapy Kirson et al. [10] 10 Recurrent GBM NovoTTF only 62.2 weeks NA 26.1 NA Kirson et al. [11] 20 Newly diagnosed GBM (n = 10) NovoTTF + TMZ >39 months 14.7 months a 155 weeks 31 weeks a Stupp et al. [9 ] 237 Recurrent GBM NovoTTF versus best choice chemotherapy 6.6 months 6.0 months 2.2 months 2.1 months 20.5 months 15.6 months 7.1 months 4.0 months Stupp et al. [12 ] 695 (315 interim analysis) Newly diagnosed GBM NovoTTF + TMZ versus TMZ alone (after chemoradiation) Trials involving solid tumors Study N Pathology Study design Results Salzberg et al. [20] 6 Multiple solid tumors NovoTTF Partial response: 1 Tumor growth arrest: 3 Disease progression: 1 Pless et al. [21] 42 NSCLC NovoTTF + pemetrexed Time to in field progression: 28 weeks Partialresponse:60 Stable disease: 20 Median survival: 13.8 months One-year survival: 57% TMZ temozolomide NA not applicable a Historical controls versus 4.9 months), though no improvement in OS was seen when TTF was compared to non-bevacizumab-based chemotherapies (6.6 versus 6.6 months). The median OS in patients treated with TTF was no different than in those treated with chemotherapy. When post hoc analyses were made stratifying for known prognostic factors, no differences between the treatment arms were detected. Finally, patients who had an average monthly compliance of >75% had a median overall survival of 7.7 months as compared to 4.5 months with in those patients who had an average monthly compliance of <75% [15]. This is likely influenced, at least in part, by patients with higher KPS (a known prognostic factor) maintaining higher compliance. NovoTTF Patient Registry Dataset The Patient Registry Dataset is a database of 457 patients diagnosed with recurrent GBM who were treated at 91 clinics with the NovoTTF system in the USA between October 2011 and November All patients in this registry had histologically diagnosed GBM that had confirmed progression on serial MRI studies. Unlike patients in the pivotal phase III study, there were no exclusions based on previous radiation or chemotherapeutic regimens. The average age of patients was 55 (18 86), and approximately a third of patients were women. The median KPS was 80 (10 100) with a median number of recurrences of 2 (1 5). Fifty-five percent of patients had previously been treated with bevacizumab, which is the greater number of patients than in EF-11 study (19%). Approximately 78 % of the patients had received previous radiation and chemotherapy while 63% of patients had debulking surgery. Median OS in patients treated with TTF in clinical practice was significantly longer as compared to the phase III trial (9.6 versus 6.6 months), and this trend extended out to the 2-year survival rate (30 versus 9%). While the patients included in the Patient Registry Dataset (PRiDe) registry were more diverse, there was a significantly longer duration of treatment as compared to those treated in the EF-11 clinical trial (4.1 versus 2.3 months). Approximately 10% of those patients in the PRiDe registry had received treatment with TTF for at least 2 years. This may reflect continuing TTF in clinical practice beyond the first or second radiographic progression. Similar to the prospective phase III study, compliance >75% was significantly associated with improved median OS (13.5 months) (p <.0001). Other positive associations with improved OS included treatment with TTF at the first recurrence (20 months), KPS >90 (14.8 months), and no prior use of bevacizumab (13.4 months). There was no difference in median OS with regard to surgical debulking versus no surgical intervention or biopsy.

5 Curr Oncol Rep (2017) 19:53 Page 5 of 8 53 While this analysis showed improved survival over that reported in the pivotal phase III trial (EF-11), this may be partially confounded by the potential concurrent use of chemotherapeutics in conjunction with TTF (these data were not recorded in the PRiDe registry). It has been shown in preclinical and early clinical studies that chemotherapy can work synergistically with TTF [11, 14, 24]. In addition, some of the patients included in PRiDe could have been initiated on TTF after exhibiting pseudoprogression following chemoradiation, a known radiographic phenomenon that typically occurs within the first 12 weeks after treatment [25]. Combination Therapy with TTF In a second prospective study, 20 patients with histologically proven GBM underwent treatment with TTF in combination with systemic chemotherapy. The inclusion criteria included histologic diagnosis of GBM, age >18, KPS >70, and no previous anti-tumor therapy within the previous 4 weeks. Patients were randomized 1:1 to receive TTF as a single therapy after tumor recurrence (n = 10) or TTF in addition to maintenance temozolomide following radiation therapy after primary diagnosis. The median OS for newly diagnosed patients treated with TTF and temozolomide was 155 weeks versus 31 weeks for concurrent controls treated with maintenance temozolomide. Both median OS and progression-free survival (PFS) were increased compared to historical controls in patients with recurrent GBM [11]. Based on these encouraging results, a prospective phase III randomized study was designed. Patients with newly diagnosed GBM were randomized to receive established standard of care (radiotherapy plus temozolomide followed by adjuvant temozolomide) versus standard of care plus TTF delivered during the adjuvant phase of therapy. The study enrolled 695 patients who were randomization in the 2:1 fashion (466 patients received chemotherapy with TTF while 229 patients received temozolomide alone). The interim analysis of the intent-to-treat population (ITT) of 315 patients was recently reported [12 ]. The primary end point, median PFS, was 7.1 months (95% CI, months) in the TTF plus temozolomide group and 4.0 months (95% CI, months) in the temozolomide alone group (hazard ratio [HR] 0.62 [98.7% CI, ]; p =.001). Median OS in the ITT population demonstrated improved OS in the TTF plus temozolomide group (19.6 months, 95% CI, months) compared to temozolomide alone (16.6 months, 95% CI, months). The differences become more pronounced in the median OS analyses in the perprotocol population with 20.5 months (95% CI, months) in the TTF plus temozolomide group (n =196) and 15.6 months (95% CI, months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, ]; p =.004) [12 ]. Results of this study led to the FDA approval of TTF in combination with temozolomide for newly diagnosed GBM in October of In another, retrospective study of 20 patients treated with TTF and bevacizumab, 14 patients received TTF after failure of bevacizumab while 6 patients received TTF therapy concurrently with bevacizumab. Adverse events included minor scalp burns, minor scalp rashes, and liquefied hydrogel as a result of high ambient temperatures. No hemorrhagic complications were reported. A single patient required treatment interruption because of a severe skin rash. The median OS of the patients treated with concurrent TTF and bevacizumab was 5.6 months, which did not differ from historical controls treated with bevacizumab alone [26]. Unique Considerations for Patients Treated with TTF Cerebrospinal fluid diversion is common in patients operated on for intracranial tumors. Many patients who could be potential candidates for TTF therapy might have intracranial hardware, including screws and plates for cranial bone flap fixation and shunts for cerebrospinal fluid diversion. While shunts with programmable valves were part of the exclusion criteria for EF-11, Mrugala et al. reported that TTF was used safely in a single patient with a non-programmable ventriculo-peritoneal shunt [27]. Additional reports of the use of nonprogrammable shunts are needed to establish their safety in the setting of TTF use. Additional data pertaining to this issue are being actively collected and will be published in the near future. Intensity of the electrical field being applied to the tumor heavily depends on the positioning of the treatment arrays on the patient s scalp. As a rule, the closer the arrays are to each other, the higher the intensity of the field and consequently potential greater efficacy of the anti-mitotic activity of the treatment. The differing conductivity of the cranial tissues and their orientations to the field influence the magnitude of the field [19 ]. To help with the optimal positioning of the transducer arrays on the scalp, the NovoTAL (transducer array layout) system was developed (Fig. 1b d) this computerized system inputs magnetic resonance imaging data of a genderspecific head morphology, tumor location, and size to optimize the intensity of TTF. The NovoTAL System, recently approved by FDA for clinical use, allows treating physicians to generate treatment maps and adjust them accordingly during treatment when tumor-specific parameters change. It is also important to identify that the cost of using TTF is comparable with chronic use of agents such as bevacizumab. Its use does not require inpatient or outpatient stay, as it can be administered entirely at home. Overall, the utilization of medical services and staff time is also lower, resulting in overall decrease in medical expenses in patients treated with TTF. As a comparison, the cost of using TTF therapy is about US$20,000 per month. A monoclonal antibody, bevacizumab

6 53 Page 6 of 8 Curr Oncol Rep (2017) 19:53 Table 2 Summary of dermatologic adverse events in selected clinical studies involving NovoTTF Study Number Pathology Study design Dermatologic AE Kirson et al. [10] 10 Recurrent GBM NovoTTF only 90% Kirson et al. [11] 20 Primary GBM NovoTTF + temozolomide 90% (n =10) Stupp et al. [9 ] 237 Recurrent GBM NovoTTF versus best choice chemotherapy Grade I/II: 16% Grade III/IV: 3% Mrugala et al. [14 ] 457 Recurrent GBM NovoTTF ± chemotherapy 24.3% Stupp et al. [12 ] 695 Primary GBM NovoTTF + temozolomide 43% frequently used for recurrent GBM costs between US$10,000 and US$20,000 per month [28]. The cost of bevacizumab is also weight dependent while for TTF, the cost is fixed. It is also important to point out, as we mentioned previously, that what is being purchased is different. With a drug, one is accruing the cost of the dispensation (pharmacy), and administration (infusion unit time), bloodwork, and other services that are frequently bundled with the outpatient infusion cost. With TTF, one is renting a device and paying for the associated technical support. Dermatologic Side Effects of TTF Gastrointestinal and hematologic side effects frequently encountered in association with chemotherapy are not seen with TTF treatment. Given the nature of therapy (direct placement of the treatment arrays on the skin), dermatologic complications were the most commonly seen side effect in all reported clinical studies [9, 10, 11]. Skin-related complications resulting from the use of TTF most commonly include dermatitis, erosions, infections, and ulcers. Most of these complications result from mechanical trauma due to repeated application of cranial arrays, poor wound healing, and potentially combination treatments with chemotherapeutics as well as prior radiation. To characterize the dermatologic manifestations after TTF use, Lacouture et al. analyzed the skin-related adverse events of patients from the completed phase III trial for recurrent GBM and post-marketing surveillance program. A total of 686 patients were included in this cohort. In the completed phase III trial, 18 patients (16%) had a dermatologic adverse event, all of which were grade 1 or 2. A single patient experienced a skin ulcer. The time to onset of these events was 2 6 weeks. Within the post-marking surveillance cohort, 156 patients (21.8%) experienced a dermatologic adverse event with 4 patients (0.7%) experiencing a skin ulcer. The time to onset of these events ranged from 2 to 520 days with a median time of 32 days [29]. When utilized with adjuvant temozolomide after concomitant radiotherapy and temozolomide, the incidence of dermatologic adverse events was much higher at 45%, with the overwhelming majority being low grade. It is possible that the recent prior radiotherapy may make patient scalps more susceptible to these toxicities [12 ]. A summary of dermatologic adverse events is shown in Table 2. Risk factors for dermatologic adverse events include placement of transducer arrays over incisions or craniotomy hardware, previous history of contact dermatitis, hyperhidrosis, previous cranial radiation, high doses of systemic corticosteroids, or concurrent use of systemic anti-cancer therapies. As a result of these complications, an interruption of treatment for several days may often be required. In a minority of cases, TTF therapy may need to be permanently discontinued. Prophylactic measures to decrease the incidence of dermatologic adverse events include removing hair from the scalp with special care not to cut the skin; removal of sebum with a mild fragrance-free shampoo or 70% isopropyl alcohol; care not to place transducer arrays over areas of skin breakdown, incision sites, or cranial hardware; and removal of adhesive residues on repeated placement of transducer arrays. In addition, infection precautions include changing cranial arrays every 3 4 days, though more frequent changes should be performed in the presence of warm weather or with increased activity causing sweating. Careful washing of the scalp between transducer array changes and shifting the transducer array locations on each change of arrays also is recommended to decrease the risk of infection. Treatments for dermatologic adverse events primarily include topical corticosteroids and antibiotics. In the setting of dermatitis, application of a high-potency topical corticosteroid is recommended whereas the presence of erosions or signs of infection require topical antibiotics. For more serious dermatologic adverse events, treatment interruptions of 2 7 days were typically sufficient for resolution prior to restarting treatment [29]. Conclusions GBM represents one of the most difficult tumors to treat. Surgical resection, radiation, and systemic chemotherapy do

7 Curr Oncol Rep (2017) 19:53 Page 7 of 8 53 not offer a cure. Additional treatment modalities to extend survival are desperately needed. TTF represents a novel and unique treatment method. This anti-mitotic device is externally worn on the scalp and is not associated with the typical systemic side effects seen with chemotherapy. The pivotal phase III clinical trial showed a median OS in recurrent GBM of 6.6 months, similar to what can be achieved with standard chemotherapies but with fewer side effects. Accumulating evidence indicates that TTF, when used in combination with systemic chemotherapy, can lead to a survival benefit in newly diagnosed GBM over chemotherapy alone. Moreover, data from PRiDe indicate that earlier introduction (first progression) of TTF may result in improved outcomes in recurrent GBM. The therapeutic modality is well tolerated with the primary side effects being dermatologic. Patient compliance with this chronic anti-cancer therapy is critical as increased usage (18 h a day or more) is associated with improved survival. The treatment can be safely and effectively used in the clinical practice setting after appropriate training and credentialing process is completed. The NovoTAL platform allows physicians to customize therapy to the individual patient and adjust treatment planning during the course of therapy. Clinical trials with TTF in brain tumors continue to enroll. Ongoing and planned neuro-oncologic clinical trials include investigations in patients with newly diagnosed glioblastoma, low-grade glioma, meningioma, and metastatic disease. Important decisions, influenced by the results of EF-14, will need to be made in how to best incorporate TTF in ongoing and planned trials of other treatment modalities for newly diagnosed GBM. Compliance with Ethical Standards Conflict of Interest Maciej M. Mrugala has served as a consultant for and received research funding for clinical trials from Novocure. Jacob Ruzevick declares that he has no conflict of interest. Piotr Zlomanczuk declares that he has no conflict of interest. Rimas V. Lukas had served on an advisory board for Novocure two years prior to contributing to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352: Stupp R, Hegi ME, Mason WP, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. 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