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A novel therapy for high-grade glioma

The concept of tumour treating fields is unique in the treatment of high-grade glioma in that it addresses tumour cell division using a novel physical concept

Martin Misch MD
Julia Onken MD
Peter Vajkoczy MD
Department of Neurosurgery,
Charité Campus Virchow, 
Medical University of Berlin, Germany
In high-grade glioma, proven standards of therapy have included operation, radiotherapy and chemotherapy for decades worldwide. Over time, new therapeutic concepts evolved that included antibody therapy (for example, anti-VEGF), vaccination therapy (dendritic cell vaccines, anti-EGFRvIII vaccine) and lately immunomodulation (for example, checkpoint inhibitors). However, the concept of tumour treating fields (TTFields) is unique in that it addresses tumour cell division using a novel physical concept. 
When introduced to the neuro-oncological society some years ago, Optune® therapy was labelled ‘voodoo medicine’ by a well-known opinion leader and neuro-oncologist. Some years down the road, we are at a point where TTFields combined with maintenance temozolomide is established as the standard of care.1
A prospective randomised Phase III trial (EF-14) of TTFields in patients with newly diagnosed glioblastoma (GBM) has allowed patient crossover to the TTFields treatment arm after the interim analysis due to successfully meeting the study endpoints. The pre-specified, protocol-based interim analysis was performed on the first 315 patients enrolled in the trial with a minimal follow up of 18 months.2
The study will complete its entire follow-up period in June 2016. Although the preliminary results appear promising, statistical significance may be absent when evaluating all randomised patients. Following standard of care concomitant radiochemotherapy, TTFields plus adjuvant temozolomide significantly extended both progression-free survival (median PFS from randomisation (randomisation took place in median 3.8 months after diagnosis) of 7.1 months compared with 4.0 months, HR=0.64, p=0.001) and overall survival (median OS from randomisation (randomisation took place in median 3.8 months after diagnosis) of 20.5 months compared to 15.6 months, HR=0.64, p=0.004) compared to temozolomide alone in patients with newly diagnosed GBM. Forty eight percent of patients were alive at two years in the TTFields plus Stupp arm compared to 32% in the Stupp arm (p=0.0058).4,5
Critics of the study explain the advantage in OS and PFS with closer clinical follow-up visits of the patients by the device specialists and suggest a bias. However, closer follow-ups unlikely explain a survival benefit of five months.
In October 2015, the US Food and Drug Administration (FDA) approved TTFields in combination with the Stupp protocol for first-line treatment of adult newly diagnosed GBM.5
Optune® is the first therapy in over a decade to demonstrate a statistically significant prolonged overall survival in newly diagnosed GBM patients. In addition this survival benefit did not add significant systemic toxicity to the treatment. Quality of life, cognitive function and activities of daily living were not impaired by the therapy.4
Optune® was previously approved in April 2011 for the treatment of adult patients with GBM following tumour recurrence and has been proven to be as effective as chemotherapy in this patient population. Best results were gained when used for more than 18 hours per day in patients with a good performance status and long-term use of the therapy.6–8
The TTFields delivery system has received marketing approval in the US under the brand name Optune™. The Optune® system is a CE-Marked device cleared for sale in the European Union, Switzerland, Australia, Japan and Israel.
Fig. 1–3: Targeting the tumour; components of the Optune® system.
Optune® is a portable, non-invasive device that delivers low-intensity, intermediate frequency, alternating electric fields within a tumour that exerts physical forces on electrically charged cellular components inhibiting mitosis and causing glioma cell death. Four transducer arrays are placed directly on the scalp to deliver the electrical field for targeting the tumour (Figure 1). The NovoTAL™ software calculates optimal array placement to maximise the therapy effect based on individual MRI scans. Due to the anatomical limits of the array placement, the therapy is currently only approved for the treatment of supratentorial tumours. 
The Optune® system includes the electric field generator with rechargeable batteries, connecting cables, transducer arrays, and a backpack for transporting the system (Figures 2,3). On the images, the first generation setup is illustrated, while the second generation device is only about half the weight and size (Figure 4). Also, background noise has been significantly reduced due to a more advanced cooling system. 
Fig. 4: Second-generation setup.
A patient support service provided by the manufacturer is available to patients and caregiver on a 24/7 basis. The device specialist will help answer questions and will offer solutions for any day-to-day issues. In order to effectively deliver TTFields to the tumour, it is necessary to keep the head shaved during Optune® therapy. If needed, a loose-knit hat, scarf, wig, or other head covering may be worn over the transducer arrays. Arrays need to be replaced one to two times per week and more often during hot weather conditions, also depending on individual sweat rate and pace of hair growth.
Minimum recommended treatment time is 18 hours per day.5–7 Patients may ‘take a break’ during the daytime when being outside and receive therapy whilst asleep. A small percentage of patients report psychological adverse effects within the first few weeks of therapy, for example, anxiety and mood swings. These effects usually resolve within one month of therapy. No effect on symptomatic epilepsy has been shown. Up to 40% of the patients show some sort of mild to moderate skin reaction (for example, folliculitis, erythema, erosion) that are almost always low-grade on the common toxicity criteria scale (CTC criteria).7,9 In most cases, a short pause of therapy and/or some topical cortisone treatment resolves the problem, allowing them to resume treatment.
As TTFields may not be suitable for every patient type in our experience, some crucial points need to be considered when introducing a patient and caregiver to the Optune® system:   
  • Be honest to the patient about what to expect (hardware weight and size, logistics of battery life, spare battery packs and where and how to recharge, temperature alarm of the device in summer, minimum treatment time per day).
  • Explain the worst-case scenario as done for any other optional treatment (psychological events, skin reactions, ‘stigma’ of the device) – at the same time: show solutions to face problems likely to be encountered.
  • Allow four weeks of adjustment time to get used to the Optune® system and the associated logistics; usually patients who pass this timeline will not abort therapy.
  • Balance the potential clinical benefit (OS; PFS) and the low toxicity with the practical implications of wearing the device, emphasising how the system can be integrated into patient’s daily life – does positive motivation outweigh possible effects of therapy for the individual patient?
  • Consider social environment (caregiver/family) – is there a person to help change the arrays; severe aphasia may prevent the patient from talking on the phone to the device specialist.
  • Trust the gut feeling of patient and physician.
If these factors are considered in patient information at the therapy initiation stage, the dropout rate is likely to be very low. 
Optune® offers some more advantages over conventional therapeutic approaches: 
There may be an additional effect beyond conventional therapy in primary therapy or recurrence without adding significant toxicity.4
The impact of the electrical field is pronounced in the periventricular zone.10 Consequently, glioma initiating cells (‘tumour stem cells’) in the subventricular zone may be addressed. The treatment effect of TTFields may be present outside the treatment volume: in solid tumours, TTFields reduced the rate of lung metastasis and induced immune cell invasion – possibly enhancing endogenous immune response versus tumour cells.11
Optune® provides a meaningful therapeutic option in heavily pre-treated patients and has shown to be equally effective compared to chemotherapy. Patients having experienced high-grade haematological toxicity (CTC grade 3 or 4) may therefore still be offered such anti-tumour therapy.6,7 Therapy may be combined with common recurrence therapies (nitrosurea, temozolomide rechallenge, bevacizumab). Post-hoc evaluation of the EF-14 data after first recurrence suggests a significant risk reduction for death as a second-line therapy, if combined with physician’s choice of chemotherapy versus chemotherapy alone (median OS 11.8 months compared with 9.2 months, HR=0.695, p=0.0489). Optune® plus bevacizumab also led to a significant risk reduction versus bevacizumab alone (median OS 11.8 months compared to 9.0 months, HR=0.606, p=0.0428).8
Therapy compliance appears to be very high after careful patient selection. However, patients need to be supported in device handling problems that might occur: in high outdoor temperature, the field generator or the arrays may give a high temperature alarm that is supposed to prevent the skin and device from overheating. In addition, battery life may change in accordance with the use of the system. Behavioural, technical and logistical steps may be taken to overcome such technical issues through direct guidance by the treating physician or the device support specialist.
The manufacturer currently provides Optune® to patients after receiving a prescription order from the treating physician for a monthly fee of €21,000 per patient. This fee includes all the required hardware, array replacement and personal on-site support for the patient’s device. The company is in the process of working with state and private healthcare payers to set a fee level for broad reimbursement in Germany, as well as in other European countries. 
Currently, in Germany healthcare insurance companies reimburse therapy costs on a case-by-case basis. A patient support service is currently being set up in Italy, France and the UK.  The company distributing the system has also set up a financial assistance programme to assist patients. The financial impact on the healthcare system will be known once a reimbursement price has been agreed. 
Incidences of primary brain tumours are approximately 5–8 per 100,000 per year, of which a smaller percentage have glioblastoma and would be eligible for this treatment (3–5 per 100,000 per year). Glioblastoma is therefore per definition an ‘orphan disease’ and overall costs for the healthcare system may not be a major issue considering that only a part of the patients may be eligible for treatment.
In conclusion, Optune® offers a significant benefit in OS and PFS-6 in newly diagnosed GBM when final results of the EF-14 trial prove its effectiveness (final trial results are expected in June 2016). Optune® is also effective in recurrent high-grade glioma, without significant toxicity and while maintaining patients’ quality of life. When carefully selected, patients tolerate therapy very well. 
The system is approved for the treatment of GBM patients in Europe, the US and other regions. Final results of the EF-14 trial are expected in June 2016 and, depending on the results, an approval as standard of care seems possible. Some issues as socioeconomic aspects have to be cleared before establishing Optune® as a standard of care in GBM.
Conflicts of interest
MM received travel costs and speaker’s fee from NovoCure for scientific meetings. JO, PV and MM advised Novocure in improvement of the optune device based on patient questionnaire and received expense allowance from NovoCure.
  1. Taillibert S, Le Rhun E, Chamberlain MC. Tumor treating fields: a new standard treatment for glioblastoma? Curr Opin Neurol 2015;28(6):659–64. 
  2. Stupp R et al. Interim analysis of the EF-14 trial: A prospective, multi-center trial of NovoTTF-100A together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. Neuro Oncol 2014;16(suppl 5):v167.
  3. Stupp R et al. Tumor treating fields (TTFields): A novel treatment modality added to standard chemo- and radiotherapy in newly diagnosed glioblastoma—First report of the full dataset of the EF14 randomized phase III trial. J Clin Oncol 2015;33(suppl):Abstr 2000.
  4. Zhu J-J et al. Quality of life, cognitive function and functional status in the EF-14 trial: a prospective, multicenter trial of tumor treating fields together with temozolomide compared to temozolomide alone in patients with newly diagnosed GBM. SNO 2015 presentation; abstract 0761.
  5. Novocure news. Last accessed April 2016.
  6. Stupp R et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 2012;48(14):2192–202.
  7. Kanner AA et al. Post hoc analyses of intention-to-treat population in phase III comparison of NovoTTF-100A™ system versus best physician’s choice chemotherapy. Semin Oncol 2014;41(Suppl 6):S25–34. Erratum in: Semin Oncol 2015;42(3):e56–66.
  8. Kesari S, Ram Z. Tumor treating fields with chemotherapy compared to chemotherapy alone in glioblastoma patients at first recurrence: A post-hoc analysis of the EF-14 trial. Neuro-Oncology 2015;17(suppl 5):v14.
  9. Lacouture ME et al. Characterization and management of dermatologic adverse events with the NovoTTF-100A System, a novel anti-mitotic electric field device for the treatment of recurrent glioblastoma. Semin Oncol 2014;41(Suppl 4):S1–14.
  10. Wenger C et al. The electric field distribution in the brain during TTFields therapy and its dependence on tissue dielectric properties and anatomy: a computational study Phys Med Biol 2015;60:7339–57.
  11. Kirson ED et al. Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs. Clin Exp Metastasis 2009;26(7):633–40.