Optune (NovoTTF Tumor Treating Fields)
by Stephen Western
NovoTTF (Tumour Treating Fields) is an innovative glioma therapy developed by Novocure Ltd. based in Israel. The system consists of "a portable device delivering low intensity, intermediate frequency, alternating electric fields using non-invasive, disposable transducer arrays" worn on the patient's shaved head for 18-22 hours per day (breaks allowed for showers). Four weeks is considered to be the minimum interval to reverse tumour growth and preliminary trials have studied the use of the device for periods of a year or more. The electric fields interfere with active cell division, leading to disruption of chromosome segregation and eventually to cell death.
There are two main components to the system: 1) an Electric Field Generator (the NovoTTF-100A device) and 2) insulated transducer arrays worn on the patient's shaved head. These arrays are replaced once or twice per week and the scalp must be regularly re-shaved. The device may be powered by portable batteries and carried in a pack, allowing mobility throughout the day. Before bed, the device is connected to an external power supply, to ensure constant operation through the night. Dermatitis (rash) beneath the transducer array has been the most common side-effect. The typical treatment for contact dermatitis is over-the-counter topical steroids such as 0.1% hydrocortisone cream. A recent dataset showed that skin reaction was the most common adverse event, occurring in 24.3% of 457 patients.
In 2012, a long term follow-up study (2) was published of the initial pilot trial of NovoTTF for newly diagnosed and recurrent glioblastoma. Four long-term survivors were singled out as individual case reports. Two of these cases were newly diagnosed glioblastoma patients. In these two cases it is unclear to what extent NovoTTF contributed to the long-term survival of at least 5.5 and 6 years post initiation of NovoTTF plus maintenance temozolomide chemotherapy. These two patients were 31 and 33 years old, both with right frontal tumours and complete tumour resections. These characteristics may indicate secondary, perhaps IDH1-mutant glioblastoma. Unfortunately we don't know the IDH status in these two cases.
More impressive are the 2 of 10 recurrent glioblastoma patients who lived for at least 7 years beyond the initiation of NovoTTF therapy. These two cases display more of the characteristics of primary de novo GBM: they had aggressive tumours which recurred only 3 and 5 months after initial surgery. Case one was a 52 year old woman, who underwent gross total resection of a right parietal tumour in April 2004 followed by standard radiochemotherapy with temozolomide. First tumour recurrence appeared in July 2004. NovoTTF was initiated in August as a monotherapy. In September, though one of the lesions had increased in size, NovoTTF treatment was maintained. By February 2005, after 6 months of treatment, both enhancing lesions had disappeared. After one year of treatment, in August 2005, NovoTTF was discontinued. As of August 2011, the woman was healthy with a KPS of 90.
Case 2 was a 41 year old man who underwent a partial resection of a left frontoparietal glioma in March 2004, followed by conventional radiochemotherapy with temozolomide. A suspected recurrence appeared 5 months after surgery, in August 2004. NovoTTF therapy was initiated at that time. In March 2005 there was further disease progression, though unsymptomatic, and NovoTTF was continued. By October 2005, after 14 months of NovoTTF therapy, there was evidence of tumour regression. After 18 months, in February 2006, the treatment was discontinued. As of November 2011, seven years after the initial recurrence, there was still evidence of a discrete enhancing lesion visible on MRI, though PET imaging showed no abnormality. The man was in good health with a KPS of 90-100.
This long term follow-up study was preceded by two studies of the same 20 glioblastoma patients, one reporting on the recurrent group, the other reporting on the newly diagnosed group. Neither of these reports give full details of baseline patient characteristics. The first report (3) tells us that the median time to progression (PFS) of the recurrent group was 6 months and PFS6 was 50%. Median overall survival from start of NovoTTF was 14.3 months. All these statistics compare very favorably with other trials of recurrent glioblastoma, however the only patient characteristics given are age, gender, weight, KPS, and tumour location. We aren't given information on the completeness of resection, number of recurrences, or prior salvage therapy of these patients (prior second line chemo? tumour re-resection at recurrence?), limiting the ability to compare the outcomes with other trials.
The initial report (4) of the newly diagnosed cohort reports a median progression-free survival of 35.7 months and an overall survival of at least 39 months. All patients underwent surgery, standard radiochemotherapy with TMZ, and NovoTTF treatment combined with maintenance TMZ. This report suffers from the fact that no patient characteristics are given. What is the median age? MGMT status? extent of resection? etc. Were only patients who responded to the initial radiochemotherapy included in the trial? It is hard to say if these patients were enriched for better prognosis because important details are lacking.
What we can say with certainty is that NovoTTF treatment compares favorably with standard chemotherapy, may even be superior as a monotherapy, with no systemic toxicity. A clear picture of its value as an addition to chemotherapy awaits the results of the phase III trial currently underway testing NovoTTF plus TMZ for newly diagnosed glioblastoma, with an estimated study completion date of April 2015. It is expected that the addition of NovoTTF to chemotherapy will act in a synergistic manner.
Phase III trial for recurrent GBM and regulatory approval in 2011
A phase III trial led by Roger Stupp compared NovoTTF alone to physician's choice chemotherapy in recurrent glioblastoma (1). Significantly, 6 month progression-free survival and response rate favored NovoTTF. As well, there was less toxicity and improved quality of life in the NovoTTF group compared to the chemotherapy group. Patients in this trial underwent a median of four cycles (of four weeks per cycle) with the NovoTTF device. Results of this phase III trial led to the FDA approval of the NovoTTF device in 2011.
PRiDe (Patient Registry Dataset)
An abstract from the 2014 ASCO meeting tells us that NovoTTF has been available at 91 centers in the USA since November 2011. PRiDE (Patient Registry Dataset) represents survival and safety data of all (n=457) recurrent glioblastoma patients initiating treatment with NovoTTF-100A between October 2011 and November 2013 in the USA. Statistics from this dataset were publicized at the 2014 ASCO meeting and at the June 2014 Canadian Neuro-Oncology meeting in Halifax. Novocure estimates that these 457 patients make up about 5% of the total recurrent GBM population treated in the USA during this timeframe.
In the PRiDE dataset, median age was 55 years, median KPS was 80, median number of recurrences prior to NovoTTF treatment was 2, and at least 55% had received prior bevacizumab (Avastin). Median NovoTTF treatment duration was 4.1 months. The median survival for the entire cohort from the start of NovoTTF treatment was 9.6 months, which is significantly longer than the 6.6 months median survival observed in the phase III trial mentioned above. It must be noted that the PRiDE cohort was favored in having more patients at first recurrence and fewer at later recurrences. Of the patients with known number of recurrences in the PRiDe cohort, 38% were at first, 31% were at second, and 31% were at third to fifth recurrence. The corresponding percentages in the phase III trial were 9%, 48%, and 43%.
The crowning piece of information which establishes NovoTTF as the most effective therapy yet reported in first-recurrent GBM is the median survival (from first recurrence) of 20 months. No other therapy has come close to this for first-recurrent GBM. We can safely assume that these first-recurrent patients were mostly Avastin-naive, as Avastin (bevacizumab) is not typically included in first-line therapy for newly diagnosed GBM. In comparison, a recent trial (6) of the 7-day on, 7-day off temozolomide schedule for recurrent GBM led to a median survival (from the start of 7-day TMZ) of 14.3 months for the 14 patients who were Avastin-naive. These 14 patients joined the trial at median first recurrence and were all treated with Avastin sometime after progression on the 7-day TMZ schedule.
When patients in the PRiDe dataset were stratified according to prior Avastin exposure, Avastin-naive patients had a median survival (from the start of NovoTTF) of 13.4 months, while patients who had previous Avastin therapy had a median survival of 7.2 months, a highly significant difference (p=.0001). This median survival of 7.2 months for NovoTTF treated patients following Avastin is still a considerable improvement over the ~4 months median survival with chemotherapy such as temozolomide or nitrosoureas after Avastin failure.
Another interesting lesson from this dataset is that patients who achieved at least 75% compliance (full compliance likely meaning operating the device properly for at least 18 hours per day) had a median survival of 13.5 months versus 4 months for those achieving less than 75% compliance. This points to the crucial importance of using the device according to instructions and ensuring a long, continuous exposure to the tumour treating fields for optimal efficacy.
The PRiDe study would have been even more interesting had it been able to include progression-free survival data and information on post-progression treatments. For example, how many of the Avastin-naive patients were treated with Avastin after NovoTTF? How many of the patients had repeat surgery prior to NovoTTF treatment? Nevertheless, in light of these newly published data, NovoTTF is likely the best available option for first-recurrent, supratentorial GBM (ages 22 and up). It is also a relatively effective option for those who have progressed on Avastin.
The importance of maximum compliance and long-term use
Several follow-up analyses of the phase III trial of NovoTTF for recurrent GBM have been published in the fall of 2014. These studies, as well as the PRiDe dataset, show that patients who achieve the greatest degree of compliance (have the device in operation for the greatest number of hours each day) are more likely to benefit from the therapy. Unlike chemotherapy which may have long-lasting biological effects after administration, NovoTTF electric fields are only effective as long as the device is turned on. The minimum number of hours recommended to patients is 18 hours per day. One of the follow-up analyses from the phase III trial (7) demonstrated that even more complete compliance may be necessary for full benefits to be realized. This study explains that "In both trials, a monthly compliance assessment was performed for each patient by downloading an internal log file that captures device “on” time. Patient compliance was calculated as the average percentage of each day the system was delivering fields out of each 24-hour period". The analyses based on patient compliance showed that out of 120 patients, 14 enjoyed a partial or complete response, and the responding patients operated the NovoTTF device with an average compliance of 92% (or 22 hours per day). 34 patients had disease stabilization, and this group had an average compliance of 85% (ie the device was in operation for an average of 20.4 hours per day). 59 patients had neither tumour response nor stabilization. This group had an average compliance of 79% (operating the device for about 19 hours per day on average). Judging by these outcomes, it would appear that having the device in operation for the maximum number of hours each day is necessary to realize the greatest benefits.
In addition to maximum compliance, this study also showed the importance of persistent use of the device, as benefits do not appear suddenly, but require months to become evident. In the 16 patients included in the study who enjoyed an objective radiographic response to NovoTTF treatment, the median time until response (tumour shrinkage) was 5.2 months. Responses in these 16 patients were durable, with a median response duration of 12.9 months. Seven of the 16 responders (44%) had delayed response after initial tumour growth. Median time to reversal of tumour growth in these delayed responders was 4 months. In other words, seven patients started NovoTTF therapy, had continued tumour progression after starting therapy, and didn't show noticeable improvement for an average of 4 months (range 2-7 months), at which time their tumours began to shrink.
A lesson to be learned from this and similar studies is that NovoTTF therapy requires time in order for benefits to become evident, and that maximum compliance (use of the device for 22 hours or more per day) appears necessary to maximize therapeutic benefit.
Annual meeting of the Society for Neuro-Oncology (SNO)
November 15, 2014. Miami Beach, Florida. This afternoon history was made as Roger Stupp presented the interim analysis of the phase III trial of NovoTTF (tumor treating fields) in addition to radiochemotherapy for newly diagnosed glioblastoma. Median progression free survival and median overall survival were both improved by three months versus the control group. PFS was 7.1 months in the TTF group and 4 months in the control group. OS was 19.6 months in the TTF group and 16.6 months in the control group. 2-year survival rate was 43% in the TTF group and 29% in the control group. The starting point for these measurements was randomization, which took place after the six week period of combined radiochemotherapy. Average time from diagnosis to randomization was 3.8 months. The improvement in overall survival was statistically significant (p=0.034). This analysis included only the first 315 patients who had at least 18 months of follow-up. Amazingly, the trial was ended early because of the early evidence of success. In the words of Roger Stupp, "a new standard of care has been established". It is indeed only a matter of time before NovoTTF is added to radiochemotherapy as a new standard of care for newly diagnosed GBM. This is the first positive phase 3 trial for newly diagnosed GBM since 2005, when the current standard of care (the "Stupp protocol") was established, and possibly the first non-toxic adjuvant therapy for cancer ever to succeed in a phase III trial for newly diagnosed patients.
A couple days prior to the beginning of the SNO conference, a "satellite meeting" was held at the Marriot Stanton Hotel, South Beach, Miami. Highlights from these sessions included a talk by Eric Wong of Harvard Medical School and the Beth Israel Deaconess Medical Center. In a presentation entitled Dexamethasone Exerts Profound Interference on NovoTTF-100A Efficacy for Recurrent Glioblastoma, Dr Wong presented retrospective data showing that patients treated with Tumor Treating Fields (NovoTTF, now called Optune) in a previous phase 3 trial had better response to this treament when they were taking less than 4.1 mg dexamethasone per day. The patients who had response to the electric fields (TTF) took 1-2 mg dexamethasone on average, while non-responders took higher doses (up to 6-7 mg). When the data was stratified by a dexamethasone intake of 4.1 mg per day, those taking under this amount had median overall survival of 11 months, while those taking more than this amount had median survival of only 4.8 months.
A talk by Kenneth Swanson of Harvard Medical School entitled Disruption of Cell Division Within Anaphase by Tumor Treating Electric Fields (TTFields) Leads to Immunogenic Cell Death: Implications for Treating Gliobastoma may shed some light on the reasons for the worse survival outcomes of patients treated with TTF who also took high doses of dexamethasone. In this talk, he described his work showing that NovoTTF disrupts cells as they enter anaphase, at the metaphase to anaphase transition, and made claims that a cytoskeletal protein called septin may be the true cellular target of NovoTTF. He also showed that NovoTTF-induced cell death leads to the exposure of calreticulin and other immunogenic molecules, and that part of the therapeutic effects of NovoTTF may be due to an activated immune response following immunogenic cell death. As dexamethasone in high doses has immunosuppressive effects, this could be the possible cause of the interference with NovoTTF of high dose dexamethasone. Swanson speculated that because NovoTTF partially acts through endoplasmic reticulum (ER) stress, other agents that also induce ER stress, such as celecoxib (Celebrex) may be synergistic with NovoTTF.
Complete list of treatment centers in the USA
Available at the Optune website
Optune outside the USA
On July 15, 2014, Novocure issued a press release stating that 18 physicians in Europe and Israel are now trained and certified to treat recurrent glioblastoma patients with NovoTTF (since renamed as Optune). These physicians are located in Vienna (Austria), Prague (Czech Republic), London (England), Lyon and Paris (France), Düsseldorf, Duisburg, Hamburg, Heidelberg, Kiel, and Regensburg (all in Germany), Athens (Greece), Lausanne and Zurich (Switzerland), and Tel Aviv (Israel).
On March 30, 2015, Novocure issued a press release that the Japanese Ministry of Health, Labour and Welfare approved Optune for the treatment of recurrent glioblastoma.
Costs, Insurance, Patient reimbursement
A news article appearing on Bloomberg.com in 2010 reveals that use of the device costs $10,000 to $15,000 per month (5).
According to the Patient Reimbursement page on the Optune website, "Many private payers also acknowledge the clinical benefit of Optune and have issued positive coverage policies for treatment. These payers include Aetna, Healthnet, Humana, and Tricare. Additionally over 100 payers, including Medicare, have covered Optune on a case-by-case basis."
Additionally, a Financial Assistance Program is available "for patients who need co-pay or cost share assistance" and a Charitable Care Program "for patients who are uninsured or underinsured".
May 11, 2015 ~ Novocure announced today that Optune (tumor treating fields) has been added to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines®). This is the organization that determines what is "standard of care". Optune should now be considered a standard of care treatment for recurrent glioblastoma. Meanwhile, Optune has been granted priority review status by the FDA, which means it is being fast-tracked in the review process prior to approval for newly diagnosed glioblastoma.
Novocure press releases
October 5, 2015
Today Novocure announced that the United States FDA has approved Optune (tumor treating fields) for newly diagnosed glioblastoma.
July 26, 2016
Novocure announces that the National Comprehensive Cancer Network has designated Optune as a category 2A treatment for newly diagnosed glioblastoma, indicating uniform consensus among panel members that Optune be added to the guidelines, essentially declaring that Optune is now considered a standard treatment for newly diagnosed GBM.
Novo TTF-100A versus physican’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Stupp et al. 2012.
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Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields. Rulseh et al. 2012.
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Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Kirson et al. 2007.
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Chemotherapeutic treatment efficacy and sensitivity are increased by adjuvant alternating electric fields (TTFields). Kirson et al. 2009.
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Electric helmet slows brain tumors without chemotherapy’s side effects. Tom Randall. 2010.
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Phase II Trial of 7days on/7 days off temozolomide for recurrent high-grade glioma. Han et al. 2014.
Response Patterns of Recurrent Glioblastomas Treated With Tumor-Treating Fields. Vymazal and Wong, 2014.
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This page was created on 06/27/2014 and last updated on 08/23/2016