Role of tumour treating fields in the management of glioblastoma
The current standard of care for glioblastoma multiforme (GBM), an aggressive primary brain tumour with a rapid disease course, consists of maximum safe surgical resection followed by radiotherapy with concomitant temozolomide (TMZ) chemotherapy and subsequent TMZ maintenance. At the 16th Annual Meeting of the Asian Society of Neuro-Oncology (ASNO) in Taipei, Taiwan, experts reviewed the evidence and shared their clinical experience on the use of tumour treating fields (TTFields), a novel treatment modality for GBM.
Inhibition of GBM growth via disruption of cell mitosis
“TTFields therapy is a localized treatment for GBM delivered via the portable, noninvasive Optune® device,” said Dr Jay-Jiguang Zhu of the University of Texas Health Science Center in Houston, Texas, US. TTFields, he noted, deliver low-intensity, intermediate-frequency (200 kHz) alternating electric fields via transducer arrays placed on the patient's shaved scalp.
“TTFields therapy works by altering and interfering with cell mitosis and cytokinesis,” said Zhu. “Cancer cells exposed to TTFields are unable to undergo cell divisions and cytokinesis, and the prolonged mitotic arrest eventually leads to cell apoptosis. By using tubulin fused to green fluorescent protein, we observed that TTFields treatment resulted in the arrest of otherwise normal mitosis process, which then led to apoptosis.”
The Optune device incorporates the US FDA-approved NovoTAL™ system, a treatment planning software that creates an individualized array placement map for each patient via measurements of each patient’s skull coordinates and tumour location within the coordinate. “With the NovoTAL system, physicians will be able to ensure optimal positioning of the transducer arrays, thereby maximizing control of tumour cell mitosis,” said Zhu.
Adding TTFields to standard chemotherapy improves survival
“The first trial to examine the efficacy of TTFields was the EF-11 trial, which evaluated the effect of TTFields treatment vs best physicians’ chose chemotherapies in patients with recurrent GBM,” noted Zhu. “Results showed that TTFields as a single modality provided similar overall survival (OS) as best physician choice chemotherapy (OS from entering the trial, 6.6 months vs 6.0 months; hazard ratio (HR), 0.86, 95 percent confidence interval (CI), 0.66 to 1.22], but fewer side effects except reversible scalp contact dermatitis.” [Eur J Cancer 2012;48:2192-2202]
The EF-14 trial was then carried out to assess the efficacy and safety of TTFields in combination with TMZ maintenance treatment in patients with newly-diagnosed GBM who had undergone chemoradiation therapy. The trial showed that patients who received TTFields treatment with TMZ maintenance chemotherapy had statistically significant improvements in both progression-free survival (PFS) and OS, compared with patients who received TMZ maintenance therapy alone. “Median PFS was 6.7 months in the TTFields plus TMZ group vs 4.0 months in the TMZ alone group [p<0.001], whereas median OS was 20.9 months vs 16.0 months [p<0.001],” said Zhu. (Figure 1) [JAMA 2017;318:2306-2316]
A subgroup analysis of the EF-14 trial showed that a compliance threshold of 50 percent in the TTFields-TMZ group correlated with significantly improved OS and PFS vs TMZ alone. “Additionally, the 5-year analysis showed that among patients treated with TTFields plus TMZ vs TMZ monotherapy, compliance of ≥90 percent was associated with a median PFS of 8.2 months vs 4.0 months and a median OS of 24.9 months vs 16.0 months,” said Zhu. (Figure 2) [J Neurooncol 2019;141:467-473]
Clinical experience with TTFields
Zhu shared a case of a 50-year-old male patient who was diagnosed with GBM in March 2009 and subsequently treated with TTFields and TMZ as a participant of the EF-14 trial. “The patient has undergone two surgeries so far. It is really encouraging that he is still alive and healthy today, with good quality of life,” noted Zhu.
In another case, a 28-year-old male was diagnosed with GBM after right frontal lobe craniotomy in 2012. A second craniotomy in 2013 revealed recurrent GBM along with necrotic tissue in his left frontal lobe, with a third craniotomy performed on his right frontal lobe in 2015.
“The patient was randomized to receive TTFields with TMZ in the EF-14 trial. He completed 33 cycles of TMZ in 2015, followed by 68 cycles of bevacizumab and irinotecan in 2016. As of 2016, he was not on any chemotherapy, but continued to receive TTFields therapy with the Optune device. He is currently alive and well,” said Zhu.
Reversible contact dermatitis has been the most common side effect observed with TTFields. Zhu noted that these dermatologic conditions can be managed with corticosteroids and antibiotics if required, or by withholding treatment for 1–2 days and resuming it once the affected area has recovered.
“Based on results of the EF-11 and EF-14 trials, as well as personal clinical experience to date, TTFields can be considered an effective treatment option for GBM,” commented Zhu. “As no systemic side effects have been observed, TTFields can be effectively combined with other treatment modalities to achieve optimal outcomes for our patients.”
TTFields well tolerated in Asian patients
“Since its approval in Hong Kong in December 2018, at least 16 patients with newly diagnosed as well as recurrent GBM have been treated with TTFields delivered by the Optune device,” said Dr Lai-Fung Li of the Division of Neurosurgery, Queen Mary Hospital, University of Hong Kong.
The Optune device, he highlighted, enables physicians to monitor patient progress as well as treatment compliance via a monthly usage report as well as an error report log. “The hot and humid climate in Hong Kong does not present any additional challenges with regards to the commonly reported side effect of allergic dermatitis,” he noted. “Most of the allergic dermatitis we encountered was mild and easily managed with corticosteroids.”
“In addition to patient education, it is important to educate caregivers on adverse event management, scalp maintenance and array placement,” he noted. “This is especially important in patients with cognitive issues.”
Besides good tolerance and compliance among patients treated to date, TTFields treatment also did not significantly increase physicians’ workload, Li added.
“While the device can be uncomfortable at the beginning, my experience is that patients tend to adapt well to TTFields once they learn how to manage the skin irritation,” said Professor Chae-Yong Kim of Seoul National University College of Medicine, South Korea. “Good family support is very important in TTFields treatment.”
Asian subgroup analysis of EF-14 trial
A subgroup analysis of 39 patients with newly diagnosed GBM in South Korea demonstrated improved PFS with TTFields plus TMZ vs TMZ monotherapy (median, 6.2 months vs 4.2 months). Median OS was 27.2 months in the TTFields plus TMZ group, which was significantly higher than the median OS in the overall population of EF-14 patients treated with TTFields plus TMZ (20.9 months) and higher than the median OS in the TMZ monotherapy arm.
Furthermore, the addition of TTFields to TMZ did not lead to increased toxicity. In general, there were fewer adverse events in the TTFields plus TMZ group compared with the TM monotherapy group. The subgroup data were presented at ASNO.
“The results of the Asian subgroup analysis were very encouraging. We believe that TTFields will become a part of the multimodal management of patients with solid malignancies,” said Kim.
“TTFields treatment alone is not enough for GBM, especially in high-grade disease. Larger multinational studies to evaluate the efficacy of TTFields in Asians, involving up to 500 patients, are needed to further understand its role in Asian GBM management,” he suggested.