Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields

Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.


Background
Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, representing as much as 30% of primary brain tumors with increasing incidence in some geographic regions [1]. Its incidence has been shown to increase with age [2]. Despite the introduction of aggressive treatment with temozolomide, the median survival time of adult patients remains approximately 10 months and as high as 14 months in patients receiving combined treatment with radiotherapy [3]. Only 3 to 5% of patients survive more than three years [4], and sporadic reports of survival exceeding five years are rare [5]. The exact clinical and molecular factors that contribute to such long-term survival are still unknown; however, younger age and a high Karnofsky performance scale (KPS) are considered prognostically favorable factors [4]. Recently, MGMT gene promoter methylation and IDH1 mutation have been shown to correlate with longer survival as well [6]. Recurrence of GBM is nearly universal, and patients with recurrent glioblastoma multiforme (RGBM) fare even worse, with a median survival of only five to seven months with optimal therapy [7].
Tumor-treating fields (TTField) therapy is a novel treatment technique with the potential to treat various forms of cancer. TTField therapy is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) have an anti-mitotic effect which acts during late metaphase and anaphase, with specific frequencies affecting specific cell types [8]. The applied fields disrupt mitotic spindle microtubule assembly and the segregation of intracellular organelles during cell division, leading to apoptosis [9]. TTField therapy has been tested in patients with advanced non-small cell lung cancer [10] and has recently received CE and FDA approval for the treatment of RGBM based on the results of a phase III clinical trial [11].
Our center was the first in the world to apply TTField treatment to histologically proven GBM patients in a small pilot study of 20 individuals in 2004 and 2005 ( Table 1). The inclusion criteria of the study included a KPS ≥70% and age ≥18 years, and the patients were divided into two groups. The first group consisted of 10 patients diagnosed with RGBM after failing temozolomide treatment that were treated with TTField therapy alone [9]. The second group consisted of 10 newly diagnosed GBM patients at least four weeks post radiation therapy (with adjuvant temozolomide) [12] that received TTField therapy combined with maintenance temozolomide. The treatment duration in individual patients varied between one and one and a half years, and all histological samples were independently examined in two laboratories in two countries. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField treatment, with no clinical or radiological evidence of recurrence.
Baseline characteristics of all 20 participants in the original pilot study. Dates are presented as month/year for simplicity, age calculations were performed on exact dates.

Case 1
A 52-year-old woman with a history of epileptic seizures and left-sided hemiparesis was diagnosed with an intraaxial brain tumor, suspected to be a high-grade glioma based on the magnetic resonance imaging (MRI) findings ( Figure 1a). The tumor was resected with the help of functional blood oxygen level dependence (BOLD-fMRI) neuronavigation in April 2004. Gross total resection was performed and pathological analysis revealed clear evidence of glioblastoma. Standard radiotherapy (60 Gy) and chemotherapy with temozolomide followed. After radiotherapy and chemotherapy, a follow-up MRI in July 2004 showed two enhancing lesions that were highly suspected to be tumor recurrence ( Figure 1b  The patient has mild, residual left-sided hemiparesis, and otherwise feels completely healthy with no subjective complaints and a KPS of 90.  Figure 2e). This small, enhancing lesion was examined with MR spectroscopy (Figure 2f ) and showed noise-signal only, while the spectra in neighboring voxels were practically normal (Figure 2g). Positron emission tomography (PET) did not reveal any tumor-like patterns. The patient is in good health, has minor difficulties with speech, and is completely independent, with a KPS of 90 to 100.

Case 3
A 31-year-old male presented with an epileptic seizure in January 2005. MRI examination revealed a tumor in the right frontal lobe that was suspected to be a high grade glioma (Figure 3a). The tumor was totally resected macroscopically (gross total resection) and showed clear histopathological characteristics of glioblastoma (World Health Organization (WHO) grade IV). Standard radiotherapy (60 Gy) and chemotherapy with temozolomide followed. TTField treatment was started in October 2005 concomitant to maintenance temozolomide and both treatments were discontinued in October 2006.
Since that time, no tumor recurrence has been detected ( Figure 3b). The patient is in good health, off all treatment and with a KPS of 100.

Discussion
Despite multi-modal treatment, the prognosis of GBM remains poor. Recurrence is likely inevitable provided the patient survives long enough, and further reduces the median survival to only five to seven months [4,7]. There have been documented cases of GBM patients   surviving longer than three years, termed long-term survival (LTS), representing approximately three to five percent of GBM patients [4]. Survival of GBM patients longer than five years, however, is exceptional, representing as few as 0.5% of patients [5]. Twenty percent of the participants in our pilot study (4 out of 20) have survived until the time of this report, roughly seven years ( Figure 5). These individuals continue to undergo regular neurological and radiological examinations, and do not show any signs of recurrence. The data from standard MR imaging are further supported by MR spectroscopy that does not show any tumor-like patterns in regions with corresponding abnormal signal intensity.
Younger age and a higher KPS have been proposed as prognostically favorable parameters for longer survival [4]. The mean age of our LTS-RGBM patients (Cases 1 and 2) was 47.5 years compared to 51.5 years for the rest of the RGBM group [9]. This difference is not striking. Although we cannot completely exclude pseudoprogression or radiation necrosis in these patients diagnosed without histological verification of the recurrent lesion, their continued survival is still remarkable. In the group of newly diagnosed GBM, the mean age of LTS-GBM patients (Cases 3 and 4) was 32 years compared to 51 years for the rest of the group. This was likely a contributing factor to their long term survival; however, this does not explain seven years of disease-free survival. All of the patients in the trial had a KPS ≥70 and the median KPS was 80.
TTField therapy has been shown to effectively inhibit glioma cell replication in vitro and in vivo [8,9]. The published results of the pilot trial using TTField therapy in GBM patients were extremely promising and served as the basis for a phase III clinical trial comparing TTField therapy to the best available active chemotherapy in patients with RGBM [11]. The phase III trial showed that patients with RGBM had comparable overall survival to those receiving chemotherapy without the side effects of chemotherapy and with a better quality of life. In the present study, no serious, probable, treatment-related adverse events occurred, with only contact dermatitis treated by topical corticosteroid documented in 17 of 20 patients. In the phase III trial, 8% of TTField therapy patients survived for longer than three years [11]. The reasons for the smaller number of long term survival patients in the phase III trial compared to the pilot trial is likely related to the younger age of the  patients presented in this report, the fact that they were at their first recurrence after temozolomide (versus second to third recurrence in the phase III trial) and, most importantly, continued TTField therapy for many months, despite initial growth of the contrast enhancing lesion while on therapy. Thus, we suggest that in order to increase the probability of response to TTField therapy and subsequent long term survival, TTField treatment should be continued even in the face of initial radiologic tumor growth.

Conclusions
In the present paper we report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence. Our results indicate that TTField treatment may be remarkably successful in a subgroup of GBM/RGBM patients, and further investigation is needed to identify any unique characteristics of this patient group.

Consent
Written informed consent was obtained from all patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.