Tumor Treating Fields for Glioblastoma
Glioblastoma (GBM) remains the most common and aggressive primary brain tumor in adults. In the U.S., approximately 18,000 new cases of GBM are diagnosed every year. The gold-standard for treatment of patients with newly diagnosed GBM consists of maximal safe surgical resection to the extent feasible or a diagnostic biopsy, followed by combined chemotherapy and radiation. Patients then continue on maintenance chemotherapy for 6-12 months. Clinical trials evaluating this treatment regimen have demonstrated a median survival time of 6-7 months without evidence of tumor growth and an overall survival of 15-16 months. Despite improvements in delivery approaches for chemoradiation and surgical techniques, such as navigation-guided surgery, awake surgeries and functional MRI to map out critical nerve fiber eloquent brain centers, the prognosis for GBM patients remains dismal. There are a number of obstacles that contribute to the poor prognosis. First, surgery can lead to damage of surrounding brain. Chemoradiation can cause toxicity to healthy surrounding brain tissue. And lastly, the inherent invasiveness of GBM allows tumor cells to travel a distance away from the main tumor mass and invade surrounding tissue. Due to this propensity to invade and rapidly divide, tumor surgery is almost always followed by tumor recurrence at a focus within 1 cm of the surgical cavity.
Over the last decade, all attempts and strategies to improve outcomes of patients with GBM failed when evaluated in large randomized trials. Neither increasing the temozolomide chemotherapy dosing, nor the addition of Avastin, the antiangiogenic agent that disrupts blood vessel growth, nor targeting the epidermal growth factor receptor (EGFR) with an anti-EGFR monoclonal antibody has shown any improvement in survival.
Tumor Treating Fields (TTFields) is a novel minimally invasive treatment that selectively disrupts GBM tumor cells by delivering low-intensity, intermediate- frequency (200 kHz) alternating electric fields via transducer arrays applied to the scalp (Figure 1). TTFields cause disruption in the division process of tumor cells, thus sending them into an apoptotic suicide mode. In order to examine the effectiveness of TTFields, a multicenter, open-label, randomized controlled phase 3 EF-14 clinical trial, was designed to recruit 700 patients at 90 sites in North America, Europe, the Republic of Korea, and Israel. Moffitt Cancer Center was one of the leading sites in the U.S., headed by Dr. Nam Tran and the Neuro-Oncology team. The trial was designed to test the efficacy and safety of TTFields in combination with best standard of care in the treatment of newly diagnosed GBM. At the completion of surgery and chemoradiation, patients were randomized to receive maintenance chemotherapy alone or with the TTField.
Between July 2009 and December 2014, 695 patients with newly diagnosed GBM were randomized to receive either TTFields + maintenance chemotherapy (n=466) or maintenance chemotherapy only (n=229). The first 315 patients randomized were used for the interim analysis. After a median follow-up of 38 months, the group receiving TTF + maintenance chemotherapy showed a statistically significant progression-free survival period of 7.2 months compared with 4.0 months for those on maintenance chemotherapy alone. The overall survival also favored TTFields treated patients with a median of 19.6 months versus 16.6 months for those without TTField (Figure 2). Based on the overwhelming response and improvement in survival, the phase III EF-14 clinical trial ended early. Thus we are entering a new era in our treatment of GBM. This new treatment modality should be the new standard of care and added to the arsenal in our battle against this dreaded disease.
Adapted from the 2016 ISSUE NEURON NEWS