1. Compared to maintenance therapy with temozolomide alone, maintenance therapy with Tumor-Treating Fields (TTFields) plus temozolomide significantly improved progression-free and overall survival in glioblastoma patients.
2. The overall adverse event/toxic effect profile of TTFields plus temozolomide combination therapy was comparable to temozolomide treatment alone.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Glioblastoma is an aggressive central nervous system malignancy with a devastating prognosis of 1 to 2 years. Standard therapy is surgical resection or biopsy followed by radiotherapy with daily temozolomide chemotherapy, and subsequent maintenance with temozolomide for 6 to 12 months. TTFields are a selective, antimitotic agent delivered locoregionally that cause apoptosis by disrupting spindle formation during metaphase and cell division. Prior studies have demonstrated no survival benefit of TTFields compared to chemotherapy, but a synergistic antitumor effect may occur with combined therapy with chemotherapy and TTFields.
This phase 3 trial aimed to evaluate the use of TTFields in combination with temozolomide as maintenance treatment in glioblastoma patients after initial treatment with temozolomide and radiotherapy. In the interim analysis of this trial, median progression-free survival improved from 4.0 months in the temozolomide alone group to 7.1 months in the TTFields plus temozolomide combination group. Median overall survival improved from 15.6 months in the temozolomide groups to 20.5 months in the TTFields plus temozolomide combination group. Limitations of this study include a limited interim analysis, variation in initial treatment with temozolomide and radiotherapy and reporting bias due to the TTFields group being more closely followed. Nevertheless, this study demonstrates a significant benefit of combination therapy with temozolomide and TTFields.
Click to read the study in JAMA
Click to read an accompanying editorial in JAMA
Relevant Reading: Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors.
In-Depth [randomized clinical trial]: Patients eligible for this study had a diagnosis of supratentorial glioblastoma and had already received debulking surgery or biopsy. After treatment with standard chemoradiotherapy and temozolomide, patients were randomized (2:1) to receive maintenance treatment with TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229). The interim analysis included 210 patients in the combination group and 105 patients in the temozolomide group alone. After a median follow-up period of 38 months, median progression-free survival was 7.1 months (95%CI 5.9-8.2 months) in the TTFields plus temozolomide group compared to 4.0 months (95%CI 3.3-5.2 months) in the temozolomide group alone. Median overall survival was 20.5 months (95%CI 16.7-25.0 months) in the TTFields plus temozolomide group compared with 15.6 months (95%CI 13.3-19.1 months) in the temozolomide group alone. Two years post-enrollment, 43% of patients in the TTFields plus temozolomide group were alive compared to 29% in the temozolomide group alone (p = 0.006). There was no significant increase in systemic toxic effects or seizures in the TTFields plus temozolomide group compared to the temozolomide group alone. Patients treated with TTFields plus temozolomide experienced localized skin toxicity from application of the transducer arrays.
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