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Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly
Kazuhiko Mishima1, Ryo Nishikawa1, Yoshitaka Narita2
1Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
Background:
The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival.
Methods:
An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ± 10 Gy boost (arm A) or WBRT ± boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS).
Results:
Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95-4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response.
Conclusions:
This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.
