Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C

Kazuhiko Mishima; Ryo Nishikawa; Yoshitaka Narita; Junki Mizusawa; Minako Sumi; Tomoyuki Koga; Nobuyoshi Sasaki; Manabu Kinoshita; Motoo Nagane; Yoshiki Arakawa; Koji Yoshimoto; Ichiyo Shibahara; Naoki Shinojima; Kenichiro Asano; Takao Tsurubuchi; Hikaru Sasaki; Akio Asai; Takashi Sasayama; Yasutomo Momii; Atsushi Sasaki; Shigeo Nakamura; Masaru Kojima; Jun-Ichi Tamaru; Kazuhiro Tsuchiya; Miho Gomyo; Kayoko Abe; Manabu Natsumeda; Fumiyuki Yamasaki; Hiroshi Katayama; Haruhiko Fukuda

doi:10.1093/neuonc/noac246

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C

Neuro Oncol. 2023 Apr 6;25(4):687-698. doi: 10.1093/neuonc/noac246.

Authors

Kazuhiko Mishima¹, Ryo Nishikawa¹, Yoshitaka Narita², Junki Mizusawa³, Minako Sumi⁴, Tomoyuki Koga^{1

5}, Nobuyoshi Sasaki⁶, Manabu Kinoshita⁷, Motoo Nagane⁶, Yoshiki Arakawa⁸, Koji Yoshimoto⁹, Ichiyo Shibahara¹⁰, Naoki Shinojima¹¹, Kenichiro Asano^{12

13}, Takao Tsurubuchi¹⁴, Hikaru Sasaki¹⁵, Akio Asai¹⁶, Takashi Sasayama¹⁷, Yasutomo Momii¹⁸, Atsushi Sasaki¹⁹, Shigeo Nakamura²⁰, Masaru Kojima²¹, Jun-Ichi Tamaru²², Kazuhiro Tsuchiya²³, Miho Gomyo²⁴, Kayoko Abe^{12

13}, Manabu Natsumeda²⁵, Fumiyuki Yamasaki²⁶, Hiroshi Katayama³, Haruhiko Fukuda³

Affiliations

¹ Department of Neuro-Oncology/Neurosurgery, Saitama Medical University International Medical Center, Saitama, Japan.
² Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, Tokyo, Japan.
³ Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan.
⁴ Radiation Oncology Department, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
⁵ Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
⁶ Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan.
⁷ Department of Neurosurgery, Osaka International Cancer Institute, Osaka, Japan.
⁸ Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁹ Department of Neurosurgery, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
¹⁰ Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Japan.
¹¹ Department of Neurosurgery, Kumamoto University Graduate School of Medicine, Kumamoto, Japan.
¹² Department of Neurosurgery, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
¹³ Department of Diagnostic Imaging and Nuclear Medicine, Tokyo Women's Medical University, Tokyo, Japan.
¹⁴ Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
¹⁵ Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan.
¹⁶ Department of Neurosurgery, Kansai Medical University, Hirakata, Japan.
¹⁷ Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Japan.
¹⁸ Department of Neurosurgery, Oita University Faculty of Medicine, Oita, Japan.
¹⁹ Department of Pathology, Saitama Medical University, Saitama, Japan.
²⁰ Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan.
²¹ Department of Anatomical and Surgical Pathology, Dokkyo University School of Medicine, Saitama, Japan.
²² Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
²³ Department of Radiology, Saitama Medical Center, Saitama Medical University, Saitama, Japan.
²⁴ Department of Radiology, Kyorin University Faculty of Medicine, Tokyo, Japan.
²⁵ Department of Neurosurgery, Brain Research Institute, University of Niigata, Niigata, Japan.
²⁶ Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.

Abstract

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.

Keywords: MGMT; primary central nervous system lymphoma; temozolomide.

Publication types

Randomized Controlled Trial
Clinical Trial, Phase III
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents, Alkylating / therapeutic use
Brain
Central Nervous System Neoplasms* / therapy
Disease-Free Survival
Humans
Lymphoma*
Methotrexate
Temozolomide / therapeutic use

Substances

Temozolomide
Methotrexate
Antineoplastic Agents, Alkylating