Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305)

Soichiro Shibui, Yoshitaka Narita, Junki Mizusawa, Takaaki Beppu, Kuniaki Ogasawara, Yutaka Sawamura, Hiroyuki Kobayashi, Ryo Nishikawa, Kazuhiko Mishima, Yoshihiro Muragaki, Takashi Maruyama, Junichi Kuratsu, Hideo Nakamura, Masato Kochi, Yoshio Minamida, Toshiaki Yamaki, Toshihiro Kumabe, Teiji Tominaga, Takamasa Kayama, Kaori Sakurada & 20 others Motoo Nagane, Keiichi Kobayashi, Hirohiko Nakamura, Tamio Ito, Takahito Yazaki, Hikaru Sasaki, Katsuyuki Tanaka, Hideaki Takahashi, Akio Asai, Tomoki Todo, Toshihiko Wakabayashi, Jun Takahashi, Shingo Takano, Takamitsu Fujimaki, Minako Sumi, Yasuji Miyakita, Yoichi Nakazato, Akihiro Sato, Haruhiko Fukuda, Kazuhiro Nomura

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

Original languageEnglish
Pages (from-to)511-521
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume71
Issue number2
DOIs
Publication statusPublished - 2013 Feb

Fingerprint

Chemoradiotherapy
Nimustine
Procarbazine
Chemotherapy
Astrocytoma
Adjuvant Chemotherapy
Glioblastoma
temozolomide
Methyltransferases
Disease-Free Survival
Survival
Japan
Patient treatment
Alkylating Agents
DNA
Radiotherapy

Keywords

  • ACNU
  • Anaplastic astrocytoma
  • Glioblastoma
  • MGMT
  • Nimustine
  • Procarbazine

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pharmacology
  • Pharmacology (medical)
  • Toxicology

Cite this

Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). / Shibui, Soichiro; Narita, Yoshitaka; Mizusawa, Junki; Beppu, Takaaki; Ogasawara, Kuniaki; Sawamura, Yutaka; Kobayashi, Hiroyuki; Nishikawa, Ryo; Mishima, Kazuhiko; Muragaki, Yoshihiro; Maruyama, Takashi; Kuratsu, Junichi; Nakamura, Hideo; Kochi, Masato; Minamida, Yoshio; Yamaki, Toshiaki; Kumabe, Toshihiro; Tominaga, Teiji; Kayama, Takamasa; Sakurada, Kaori; Nagane, Motoo; Kobayashi, Keiichi; Nakamura, Hirohiko; Ito, Tamio; Yazaki, Takahito; Sasaki, Hikaru; Tanaka, Katsuyuki; Takahashi, Hideaki; Asai, Akio; Todo, Tomoki; Wakabayashi, Toshihiko; Takahashi, Jun; Takano, Shingo; Fujimaki, Takamitsu; Sumi, Minako; Miyakita, Yasuji; Nakazato, Yoichi; Sato, Akihiro; Fukuda, Haruhiko; Nomura, Kazuhiro.

In: Cancer Chemotherapy and Pharmacology, Vol. 71, No. 2, 02.2013, p. 511-521.

Research output: Contribution to journalArticle

Shibui, S, Narita, Y, Mizusawa, J, Beppu, T, Ogasawara, K, Sawamura, Y, Kobayashi, H, Nishikawa, R, Mishima, K, Muragaki, Y, Maruyama, T, Kuratsu, J, Nakamura, H, Kochi, M, Minamida, Y, Yamaki, T, Kumabe, T, Tominaga, T, Kayama, T, Sakurada, K, Nagane, M, Kobayashi, K, Nakamura, H, Ito, T, Yazaki, T, Sasaki, H, Tanaka, K, Takahashi, H, Asai, A, Todo, T, Wakabayashi, T, Takahashi, J, Takano, S, Fujimaki, T, Sumi, M, Miyakita, Y, Nakazato, Y, Sato, A, Fukuda, H & Nomura, K 2013, 'Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305)', Cancer Chemotherapy and Pharmacology, vol. 71, no. 2, pp. 511-521. https://doi.org/10.1007/s00280-012-2041-5
Shibui, Soichiro ; Narita, Yoshitaka ; Mizusawa, Junki ; Beppu, Takaaki ; Ogasawara, Kuniaki ; Sawamura, Yutaka ; Kobayashi, Hiroyuki ; Nishikawa, Ryo ; Mishima, Kazuhiko ; Muragaki, Yoshihiro ; Maruyama, Takashi ; Kuratsu, Junichi ; Nakamura, Hideo ; Kochi, Masato ; Minamida, Yoshio ; Yamaki, Toshiaki ; Kumabe, Toshihiro ; Tominaga, Teiji ; Kayama, Takamasa ; Sakurada, Kaori ; Nagane, Motoo ; Kobayashi, Keiichi ; Nakamura, Hirohiko ; Ito, Tamio ; Yazaki, Takahito ; Sasaki, Hikaru ; Tanaka, Katsuyuki ; Takahashi, Hideaki ; Asai, Akio ; Todo, Tomoki ; Wakabayashi, Toshihiko ; Takahashi, Jun ; Takano, Shingo ; Fujimaki, Takamitsu ; Sumi, Minako ; Miyakita, Yasuji ; Nakazato, Yoichi ; Sato, Akihiro ; Fukuda, Haruhiko ; Nomura, Kazuhiro. / Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). In: Cancer Chemotherapy and Pharmacology. 2013 ; Vol. 71, No. 2. pp. 511-521.
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abstract = "Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 {\%} of patients in both arms, and 27 {\%} of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.",
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T1 - Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305)

AU - Shibui, Soichiro

AU - Narita, Yoshitaka

AU - Mizusawa, Junki

AU - Beppu, Takaaki

AU - Ogasawara, Kuniaki

AU - Sawamura, Yutaka

AU - Kobayashi, Hiroyuki

AU - Nishikawa, Ryo

AU - Mishima, Kazuhiko

AU - Muragaki, Yoshihiro

AU - Maruyama, Takashi

AU - Kuratsu, Junichi

AU - Nakamura, Hideo

AU - Kochi, Masato

AU - Minamida, Yoshio

AU - Yamaki, Toshiaki

AU - Kumabe, Toshihiro

AU - Tominaga, Teiji

AU - Kayama, Takamasa

AU - Sakurada, Kaori

AU - Nagane, Motoo

AU - Kobayashi, Keiichi

AU - Nakamura, Hirohiko

AU - Ito, Tamio

AU - Yazaki, Takahito

AU - Sasaki, Hikaru

AU - Tanaka, Katsuyuki

AU - Takahashi, Hideaki

AU - Asai, Akio

AU - Todo, Tomoki

AU - Wakabayashi, Toshihiko

AU - Takahashi, Jun

AU - Takano, Shingo

AU - Fujimaki, Takamitsu

AU - Sumi, Minako

AU - Miyakita, Yasuji

AU - Nakazato, Yoichi

AU - Sato, Akihiro

AU - Fukuda, Haruhiko

AU - Nomura, Kazuhiro

PY - 2013/2

Y1 - 2013/2

N2 - Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

AB - Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone (n = 55) or ACNU + PCZ (n = 56) in the intention-to-treat population were 27.4 and 22.4 months (p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone (n = 40) or ACNU + PCZ (n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM.

KW - ACNU

KW - Anaplastic astrocytoma

KW - Glioblastoma

KW - MGMT

KW - Nimustine

KW - Procarbazine

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U2 - 10.1007/s00280-012-2041-5

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