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

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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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Abbreviations

GBM:

Glioblastoma

AA:

Anaplastic astrocytoma

ACNU:

Nimustine hydrochloride

BCNU:

Carmustine

TMZ:

Temozolomide

MGMT:

Methylguanine DNA methyltransferase

WHO:

World Health Organization

PFS:

Progression-free survival

OS:

Overall survival

RT:

Radiotherapy

HR:

Hazard ratio

AE:

Adverse event

ND:

Not determined

CR:

Complete response

PR:

Partial response

SD:

Stable disease

PD:

Progressive disease

WBC:

White blood cell

3D-CRT:

Three-dimensional conformal radiotherapy

CT:

Computed tomography

IMRT:

Intensity-modulated radiation therapy

BEV:

Beam’s eye views

DVH:

Dose–volume histograms

GTV:

Gross tumor volume

CTV:

Clinical target volume

PTV:

Planning target volume

ICRU:

International Commission on Radiation Units

FLAIR:

Fluid-attenuated inversion recovery

OAR:

Organ-at-risk

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Acknowledgments

We thank all the members of the JCOG Brain Tumor Study Group and the staff of the JCOG Data Center. We appreciate Dr. Nobuaki Funata and Dr. Toru Iwaki for pathological review, Dr. Satoshi Ishikura for quality assurance of radiation therapy, and Dr. Hiroshi Katayama, Dr. Kenichi Nakamura, and Mr. Hidenobu Yamada for review of the manuscript. This work was supported in part by the National Cancer Center Research and Development Fund (23A-16 and 23A-20), the Health and Labour Sciences Research Grants (H14-032, H15-025, H16-005, H17-005), and the Grant-in Aid for Cancer Research (20S-4, 20S-6) from the Ministry of Health, Labour and Welfare.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Soichiro Shibui, Yoshitaka Narita, Yasuji Miyakita & Kazuhiro Nomura

  2. Japan Clinical Oncology Group Data Center, National Cancer Center, Tokyo, Japan

    Junki Mizusawa, Akihiro Sato & Haruhiko Fukuda

  3. Department of Neurosurgery, Iwate Medical University, Iwate, Japan

    Takaaki Beppu & Kuniaki Ogasawara

  4. Department of Neurosurgery, Hokkaido University Graduate School of Medicine, Hokkaido, Japan

    Yutaka Sawamura & Hiroyuki Kobayashi

  5. Department of Neuro-Oncology/Neurosurgery, International Medical Center, Saitama Medical University, Saitama, Japan

    Ryo Nishikawa & Kazuhiko Mishima

  6. Department of Neurosurgery, Tokyo Women’s Medical University, Tokyo, Japan

    Yoshihiro Muragaki & Takashi Maruyama

  7. Department of Neurosurgery, Kumamoto University, Kumamoto, Japan

    Junichi Kuratsu, Hideo Nakamura & Masato Kochi

  8. Department of Neurosurgery, Sapporo Medical University, Sapporo, Japan

    Yoshio Minamida & Toshiaki Yamaki

  9. Department of Neurosurgery, Tohoku University School of Medicine, Miyagi, Japan

    Toshihiro Kumabe & Teiji Tominaga

  10. Department of Neurosurgery, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Takamasa Kayama & Kaori Sakurada

  11. Department of Neurosurgery, Kyorin University Faculty of Medicine, Tokyo, Japan

    Motoo Nagane & Keiichi Kobayashi

  12. Department of Neurosurgery, Nakamura Memorial Hospital, Hokkaido, Japan

    Hirohiko Nakamura & Tamio Ito

  13. Department of Neurosurgery, Keio University School of Medicine, Tokyo, Japan

    Takahito Yazaki & Hikaru Sasaki

  14. Department of Neurosurgery, St. Marianna University School of Medicine, Kanagawa, Japan

    Katsuyuki Tanaka

  15. Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan

    Hideaki Takahashi

  16. Department of Neurosurgery, Saitama Medical Center, Saitama, Japan

    Akio Asai

  17. Department of Neurosurgery, University of Tokyo, Tokyo, Japan

    Tomoki Todo

  18. Department of Neurosurgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Toshihiko Wakabayashi

  19. Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Jun Takahashi

  20. Department of Neurosurgery, Tsukuba University, Tsukuba, Japan

    Shingo Takano

  21. Department of Neurosurgery, Teikyo University School of Medicine, Tokyo, Japan

    Takamitsu Fujimaki

  22. Department of Radiation-Oncology, National Cancer Center Hospital, Tokyo, Japan

    Minako Sumi

  23. Department of Pathology, Gunma University, Gunma, Japan

    Yoichi Nakazato

Authors
  1. Soichiro Shibui
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  2. Yoshitaka Narita
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  3. Junki Mizusawa
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  28. Hideaki Takahashi
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  35. Minako Sumi
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  37. Yoichi Nakazato
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  38. Akihiro Sato
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  39. Haruhiko Fukuda
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  40. Kazuhiro Nomura
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Corresponding author

Correspondence to Soichiro Shibui.

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Shibui, S., Narita, Y., Mizusawa, J. et al. Randomized trial of chemoradiotherapy and adjuvant chemotherapy with nimustine (ACNU) versus nimustine plus procarbazine for newly diagnosed anaplastic astrocytoma and glioblastoma (JCOG0305). Cancer Chemother Pharmacol 71, 511–521 (2013). https://doi.org/10.1007/s00280-012-2041-5

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  • DOI: https://doi.org/10.1007/s00280-012-2041-5

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