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Clinical Trial
. 2018 Jul;138(3):627-636.
doi: 10.1007/s11060-018-2831-7. Epub 2018 Mar 20.

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma

Toshihiko Wakabayashi  1 , Atsushi Natsume  2 , Junki Mizusawa  3 , Hiroshi Katayama  3 , Haruhiko Fukuda  3 , Minako Sumi  4 , Ryo Nishikawa  5 , Yoshitaka Narita  6 , Yoshihiro Muragaki  7 , Takashi Maruyama  7 , Tamio Ito  8 , Takaaki Beppu  9 , Hideo Nakamura  10 , Takamasa Kayama  11 , Shinya Sato  11 , Motoo Nagane  12 , Kazuhiko Mishima  5 , Yoko Nakasu  13 , Kaoru Kurisu  14 , Fumiyuki Yamasaki  14 , Kazuhiko Sugiyama  15 , Takanori Onishi  16 , Yasuo Iwadate  17 , Mizuhiko Terasaki  18 , Hiroyuki Kobayashi  19 , Akira Matsumura  20 , Eiichi Ishikawa  20 , Hikaru Sasaki  21 , Akitake Mukasa  22 , Takayuki Matsuo  23 , Hirofumi Hirano  24 , Toshihiro Kumabe  25   26 , Nobusada Shinoura  27 , Naoya Hashimoto  28 , Tomokazu Aoki  29 , Akio Asai  30 , Tatsuya Abe  31 , Atsuo Yoshino  32 , Yoshiki Arakawa  33 , Kenichiro Asano  34 , Koji Yoshimoto  35 , Soichiro Shibui  6 ; Members of Japan Clinical Oncology Group Brain Tumor Study Group (JCOG-BTSG)
Affiliations
Clinical Trial

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonβ plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma

Toshihiko Wakabayashi et al. J Neurooncol. 2018 Jul.

Abstract

Purpose: This study explored the superiority of temozolomide (TMZ) + interferonβ (IFNβ) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design.

Experimental design: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by TMZ maintenance (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNβ + RT arm intravenously received IFNβ (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8).

Results: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNβ + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNβ + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%.

Conclusions: TMZ + IFNβ + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

Keywords: Glioblastoma; Interferon-beta; MGMT; RCT; Temozolomide.

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Conflict of interest statement

T.W. has received research funding from Toray Co, Ltd, and MSD Co. Ltd. K.S. received honorarium fundings from MSD. M.N. received honorarium and research fundings from MSD, Chugai, and Eisai, and research funding from Daiichi-Sankyo. R.N. received honorarium and research fundings from MSD, Chugai, and Eisai. The other authors declare that they have no conflict of interest. All authors have registered online Self-reported COI Disclosure Statement Forms through the website for Japan Neurosurgical Society members.

Figures

Fig. 1
Fig. 1
Patient flow diagram of a randomized screening phase II trial of chemoradiotherapy with interferonβ plus temozolomide in comparison with chemoradiotherapy with temozolomide alone for newly diagnosed glioblastoma
Fig. 2
Fig. 2
Consort diagram. From April 2010 to January 2012, 122 patients were accrued, of whom 63 and 59 patients were assigned to the TMZ + RT and TMZ + IFNβ + RT arms, respectively
Fig. 3
Fig. 3
Clinical outcomes. The median survival time was 20.3 months (95% CI 15.4–26.9 months) and 24.0 months (95% CI 18.8–27.4 months) in the TMZ + RT arm and the TMZ + IFNβ + RT arm, respectively (HR 1.00, 95% CI 0.65–1.55; one-sided log rank P = 0.51). OS did not statistically differ between the two arms (a). The median PFS was 10.1 months (95% CI 7.5–11.8 months) and 8.5 months (95% CI 6.6–11.9 months) in the TMZ + RT arm and the TMZ + IFNβ + RT arm, respectively (HR 1.25, 95% CI 0.85–1.84; two-sided P = 0.25) (b)
Fig. 4
Fig. 4
Subgroup analyses were performed for OS by sex (male/female), age (≤ 49 years/≥ 50 years), residual tumor after resection (absent/present) and ECOG PS (0/1/2–3). Male, Younger patients (≤ 49 years) and ECOG PS 0 in the TMZ + IFNβ + RT arm showed good OS compared with RT/TMZ arm
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