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Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol

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Abstract

Background

Control of serum uric acid (sUA) levels is very important during chemotherapy in patients with malignant tumors, as the risks of tumor lysis syndrome (TLS) and renal events are increased with increasing levels of sUA. We investigated the efficacy and safety of febuxostat, a potent non-purine xanthine oxidase inhibitor, compared with allopurinol for prevention of hyperuricemia in patients with malignant tumors, including solid tumors, receiving chemotherapy in Japan.

Methods

An allopurinol-controlled multicenter, open-label, randomized, parallel-group comparative study was carried out. Patients with malignant tumors receiving chemotherapy, who had an intermediate risk of TLS or a high risk of TLS and were not scheduled to be treated with rasburicase, were enrolled and then randomized to febuxostat (60 mg/day) or allopurinol (300 or 200 mg/day). All patients started to take the study drug 24 h before chemotherapy. The primary objective was to confirm the non-inferiority of febuxostat to allopurinol based on the area under the curve (AUC) of sUA for a 6-day treatment period.

Results

Forty-nine and 51 patients took febuxostat and allopurinol, respectively. sUA decreased over time after initiation of study treatment. The least squares mean difference of the AUC of sUA between the treatment groups was −33.61 mg h/dL, and the 95 % confidence interval was −70.67 to 3.45, demonstrating the non-inferiority of febuxostat to allopurinol. No differences were noted in safety outcomes between the treatment groups.

Conclusion

Febuxostat demonstrated an efficacy and safety similar to allopurinol in patients with malignant tumors receiving chemotherapy.

Trial registry

http://www.clinicaltrials.jp; Identifier: JapicCTI-132398.

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Acknowledgments

This study was conducted by the following physicians and study centers—Kenichi Ishizawa and Yoko Okitsu (Tohoku University Hospital); Osamu Sasaki (Miyagi Cancer Center); Makoto Maemondo (Miyagi Cancer Center); Masahiro Kizaki (Saitama Medical Center); Noriko Doki (Komagome Hospital); Hiroki Yamaguchi (Nippon Medical School Hospital); Kaoru Kubota (Nippon Medical School Hospital); Kentaro Watanabe (Tokyo Saiseikai Central Hospital); Hironori Ueno (Tokyo Medical Center); Akira Fujita (Showa General Hospital); Katsumichi Fujimaki (Fujisawa City Hospital); Yasukazu Kawai (Fukui Prefectural Hospital); Takashi Nakayama (Fukui-ken Saiseikai Hospital); Keita Kirito (University of Yamanashi); Masataka Okamoto (Fujita Health University Hospital); Toshiki Uchida (Japanese Red Cross Nagoya Daini Hospital); Hirokazu Nagai and Hiroatsu Iida (Nagoya Medical Center); Mitsuru Itoh (Kyoto City Hospital); Masaya Okada (Hyogo College of Medicine); Junji Suzumiya (Shimane University Faculty of Medicine); Kenichi Gemba (Fukuyama Medical Center); Toru Kiguchi (Chugoku Central Hospital); Tetsuya Goto (Tokushima Red Cross Hospital); Masahiko Kaneko (Uwajima City Hospital); Tomoaki Fujisaki (Matsuyama Red Cross Hospital); and Kazuo Tamura (Fukuoka University Hospital). This study was funded by Teijin Pharma Ltd., Tokyo, Japan. Teijin Pharma was involved in the design, conduct, and analysis of the study.

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Authors and Affiliations

  1. General Medical Research Center, Fukuoka University, Fukuoka, Fukuoka, Japan

    Kazuo Tamura

  2. Department of Hematology and Oncology, Fukui Prefectural Hospital, Fukui, Fukui, Japan

    Yasukazu Kawai

  3. Division of Hematology, Chugoku Central Hospital, Fukuyama, Hiroshima, Japan

    Toru Kiguchi

  4. Department of Hematology and Medical Oncology, Fujita Health University Hospital, Toyoake, Aichi, Japan

    Masataka Okamoto

  5. Department of Internal Medicine, Uwajima City Hospital, Uwajima, Ehime, Japan

    Masahiko Kaneko

  6. Department of Respiratory Medicine, Miyagi Cancer Center, Natori, Miyagi, Japan

    Makoto Maemondo

  7. Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Hiroshima, Japan

    Kenichi Gemba

  8. Department of Hematology, Fujisawa City Hospital, Fujisawa, Kanagawa, Japan

    Katsumichi Fujimaki

  9. Department of Hematology and Oncology, University of Yamanashi, Chuo, Yamanashi, Japan

    Keita Kirito

  10. Department of Internal Medicine, Tokushima Red Cross Hospital, Komatsushima, Tokushima, Japan

    Tetsuya Goto

  11. Department of Internal Medicine, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan

    Tomoaki Fujisaki

  12. Pharmaceutical Development Department I, Teijin Pharma Limited, Chiyoda, Tokyo, Japan

    Kenji Takeda

  13. Pharmaceutical Development Administration Department, Teijin Pharma Limited, Chiyoda, Tokyo, Japan

    Akihiro Nakajima

  14. Department of Hematology and Oncology, Faculty of Medical Sciences, University of Fukui, Fukui, Fukui, Japan

    Takanori Ueda

Authors
  1. Kazuo Tamura
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  2. Yasukazu Kawai
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  3. Toru Kiguchi
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  4. Masataka Okamoto
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  5. Masahiko Kaneko
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  6. Makoto Maemondo
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  7. Kenichi Gemba
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  8. Katsumichi Fujimaki
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  9. Keita Kirito
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  10. Tetsuya Goto
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  11. Tomoaki Fujisaki
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  12. Kenji Takeda
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  13. Akihiro Nakajima
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  14. Takanori Ueda
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Corresponding author

Correspondence to Kazuo Tamura.

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Conflict of interest

This study was funded by Teijin Pharma Ltd., Tokyo, Japan. Kazuo Tamura was the Coordinating Investigator and Takanori Ueda was the Medical Expert for this study. In addition, Takanori Ueda received honoraria, fees for promotional materials, and research funding from Teijin Pharma Ltd. Toru Kiguchi received honoraria from Teijin Pharma Ltd. Kenji Takeda and Akihiro Nakajima are employees of Teijin Pharma Ltd. The other authors have no conflict of interest to declare.

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Tamura, K., Kawai, Y., Kiguchi, T. et al. Efficacy and safety of febuxostat for prevention of tumor lysis syndrome in patients with malignant tumors receiving chemotherapy: a phase III, randomized, multi-center trial comparing febuxostat and allopurinol . Int J Clin Oncol 21, 996–1003 (2016). https://doi.org/10.1007/s10147-016-0971-3

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  • DOI: https://doi.org/10.1007/s10147-016-0971-3

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