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Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903)

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Abstract

Background

Definitive chemoradiotherapy (CRT) with 5-fluorouracil plus mitomycin-C is a standard treatment for stage II/III squamous cell carcinoma of the anal canal (SCCA). We performed this dose-finding and single-arm confirmatory trial of CRT with S-1 plus mitomycin-C to determine the recommended dose (RD) of S-1 and evaluate its efficacy and safety for locally advanced SCCA.

Methods

Patients with clinical stage II/III SCCA (UICC 6th) received CRT comprising mitomycin-C (10 mg/m2 on days 1 and 29) and S-1 (60 mg/m2/day at level 0 and 80 mg/m2/day at level 1 on days 1–14 and 29–42) with concurrent radiotherapy (59.4 Gy). Dose-finding used a 3 + 3 cohort design. The primary endpoint of the confirmatory trial was 3-year event-free survival. The sample size was 65, with one-sided alpha of 5%, power of 80%, and expected and threshold values of 75% and 60%, respectively.

Results

Sixty-nine patients (dose-finding, n = 10; confirmatory, n = 59) were enrolled. The RD of S-1 was determined as 80 mg/m2/day. Three-year event-free survival in 63 eligible patients who received the RD was 65.0% (90% confidence interval 54.1–73.9). Three-year overall, progression-free, and colostomy-free survival rates were 87.3%, 85.7%, and 76.2%, respectively; the complete response rate was 81% on central review. Common grade 3/4 acute toxicities were leukopenia (63.1%), neutropenia (40.0%), diarrhea (20.0%), radiation dermatitis (15.4%), and febrile neutropenia (3.1%). No treatment-related deaths occurred.

Conclusions

Although the primary endpoint was not met, S-1/mitomycin-C chemoradiotherapy had an acceptable toxicity profile and favorable 3-year survival and could be a treatment option for locally advanced SCCA.

Clinical trial information

jRCTs031180002.

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Acknowledgements

We thank all the patients and their families, and all staff in participating institutions and at the JCOG Data Center and Operations Office. JCOG Data Center and Operations Office: Ayaka Nakano and Michiko Murai (Data Management Section), and Junko Eba (Operations Office). We also thank Yoshihiro Moriya (first study group chair of Colorectal Cancer study Group at the start of this trial) for his encouragement and for supporting this trial. We also thank Editage and ThinkSCIENCE for English language editing. Part of the data was presented at the 2019 Gastrointestinal Cancers Symposium, held in San Francisco, CA, USA in 2019.

Funding

This study was supported in part by the National Cancer Center Research and Development Funds (26-A-4, 29-A-3, 2020-J-3, 2023-J-03), and Grants-in-Aid for Clinical Cancer Research (H23Gann-012) from the Ministry of Health, Labour and Welfare of Japan.

Author information

Author notes

  1. Yoshinori Ito and Tetsuya Hamaguchi contributed equally to this work as co-first authors.

Authors and Affiliations

  1. Department of Radiation Oncology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-Ku, Tokyo, 142-8666, Japan

    Yoshinori Ito

  2. Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Saitama, Japan

    Tetsuya Hamaguchi

  3. Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan

    Atsuo Takashima

  4. Japan Clinical Oncology Group Data Center, National Cancer Center Hospital, Tokyo, Japan

    Junki Mizusawa & Haruhiko Fukuda

  5. Division of Clinical Oncology, Kochi Health Sciences Center, Kochi, Japan

    Yasuhiro Shimada

  6. Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan

    Manabu Shiozawa

  7. Department of Radiation Oncology, Kanagawa Cancer Center, Yokohama, Japan

    Nobutaka Mizoguchi

  8. Department of Radiation Oncology, Aichi Cancer Center Hospital, Nagoya, Japan

    Takeshi Kodaira

  9. Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Japan

    Koji Komori

  10. Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan

    Masayuki Ohue

  11. Department of Radiation Oncology, Osaka International Cancer Institute, Osaka, Japan

    Koji Konishi

  12. Department of Gastroenterological Surgery, Kochi Health Sciences Center, Kochi, Japan

    Fuminori Teraishi

  13. Department of Surgery, Miyagi Cancer Center, Miyagi, Japan

    Makoto Kinouchi

  14. Department of Surgery, Suita Municipal Hospital, Suita, Japan

    Kohei Murata

  15. Department of Surgery, Kurume University School of Medicine, Kurume, Japan

    Fumihiko Fujita

  16. Department of Surgery, Kitasato University School of Medicine, Sagamihara, Japan

    Masahiko Watanabe

  17. Department of Diagnostic Radiology, National Cancer Center Hospital, Tokyo, Japan

    Gen Iinuma

  18. Digestive Disease Center, Showa University Northern Yokohama Hospital, Yokohama, Japan

    Fumio Ishida

  19. Department of Surgery, Toho University Ohashi Medical Center, Tokyo, Japan

    Yoshihisa Saida

  20. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan

    Takahisa Matsuda

  21. Japan Clinical Oncology Group Operations Office, National Cancer Center Hospital, Tokyo, Japan

    Hiroshi Katayama

  22. Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan

    Yukihide Kanemitsu

Authors
  1. Yoshinori Ito
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  2. Tetsuya Hamaguchi
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Consortia

The Colorectal Cancer Study Group of the Japan Clinical Oncology Group

Contributions

Y, TH, AT, JM, YS, HK, and YK conceived the study design. YI, TH, AT, YS, MS, NM, TK, KK, MO, KK, FT, MK, KM, FF, MW, and YK contributed to data collection. YI, TH, AT, JM, YS, HK, HF, and YK analyzed the data and interpreted the results. All authors wrote manuscript and approved the final version. All authors had accountable for all aspects of the work.

Corresponding authors

Correspondence to Yoshinori Ito or Junki Mizusawa.

Ethics declarations

Conflict of interest

Tetsuya Hamaguchi has received honoraria and research funding from Taiho Pharmaceutical. All other authors have no disclosures to declare.

Ethical approval

The study protocol was reviewed and approved by the Protocol Review Committee of JCOG and the institutional review board at each institution.

Consent to participate

All patients provided written informed consent.

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Ito, Y., Hamaguchi, T., Takashima, A. et al. Definitive S-1/mitomycin-C chemoradiotherapy for stage II/III anal canal squamous cell carcinoma: a phase I/II dose-finding and single-arm confirmatory study (JCOG0903). Int J Clin Oncol 28, 1063–1072 (2023). https://doi.org/10.1007/s10147-023-02361-7

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  • DOI: https://doi.org/10.1007/s10147-023-02361-7

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