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Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05)

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Abstract

Background

Retrospective studies have found that early tumor shrinkage (ETS) and depth of response (DpR) are associated with favorable outcomes in patients with metastatic colorectal cancer (mCRC); however, few prospective studies have evaluated ETS and DpR.

Patients and Methods

We performed a phase II study of FOLFOX plus cetuximab as first-line treatment in Japanese patients with KRAS wild-type mCRC. The primary endpoint was response rate (RR), and secondary endpoints included progression-free survival (PFS), overall survival (OS), chronological tumor shrinkage (evaluated every 8 weeks), and safety. The association of ETS and DpR with survival time was analyzed using Spearman’s rank correlation coefficient.

Results

In 54 participants, the RR, median PFS, and OS were 66.7 % (95 % CI, 53.4–77.8 %), 11.1 months, and 33.9 months, respectively. There was no unexpected toxicity. Forty (80 %) of 50 assessable patients had ETS, which was associated with prolonged PFS and OS (11.3 vs. 3.7 months, HR 0.26, p = 0.0003; 42.8 vs. 9.0 months, HR 0.40, p = 0.0279, respectively). Median DpR was 56.3 %. The DpR correlated with OS (r s = 0.314, p = 0.027) as well as post-progression survival (PPS) (r s = 0.366, p = 0.017). Interestingly, DpR was moderately associated with OS and PPS (r s = 0.587, r s = 0.570, respectively) in patients harboring tumors with larger target lesions, but was not associated with OS or PPS in patients with smaller target lesions. FOLFOX plus cetuximab was active as a first-line treatment for Japanese mCRC patients, with no unexpected toxicities.

Conclusions

Our prospective evaluation of chronological tumor shrinkage showed that ETS and DpR correlate with outcomes in patients with KRAS wild-type mCRC who receive cetuximab-based chemotherapy (UMIN000004197).

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Acknowledgments

We thank the patients, their families, and the investigators who participated in the JACCRO CC-05 trial. We also thank Sachika Koyama for editorial assistance and Peter Star (Medical Network K.K.) and Martin D. Berger for English editorial support. Akihito Tsuji and Yu Sunakawa contributed equally to this work.

Author information

Author notes

    Authors and Affiliations

    1. Department of Clinical Oncology, Kagawa University Faculty of Medicine Cancer Center, Kagawa University Hospital, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan

      Akihito Tsuji

    2. Division of Medical Oncology, Department of Internal Medicine, Showa University Northern Yokohama Hospital, 35-1, Chigasaki-chuo, Tsuzuki-ku, Yokohama, Kanagawa, 224-8503, Japan

      Yu Sunakawa

    3. Division of Medical Oncology, Showa University Fujigaoka Hospital, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan

      Wataru Ichikawa

    4. Aizawa Comprehensive Cancer Center, Aizawa Hospital, 2-5-1, Honjyo, Matsumoto, Nagano, 390-8510, Japan

      Masato Nakamura

    5. Department of Digestive Surgery, Nihon University School of Medicine, 30-1, Oyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan

      Mitsugu Kochi & Masashi Fujii

    6. Division of Gastroenterology, Chiba Cancer Center, 666-2, Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan

      Tadamichi Denda

    7. Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan

      Tatsuro Yamaguchi

    8. Division of Medical Oncology, Department of Internal Medicine, Showa University Koto Toyosu Hospital, 5-1-38 Toyosu, Koto-ku, Tokyo, 135-8577, Japan

      Ken Shimada

    9. Department of Surgery, Hakodate Goryoukaku Hospital, 38-3, Goryokaku-machi, Hakodate, Hokkaido, 040-8611, Japan

      Akinori Takagane

    10. Department of Internal Medicine, Konan Hospital, 1-5-16, Kamokogahara, Higashinada-ku, Kobe, Hyogo, 658-0064, Japan

      Satoshi Tani

    11. Gastrointestinal Cancer Center, Sano Hospital, 2-5-1, Shimizugaoka, Tarumi-ku, Kobe, Hyogo, 655-0031, Japan

      Masahito Kotaka

    12. Department of gastroenterological Surgery, Tokyo Women’s Medical University Yachiyo Medical Center, 477-96, Owadashinden, Yachiyo, Chiba, 276-8524, Japan

      Hidekazu Kuramochi

    13. Department of Surgery, NTT Medical Center, 5-9-22, Higashi-Gotanda, Shinagawa-ku, Tokyo, 141-8625, Japan

      Kaoru Furushima

    14. Department of Digestive Surgery, Toho University School of Medicine, 6-11-1, Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan

      Junichi Koike

    15. Department of Surgery, Kishiwada Tokushukai Hospital, 4-27-1, Kamoricho, Kishiwada, Osaka, 596-0042, Japan

      Yutaka Yonemura

    16. Department of Clinical Medicine (Biostatistics), Kitasato University School of Pharmacy, 5-9-1, Shirokane, Minato-ku, Tokyo, 108-8641, Japan

      Masahiro Takeuchi

    17. Japan Clinical Cancer Research Organization, 7F Ginza Wing Bldg. 1-14-5, Ginza, Chuo-ku, Tokyo, 104-0061, Japan

      Toshifusa Nakajima

    Authors
    1. Akihito Tsuji
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    2. Yu Sunakawa
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    Corresponding author

    Correspondence to Wataru Ichikawa.

    Ethics declarations

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

    Conflict of Interest

    Author A.T. has received honoraria from Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, and Merck Serono. Author Y.S. has received honoraria from Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, and Merck Serono. Author W.I. has received consulting fees from Merck Serono, Daiichi Sankyo, Zeria Pharmaceutical, and Ono Pharmaceutical; research funding from Merck Serono, Taiho Pharmaceutical, Takeda, and Eisai; and honoraria from Taiho Pharmaceutical, Merck Serono, Chugai Pharma, Daiichi Sankyo, Takeda, Nippon Kayaku, and Sawai Pharmaceutical Co. Author M.N. has received honoraria from Merck Serono, Takeda, Chugai Pharma, Taiho Pharmaceutical, Nihonkayaku, Novartis, Yakult Honsha, Lilly Japan, Bristol-Myers Squibb, Bayer, Ajinomoto, Shionogi, Pfizer, and Ono Pharmaceutical. Author M.K. has received honoraria from Merck Serono, Takeda, Chugai Pharma, and Yakult Honsha. Author M.T. has received consulting fees from Taiho Pharmaceutical, Shionogi, AbbVie GK, AstraZeneca, and Hisamitsu Pharma Co. ; honoraria from Mitsubishi Tanabe Pharma. Author M.F. has received consulting fees from Taiho Pharmaceutical. The other authors have declared no conflicts of interest.

    Funding

    This study was funded by the Japan Clinical Cancer Research Organization (JACCRO).

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    Tsuji, A., Sunakawa, Y., Ichikawa, W. et al. Early Tumor Shrinkage and Depth of Response as Predictors of Favorable Treatment Outcomes in Patients with Metastatic Colorectal Cancer Treated with FOLFOX Plus Cetuximab (JACCRO CC-05). Targ Oncol 11, 799–806 (2016). https://doi.org/10.1007/s11523-016-0445-6

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