Efficacy of probiotics and trimebutine maleate for abemaciclib-induced diarrhea: A randomized, open-label phase II trial (MERMAID, WJOG11318B)
Hiroko Masuda,
Yuko Tanabe,
Hitomi Sakai,
Koji Matsumoto,
Akihiko Shimomura,
Mihoko Doi,
Yasuo Miyoshi,
Masato Takahashi,
Yasuaki Sagara,
Shinya Tokunaga,
Tsutomu Iwasa,
Naoki Niikura,
Kenichi Yoshimura,
Toshimi Takano,
Junji Tsurutani
Affiliations
Hiroko Masuda
Department of Breast Surgical Oncology, Showa University, 1-5-8 Hatanodai Shinagawa-ku Tokyo 142-8555, Japan
Yuko Tanabe
Department of Medical Oncology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470, Japan
Hitomi Sakai
Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo,142-8555, Japan
Koji Matsumoto
Medical Oncology Division, Hyogo Cancer Center, 13-70 Kitaoji-cho, Akashi-city Hyogo, 673-8558, Japan
Akihiko Shimomura
Department of Breast and Medical Oncology, National Center for Global Health and Medicine, 1-21-1 Toyama Shinjuku-ku, Tokyo, 162-8655, Japan
Mihoko Doi
Department of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda Minami-ku Hiroshima-city Hiroshima, 734-8530, Japan
Yasuo Miyoshi
Department of Surgery, Division of Breast and Endocrine Surgery, School of Medicine, Hyogo Medical University, 1-1 Mukogawa-cho Nishinomiya-city Hyogo, 663-8501, Japan
Masato Takahashi
Department of Breast Surgery, Hokkaido University Hospital, Kita 14, Nishi 5, Kita-ku, Sapporo, Hokkaido, 060-8648 Japan
Yasuaki Sagara
Department of Breast Surgery, Sagara Hospital, Kagoshima, 3-31 Matsubara-cho Kagoshima City, Kagoshima 892-0833, Japan
Shinya Tokunaga
Department of Medical Oncology, Osaka City General Hospital, 2-13-22 Miyakojima-hondori Miyakojima-ku Osaka 534-0021, Japan
Tsutomu Iwasa
Department of Medical Oncology, Kindai University, 3-4-1 Kowakae, Higashiosaka City Osaka 577-8502, Japan
Naoki Niikura
Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi Kanagawa 259-1193, Japan
Kenichi Yoshimura
Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Kasumi 1-2-3 Minami-ku, Hiroshima 734-8551, Japan
Toshimi Takano
Department of Breast Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
Junji Tsurutani
Advanced Cancer Translational Research Institute, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo,142-8555, Japan; Corresponding author.
Background: Abemaciclib-induced diarrhea (AID) impairs quality of life (QOL) and treatment adherence in patients with breast cancer. Supportive treatment with loperamide is associated with constipation. We hypothesized that probiotics and trimebutine maleate (TM) would decrease the frequency of AID without causing constipation. Methods: Hormone receptor-positive, human epidermal growth factor 2-negative advanced breast cancer patients were randomized into the probiotic Bifidobacterium (A) or probiotic Bifidobacterium and TM (B) groups. Endocrine therapy, Abemaciclib and probiotic Bifidobacterium three times a day for 28 days, was administered to both arms. Arm B was treated with TM upon the onset of diarrhea. The primary endpoint was the percentage of patients who experienced grade ≥2 diarrhea. The secondary endpoints were safety, frequency, and duration of all-grade diarrhea; frequency of emesis and constipation; usage of loperamide; and health-related QOL/patient-reported outcome during the study. We evaluated whether the primary endpoint of each arm exceeded the predetermined threshold. Results: Fifty-one patients completed treatment. Grade 2 diarrhea occurred in 52% and 50% of patients in Arm A and Arm B, respectively. One patient experienced grade 3 diarrhea in each arm. The median duration of grade2 diarrhea was 2 and 2.5day, and only one patient required dose reduction. Grade ≥2 constipation was observed in 4% of Arm A and 3.6% of Arm B. Conclusions: Probiotic Bifidobacterium or the combination of probiotic Bifidobacterium with TM did not decrease the incidence of grade 2 or greater diarrhea compared with historical control, although the grade 3 or greater diarrhea was reduced. Clinical trial registration: jRCT (Japan registry of clinical trials).jRCTs031190154.
