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Okuno T, Morizane C, Mizusawa J, Yanagimoto H, Kobayashi S, Imaoka H, Terashima T, Kawakami H, Sano Y, Okusaka T, Ikeda M, Ozaka M, Miwa H, Todaka A, Shimizu S, Mizuno N, Sekimoto M, Sano K, Tobimatsu K, Katanuma A, Gotoh K, Yamaguchi H, Ishii H, Furuse J, Ueno M. Influence of major hepatectomy on gemcitabine-based chemotherapy for recurrent biliary tract cancer after surgery: a subgroup analysis of JCOG1113. Int J Clin Oncol 2025; 30:83-91. [PMID: 39441453 DOI: 10.1007/s10147-024-02642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Accepted: 10/05/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND Major hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC. METHODS Of the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed. RESULTS Grade ≥ 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms. CONCLUSIONS The safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.
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Affiliation(s)
- Tatsuya Okuno
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama City, 377-2, Ohno-Higashi, Osaka, 589-8511, Japan.
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Junki Mizusawa
- JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroaki Yanagimoto
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Satoshi Kobayashi
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Hiroshi Imaoka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takeshi Terashima
- Department of Gastroenterology, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
| | - Hisato Kawakami
- Department of Medical Oncology, Faculty of Medicine, Kindai University, Osakasayama City, 377-2, Ohno-Higashi, Osaka, 589-8511, Japan
| | - Yusuke Sano
- JCOG Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Masato Ozaka
- Hepato-Biliary-Pancreatic Medicine Department, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Haruo Miwa
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Akiko Todaka
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Satoshi Shimizu
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Mitsugu Sekimoto
- Department of Surgery, Kansai Medical University Hospital, Osaka, Japan
| | - Keiji Sano
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
| | - Kazutoshi Tobimatsu
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Akio Katanuma
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Kunihito Gotoh
- Department of Surgery, NHO Osaka National Hospital, Osaka, Japan
| | - Hironori Yamaguchi
- Department of Clinical Oncology, Jichi Medical University, Tochigi, Japan
| | - Hiroshi Ishii
- Clinical Research Center, Chiba Cancer Center, Chiba, Japan
| | - Junji Furuse
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
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Nara S, Esaki M, Ban D, Takamoto T, Shimada K, Ioka T, Okusaka T, Ishii H, Furuse J. Adjuvant and neoadjuvant therapy for biliary tract cancer: a review of clinical trials. Jpn J Clin Oncol 2021; 50:1353-1363. [PMID: 33037430 DOI: 10.1093/jjco/hyaa170] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 08/21/2020] [Indexed: 12/14/2022] Open
Abstract
Cancer originating in the biliary tract can be classified as bile duct cancer (cholangiocarcinoma), gallbladder cancer, or ampullary cancer. Bile duct cancer is further divided to intrahepatic, perihilar and distal bile duct subtypes according to the anatomical location of the tumor. The biological characteristics of each tumor are heterogeneous. However, because of the rarity of each disease, the efficacy of new drugs has been tested in groups of patients with different biliary tract cancers. In patients with metastatic or recurrent biliary tract cancer, recent randomized clinical trials revealed the non-inferiority of gemcitabine + S-1 and the superiority of gemcitabine + cisplatin + S-1 compared with gemcitabine + cisplatin in terms of overall survival, thereby establishing a new standard treatment. In the field of adjuvant therapy for biliary tract cancer, the British BILCAP (capecitabine compared with observation in resected biliary tract cancer) study revealed longer median overall survival in the capecitabine group than in the observation group in the per-protocol analysis (but not in the intention-to-treat analysis), bringing a shift toward postoperative management. Several other studies of adjuvant therapy are ongoing, and they may lead to reforms in treatment strategy for resectable biliary tract cancer in the future. The use of neoadjuvant therapy for biliary tract cancer is in its infancy, but it is expected to overcome the limitations of adjuvant therapy for this malignancy. In this review, we summarized the evidence available from clinical trials of adjuvant and neoadjuvant therapy for biliary tract cancer and described ongoing clinical trials.
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Affiliation(s)
- Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Minoru Esaki
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Takeshi Takamoto
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Kazuaki Shimada
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Tatsuya Ioka
- Oncology Center, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami Kogushi Ube-shi, Yamaguchi, 755-8505, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Hiroshi Ishii
- Division of Gastroenterology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba, 260-8717, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
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Fujiwara Y, Kobayashi S, Nagano H, Kanai M, Hatano E, Toyoda M, Ajiki T, Takashima Y, Yoshimura K, Hamada A, Minami H, Ioka T. Pharmacokinetic Study of Adjuvant Gemcitabine Therapy for Biliary Tract Cancer following Major Hepatectomy (KHBO1101). PLoS One 2015; 10:e0143072. [PMID: 26633034 PMCID: PMC4669083 DOI: 10.1371/journal.pone.0143072] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 10/29/2015] [Indexed: 12/19/2022] Open
Abstract
Background Biliary tract cancer (BTC) patients who have undergone surgical resection with major hepatectomy cannot tolerate the standard gemcitabine regimen (1,000 mg/m2 on days 1, 8, and 15 every 4 weeks) due to severe toxicities such as myelosuppression. Our dose-finding study of adjuvant gemcitabine therapy for biliary tract cancer following major hepatectomy determined that the recommended dose is 1,000 mg/m2 on days 1 and 15 every 4 weeks. Here, we evaluate the pharmacokinetics and pharmacodynamics of gemcitabine in these subjects. Methods We evaluated BTC patients scheduled to undergo surgical resection with major hepatectomy followed by gemcitabine therapy. A pharmacokinetic evaluation of gemcitabine and its main metabolite, 2′,2′-difluorodeoxyuridine (dFdU), was conducted at the initial administration of gemcitabine, which was given by intravenous infusion over 30 min at a dose of 800–1,000 mg/m2. Physical examination and adverse events were monitored for 12 weeks. Results Thirteen patients were enrolled from August 2011 to January 2013, with 12 ultimately completing the pharmacokinetic study. Eight patients had hilar cholangiocarcinoma, three had intrahepatic cholangiocarcinoma, and one had superficial spreading type cholangiocarcinoma. The median interval from surgery to first administration of gemcitabine was 65.5 days (range, 43–83 days). We observed the following toxicities: neutropenia (n = 11, 91.7%), leukopenia (n = 10, 83.3%), thrombocytopenia (n = 6, 50.0%), and infection (n = 5, 41.7%). Grade 3 or 4 neutropenia was observed in 25% (n = 3) of patients. There were differences in clearance of gemcitabine and dFdU between our subjects and the subjects who had not undergone hepatectomy. Conclusion Major hepatectomy did not affect the pharmacokinetics of gemcitabine or dFdU. Trial Registration UMIN-CTR in (JPRN) UMIN000005109
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Affiliation(s)
- Yutaka Fujiwara
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
- Department of Experimental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center Hospital, Tokyo, Japan
- * E-mail:
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Masashi Kanai
- Outpatient Oncology Unit, Kyoto University Hospital, Kyoto, Japan
| | - Etsuo Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University Hospital, Kyoto, Japan
| | - Masanori Toyoda
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tetsuo Ajiki
- Department of Surgery, Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yuki Takashima
- Department of Clinical Pharmacology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan
| | - Kenichi Yoshimura
- Innovative Clinical Research Center, Kanazawa University, Kanazawa, Japan
| | - Akinobu Hamada
- Department of Clinical Pharmacology, Fundamental Innovative Oncology Core, National Cancer Center Research Institute, Tokyo, Japan
| | - Hironobu Minami
- Division of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tatsuya Ioka
- Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan
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Sasaki T, Isayama H, Nakai Y, Ito Y, Yasuda I, Toda N, Yagioka H, Matsubara S, Hanada K, Maguchi H, Kamada H, Hasebe O, Mukai T, Okabe Y, Maetani I, Koike K. Treatment outcomes of chemotherapy between unresectable and recurrent biliary tract cancer. World J Gastroenterol 2014; 20:18452-18457. [PMID: 25561816 PMCID: PMC4277986 DOI: 10.3748/wjg.v20.i48.18452] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Revised: 06/09/2014] [Accepted: 07/15/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To evaluate the differences in the treatment outcomes between the unresectable and recurrent biliary tract cancer patients who received chemotherapy. METHODS Patients who were treated with gemcitabine and S-1 combination therapy in the previous prospective studies were divided into groups of unresectable and recurrent cases. The tumor response, time-to-progression, overall survival, toxicity, and dose intensity were compared between these two groups. RESULTS Response rate of the recurrent group was higher than that of the unresectable group (40.0% vs 25.5%; P = 0.34). Median time-to-progression of the recurrent and unresectable groups were 8.7 mo (95%CI), 1.2 mo, not reached) and 5.7 mo (95%CI: 4.0-7.0 mo), respectively (P = 0.14). Median overall survival of the recurrent and the unresectable groups were 16.1 mo (95%CI: 2.0 mo-not reached) and 9.6 mo (95%CI: 7.1-11.7 mo), respectively (P = 0.10). Dose intensities were significantly lower in the recurrent groups (gemcitabine: recurrent group 83.5% vs unresectable group 96.8%; P < 0.01, S-1: Recurrent group 75.9% vs unresectable group 91.8%; P < 0.01). Neutropenia occurred more frequently in recurrent group (recurrent group 90% vs unresectable group 55%; P = 0.04). CONCLUSION Not only the efficacy but also the toxicity and dose intensity were significantly different between unresectable and recurrent biliary tract cancer.
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