|
1
|
Booka E, Imamura CK, Takeuchi M, Kawakubo H, Takeuchi H, Tanigawara Y, Kitagawa Y, Boku N. Evaluation of clinical validity of an S-1 dosage formula based on renal function using data of the SPIRITS and the G-SOX trials. Gastric Cancer 2022; 25:770-782. [PMID: 35357635 DOI: 10.1007/s10120-022-01291-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The aim of this study was to evaluate clinical validity of the S-1 dosage formula based on body surface area (BSA) and creatinine clearance (CLcr) to achieve the target area under the concentration-time curve of 5-FU, which we had developed and refined in each prospective pharmacokinetic study. METHODS The recommended dose determined by the refined formula was assessed using data of the SPIRITS (S-1 vs. S-1 plus cisplatin [SP]) and the G-SOX (SP vs. S-1 plus oxaliplatin [SOX]) trials. Nine hundred and thirty-eight patients in these trials were classified into three groups according to their actual S-1 starting doses compared with the recommended doses (under-dosed, <recommended dose; equal-dosed, =recommended dose; over-dosed, >recommended dose). RESULTS The patients in the under-dosed group in both trials showed similar tendencies: male, younger, higher BSA, and higher CLcr. The incidence of any grade neutropenia was significantly greater in the over-dosed group compared with the equal-dosed group in the S-1 and the SOX arms. The hazard ratios (HR) of overall survival (OS) (under-dosed vs. equal-dosed) were 1.361 (S-1 arm), 1.259 (SP arm) in the SPIRITS trial, and 1.381 (SOX arm), 0.999 (SP arm) in the G-SOX trial. Multivariate analysis in all the patients demonstrated that OS of the over-dosed group was equivalent (HR 1.002, 95% confidence interval [CI] 0.850-1.182, p = 0.980) and that of the under-dosed group was inferior (HR 1.267, 95% CI 1.005-1.597, p = 0.045) to the equal-dosed group. CONCLUSIONS It is suggested that the refined S-1 dosage formula can recommend optimal dose in terms of safety and efficacy.
Collapse
Affiliation(s)
- Eisuke Booka
- Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Chiyo K Imamura
- Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
| | - Masashi Takeuchi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yusuke Tanigawara
- Laboratory of Pharmacometrics and Systems Pharmacology, Keio Frontier Research & Education Collaborative Square at Tonomachi, Keio University, Kanagawa, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Narikazu Boku
- Department of Medical Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, University of Tokyo, 4-6-1Minato-ku, Shiroganedai, Tokyo, 108-8639, Japan.
| |
Collapse
|
|
2
|
Anaka M, Abdel-Rahman O. Managing 5FU Cardiotoxicity in Colorectal Cancer Treatment. Cancer Manag Res 2022; 14:273-285. [PMID: 35115827 PMCID: PMC8799936 DOI: 10.2147/cmar.s273544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Accepted: 01/11/2022] [Indexed: 11/28/2022] Open
Abstract
Fluorouracil (5FU) is the backbone chemotherapy agent in the treatment of colorectal cancer (CRC). Cardiotoxicity represents an uncommon but serious side effect of treatment with 5FU. Here, we review the current literature on 5FU-cardiotoxicity in the setting of CRC specifically, with a focus on data from the modern era of combination chemotherapy. Despite decades of study, there is little consensus on risk factors and biomarkers for 5FU-cardiotoxicity, nor how patients with CRC should be managed following a cardiotoxicity event. Given the elevated risk of recurrent cardiotoxicity on rechallenge, the use of alternative regimens that do not contain 5FU is a critical aspect of management. Data on the cardiotoxicity risk and efficacy of non-5FU regimens in CRC are therefore reviewed in detail.
Collapse
Affiliation(s)
- Matthew Anaka
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
| | - Omar Abdel-Rahman
- Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB, Canada
- Correspondence: Omar Abdel-Rahman, Department of Oncology, Cross Cancer Institute, University of Alberta, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada, Tel +1 780-432-8290, Fax +1 780-432-8888, Email
| |
Collapse
|
|
3
|
Hironaka S, Sadachi R, Machida N, Iwasa S, Yamada Y, Sasako M, Yoshikawa T, Boku N, Terashima M. Association of renal function with the safety and efficacy of cisplatin plus S-1 therapy and docetaxel plus cisplatin plus S-1 therapy in patients with advanced gastric cancer: an exploratory analysis of JCOG1013. Jpn J Clin Oncol 2021; 52:14-23. [PMID: 34668562 DOI: 10.1093/jjco/hyab160] [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: 04/25/2021] [Accepted: 09/28/2021] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Although cisplatin and 5-chloro-2,4-dihydropyrimidine (dihydropyrimidine dehydrogenase inhibitor contained in S-1) are excreted into the urine, it remains unknown how creatinine clearance (CrCl) affects the safety and efficacy of cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 in patients with advanced gastric cancer. METHODS Among the 741 participants in JCOG1013 comparing cisplatin plus S-1 with docetaxel plus cisplatin plus S-1, 723 with serum creatinine levels ≤1.2 mg/dL were categorized into A1 (CrCl ≥ 80 mL/min), A2 (60 ≤ CrCl <80) and A3 (CrCl < 60) in the cisplatin plus S-1 arm and similarly B1, B2 and B3 in the docetaxel plus cisplatin plus S-1 arm. The initial dose modification by CrCl was pre-specified in the docetaxel plus cisplatin plus S-1 arm but not in the cisplatin plus S-1 arm. RESULTS The numbers of patients categorized as A1/A2/A3 and B1/B2/B3 were 169/136/57 and 170/138/53, respectively. In the cisplatin plus S-1 arm, a lower CrCl was associated with higher incidences of grade 4 leukopenia (P = 0.006), neutropenia (P = 0.002), and grade 3/4 anorexia (P = 0.004) and febrile neutropenia (P = 0.049), whereas there was no association in the docetaxel plus cisplatin plus S-1 arm. No significant differences were observed according to CrCl in the overall survival [median: 15.4/15.5/15.4 months in A1/A2/A3 (P = 0.886) and 15.3/13.7/13.7 months in B1/B2/B3 (P = 0.719)], progression-free survival [median: 7.1/6.8/6.2 months in A1/A2/A3 (P = 0.884) and 7.5/7.2/7.8 months in B1/B2/B3 (P = 0.851)] and response rates [58.9/57.8/46.9% in A1/A2/A3 (P = 0.311) and 62.0/61.5/51.5% in B1/B2/B3 (P = 0.362)]. CONCLUSIONS Renal impairment was associated with severe adverse events in cisplatin plus S-1 therapy but not with the efficacy in cisplatin plus S-1 and docetaxel plus cisplatin plus S-1 therapy.
Collapse
Affiliation(s)
- Shuichi Hironaka
- Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Yufu, Japan
| | - Ryo Sadachi
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo, Japan
| | - Nozomu Machida
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Satoru Iwasa
- Division of Gastrointestinal Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan
| | - Yasuhide Yamada
- Comprehensive Cancer Center, National Center for Global Health and Medicine, Tokyo, Japan.,Department of Medical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mitsuru Sasako
- Department of Surgery, Yodogawa Christian Hospital, Osaka, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Narikazu Boku
- Division of Gastrointestinal Medical Oncology, National Cancer Centre Hospital, Tokyo, Japan
| | | |
Collapse
|
|
4
|
Kawakami K, Aoyama T, Yokokawa T, Kobayashi K, Takahari D, Chin K, Ide T, Machida Y, Yamaguchi K, Hama T. The Combined Use of 5 or More Drugs Is a Factor Related to Lower Adherence to S-1 in S-1 and Oxaliplatin Treatment for Advanced Gastric Cancer. Biol Pharm Bull 2021; 44:1075-1080. [PMID: 34334492 DOI: 10.1248/bpb.b21-00184] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
S-1 plus oxaliplatin (SOX) is an established treatment for advanced gastric cancer. S-1 adherence is the key to successful SOX treatment. This study focused on S-1 adherence by evaluating real-world adherence to S-1 and investigating factors related to decreased S-1 adherence. This study included cases treated between August 1, 2014 and October 12, 2016 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. The S-1 adherence rate per cycle was defined as the number of times a patient took S-1/28. In this study, adherence to S-1 was assessed through pill counts and by asking the patient about the reason for non-adherence at a pharmaceutical outpatient clinic. Univariate and multivariate analyses were performed to investigate factors influencing lower adherence. This analysis included 116 patients evaluated for adherence to S-1 on SOX treatment. The median rate of adherence to S-1 was 92.8% in the first cycle and 90.5% in the seventh cycle. The median relative dose intensity of S-1 was 84.6%. In terms of reasons for nonadherence, patients most commonly cited nausea/vomiting (43.7%), diarrhea (20.8%), missed dose (11.8%), and fever (8.1%). Logistic regression analysis was performed using the most appropriate regression equation, and a significant association was detected with 1 factor, number of combined drugs ≥5 (odds ratio (OR) = 2.50; 95% confidence interval (CI), 1.04-6.03, p = 0.04). Eliminating unnecessary concomitant medications helps maintain proper adherence to S-1 in SOX treatment.
Collapse
Affiliation(s)
- Kazuyoshi Kawakami
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Takeshi Aoyama
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Takashi Yokokawa
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Kazuo Kobayashi
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Daisuke Takahari
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Keisho Chin
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Tsugumi Ide
- Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences
| | - Yoshiaki Machida
- Section for Practical Education, Hoshi University School of Pharmacy and Pharmaceutical Sciences
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| | - Toshihiro Hama
- Department of Pharmacy, Cancer Institute Hospital, Japanese Foundation for Cancer Research
| |
Collapse
|
|
5
|
Kobayashi S, Ueno M, Ogawa G, Fukutomi A, Ikeda M, Okusaka T, Sato T, Ito Y, Kadota T, Ioka T, Sugimori K, Sata N, Nakamori S, Shimizu K, Mizuno N, Ishii H, Furuse J. Impact of Renal Function on S-1 + Radiotherapy for Locally Advanced Pancreatic Cancer: An Integrated Analysis of Data From 2 Clinical Trials. Pancreas 2021; 50:965-971. [PMID: 34629456 DOI: 10.1097/mpa.0000000000001879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
OBJECTIVES S-1 monotherapy with concurrent radiotherapy (RT) is a standard of care for patients with locally advanced pancreatic cancer (LAPC). Although renal dysfunction increases S-1 monotherapy toxicity, its effect in S-1 with concurrent RT remains unknown. We evaluated the effect of renal function on the safety of S-1 with RT for LAPC. METHODS We performed an integrated exploratory post hoc analysis of data from 2 prospective studies (JCOG1106 and LAPC-S1RT), where patients with LAPC received RT (50.4 Gy/28 fraction for 5.5 weeks) and concurrent S-1 (40 mg/m2 per dose, twice daily on the day of irradiation). We split the patients into high creatinine clearance (CCr; ≥80 mL/min) and low CCr (<80 mL/min) groups and compared the findings to determine treatment safety. RESULTS The high and low CCr groups showed a median of 97.5 (range, 80.0-194.6) and 64.4 (range, 50.0-78.3) mL/min, respectively. The low CCr group presented more adverse reactions (ARs) of grade 3 or higher and gastrointestinal ARs of grade 2 or higher than the high CCr group (30.8% vs 15.8% and 51.9% vs 36.8%). CONCLUSIONS The incidence of ARs associated with concurrent S-1 and RT increases in patients with low CCr; therefore, ARs should be duly considered in such patients.
Collapse
Affiliation(s)
- Satoshi Kobayashi
- From the Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama City
| | - Makoto Ueno
- From the Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama City
| | - Gakuto Ogawa
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo
| | - Akira Fukutomi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo
| | - Tosiya Sato
- Department of Biostatistics, Kyoto University School of Public Health, Kyoto City
| | - Yoshinori Ito
- Department of Radiation Oncology, Showa University School of Medicine, Shinagawa City
| | - Tomohiro Kadota
- Japan Clinical Oncology Group Data Center/Operations Office, National Cancer Center Hospital, Tokyo
| | - Tatsuya Ioka
- Department of Cancer Survey and Gastrointestinal Oncology, Osaka International Cancer Center, Osaka City
| | - Kazuya Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama City
| | - Naohiro Sata
- Department of Surgery, Jichi Medical University, Simono City
| | - Shoji Nakamori
- Department of Hepatobiliary and Pancreatic Surgery, Osaka National Hospital, Osaka City
| | - Kyoko Shimizu
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, Tokyo
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya City
| | - Hiroshi Ishii
- Gastrointestinal Medical Oncology, Chiba Cancer Center, Chiba City
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka City, Japan
| |
Collapse
|
|
6
|
Ueno M, Morizane C, Okusaka T, Mizusawa J, Kataoka T, Ikeda M, Ozaka M, Okano N, Sugimori K, Todaka A, Shimizu S, Mizuno N, Yamamoto T, Sano K, Tobimatsu K, Katanuma A, Miyamoto A, Yamaguchi H, Nishina T, Shirakawa H, Kojima Y, Oono T, Kawamoto Y, Furukawa M, Iwai T, Sudo K, Miyakawa H, Yamashita T, Yasuda I, Takahashi H, Kato N, Shioji K, Shimizu K, Nakagohri T, Kamata K, Ishii H, Furuse J. Comparison of gemcitabine-based chemotherapies for advanced biliary tract cancers by renal function: an exploratory analysis of JCOG1113. Sci Rep 2021; 11:12885. [PMID: 34145336 PMCID: PMC8213853 DOI: 10.1038/s41598-021-92166-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 06/07/2021] [Indexed: 11/23/2022] Open
Abstract
JCOG1113 is a randomized phase III trial in patients with advanced biliary tract cancers (BTCs) (UMIN000001685), and gemcitabine plus S-1 (GS) was not inferior to gemcitabine plus cisplatin (GC). However, poor renal function often results in high toxicity of S-1. Therefore, we examined whether GS can be recommended for patients with low creatinine clearance (CCr). Renal function was classified by CCr as calculated by the Cockcroft-Gault formula: high CCr (CCr ≥ 80 ml/min) and low CCr (80 > CCr ≥ 50 ml/min). Of 354 patients, 87 patients on GC and 91 on GS were included in the low CCr group, while there were 88 patients on GC and 88 patients on GS in the high CCr group. The HR of overall survival for GS compared with GC was 0.687 (95% CI 0.504–0.937) in the low CCr group. Although the total number of incidences of all Grade 3–4 non-haematological adverse reactions was higher (36.0% vs. 11.8%, p = 0.0002), the number of patients who discontinued treatment was not different (14.1% vs. 16.9%, p = 0.679) for GS compared with GC in the low CCr group. This study suggests that GS should be selected for the treatment of advanced BTC patients with reduced renal function.
Collapse
Affiliation(s)
- Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, 2-3-2 Nakao, Asahi ku, Yokohama, 241-0815, Japan.
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Junki Mizusawa
- Japan Clinical Oncology Group/Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Tomoko Kataoka
- Japan Clinical Oncology Group/Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
| | - Masato Ozaka
- Hepato-Biliary-Pancreatic Medicine Department, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan
| | - Kazuya Sugimori
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Akiko Todaka
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Sunto-Gun, Shizuoka, Japan
| | - Satoshi Shimizu
- Department of Gastroenterology, Saitama Cancer Center, Kita-Adachi-Gun, Saitama, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Tomohisa Yamamoto
- Department of Surgery, Kansai Medical University Hospital, Hirakata, Osaka, Japan
| | - Keiji Sano
- Department of Surgery, Teikyo University School of Medicine, Itabashi-ku, 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
| | - Atsushi Miyamoto
- Department of Hepatobiliary and Pancreatic Surgery, Osaka National Hospital, Osaka, Japan
| | - Hironori Yamaguchi
- Department of Surgery, Jichi Medical University, Shimono, Tochigi, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Ehime, Japan
| | - Hirofumi Shirakawa
- Department of Medical Oncology, Tochigi Cancer Center, Utsunomiya, Tochigi, Japan
| | - Yasushi Kojima
- Department of Gastroenterology, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan
| | - Takamasa Oono
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuyuki Kawamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Masayuki Furukawa
- Department of Hepato-Biliary-Pancreatology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Tomohisa Iwai
- Department of Gastroenterology, Kitasato University Hospital, Sagamihara, Kanagawa, Japan
| | - Kentaro Sudo
- Gastrointestinal Medical Oncology, Chiba Cancer Center, Chiba, Japan
| | - Hiroyuki Miyakawa
- Department of Bilio-Pancreatology, Sapporo-Kosei General Hospital, Sapporo, Japan
| | - Tatsuya Yamashita
- Department of Gastroenterology, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Ichirou Yasuda
- Department of Gastroenterology and Hematology, Faculty of Medicine, University of Toyama, Toyama, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Naoya Kato
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kazuhiko Shioji
- Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan
| | - Kyoko Shimizu
- Department of Gastroenterology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan
| | - Toshio Nakagohri
- Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Kanagawa, Japan
| | - Ken Kamata
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osakasayama, Osaka, Japan
| | - Hiroshi Ishii
- Gastrointestinal Medical Oncology, Chiba Cancer Center, Chiba, Japan
| | - Junji Furuse
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Mitaka, Tokyo, Japan
| | | |
Collapse
|
|
7
|
Takeuchi M, Imamura CK, Booka E, Takeuchi H, Mizukami T, Kawakami T, Funakoshi T, Wakuda K, Aoki Y, Hamamoto Y, Kitago M, Kawakubo H, Boku N, Tanigawara Y, Kitagawa Y. Prospective evaluation and refinement of an S-1 dosage formula based on renal function for clinical application. Cancer Sci 2021; 112:751-759. [PMID: 33277781 PMCID: PMC7894007 DOI: 10.1111/cas.14758] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 12/27/2022] Open
Abstract
In patients with impaired renal function, S-1-related toxicities increase due to higher exposure of 5-fluorouracil (5-FU). Our previous pharmacokinetic study in 16 cancer patients with various renal functions developed an S-1 dosage formula based on individual creatinine clearance (CLcr) and body surface area (BSA). To evaluate and refine the formula, this prospective study was conducted. Thirty-three patients with various renal functions received S-1 for 4 weeks at doses determined by the nomogram derived from the previously developed formula. A series of blood samples were collected after the first dose to calculate the area under the concentration-time curve (AUC) of 5-FU. Thirty patients with BSA of 1.14-1.84 m2 and CLcr of 23.8-96.4 mL/min were assessable for pharmacokinetics. The observed daily AUC ranged from 712.6 to 2868.7 ng·h/mL, and 18 patients achieved the target AUC (1447.8 ± 545.4 ng·h/mL). Three patients experienced S-1-related grade 3 adverse events during the first course. In the population pharmacokinetic analysis from the combined data of 46 patients in this study and the previous study, sex was identified as a statistically significant covariate for 5-FU clearance. Hence, the refined formula includes sex as an additional factor: Recommended daily dose = target AUC × (14.5 + 8.23 × SEX [0 for female and 1 for male] + 0.301 × CLcr) × BSA. Revised nomograms for recommended daily doses derived from the refined formula can be used in clinical practice to achieve the target AUC ensuring efficacy and safety of S-1.
Collapse
Affiliation(s)
- Masashi Takeuchi
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Chiyo K Imamura
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan.,Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan
| | - Eisuke Booka
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan.,Department of Surgery, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Japan
| | - Hiroya Takeuchi
- Department of Surgery, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takuro Mizukami
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kanagawa, Japan
| | - Takeshi Kawakami
- Department of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Taro Funakoshi
- Department of Therapeutic Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazushige Wakuda
- Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yu Aoki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yasuo Hamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Minoru Kitago
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Hirofumi Kawakubo
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| | - Narikazu Boku
- Department of Gastrointestinal Medical Oncology, National Cancer Center, Tokyo, Japan
| | - Yusuke Tanigawara
- Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, Tokyo, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
8
|
5-FU induced cardiotoxicity: case series and review of the literature. CARDIO-ONCOLOGY 2019; 5:13. [PMID: 32154019 PMCID: PMC7048125 DOI: 10.1186/s40959-019-0048-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022]
Abstract
Background 5-Fluorouracil (5-FU) is an antimetabolite chemotherapy used for a variety of solid tumors. It has the potential to cause a wide spectrum of cardiotoxicity, ranging from asymptomatic electrocardiographic changes to cardiomyopathy and subsequent cardiac failure. Main body of the abstract: We present two descriptive cases of new-onset severe cardiomyopathy induced by 5-FU followed by a review of the literature. Conclusion Our case series emphasizes the importance of early recognition of this rare complication and prompt cessation of 5-FU, as cardiac dysfunction in this context is potentially reversible.
Collapse
|
|
9
|
Goto K, Fujiwara Y, Isobe T, Chayahara N, Kiyota N, Mukohara T, Tsubata Y, Hotta T, Tamura K, Yamamoto N, Minami H. Pharmacokinetic study of the oral fluorouracil antitumor agent S-1 in patients with impaired renal function. Cancer Sci 2019; 110:1987-1994. [PMID: 30989775 PMCID: PMC6550132 DOI: 10.1111/cas.14025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 03/11/2019] [Accepted: 03/28/2019] [Indexed: 11/27/2022] Open
Abstract
Although dose reduction of S-1 is recommended for patients with impaired renal function, dose modification for such patients has not been prospectively evaluated. The aim of the present study was to investigate the pharmacokinetic parameters of 5-fluorouracil, 5-chloro-2,4 dihydroxypyridine and oteracil potassium, and to review the recommended dose modification of S-1 in patients with renal impairment. We classified patients receiving S-1 into 4 groups according to their renal function, as measured using the Japanese estimated glomerular filtration rate (eGFR) equation. The daily S-1 dose was adjusted based on the patient's eGFR and body surface area. Blood samples were collected for pharmacokinetic analysis. A total of 33 patients were enrolled and classified into 4 groups as follows: 10 patients in cohort 1 (eGFR ≥ 80 mL/min/1.73 m2 ), 10 patients in cohort 2 (eGFR = 50-79 mL/min/1.73 m2 ), 10 patients in cohort 3 (eGFR = 30-49 mL/min/1.73 m2 ), and 3 patients in cohort 4 (eGFR < 30 mL/min/1.73 m2 ). Those in cohorts 3 and 4 treated with an adjusted dose of S-1 showed a similar area under the curve for 5-fluorouracil (941.9 ± 275.6 and 1043.5 ± 224.8 ng/mL, respectively) compared with cohort 2 (1034.9 ± 414.3 ng/mL). Notably, while there was a statistically significant difference between cohort 1 (689.6 ± 208.8 ng/mL) and 2 (P = 0.0474) treated with an equal dose of S-1, there was no significant difference observed in the toxicity profiles of the cohorts. In conclusion, dose adjustment of S-1 in patients with impaired renal function using eGFR is appropriate and safe.
Collapse
Affiliation(s)
- Keiko Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yutaka Fujiwara
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Experimental Therapeutics, National Cancer Center Hospital, Shimane, Tokyo.,Division of Respiratory Medicine, Mitsui Memorial Hospital, Tokyo, Japan
| | - Takeshi Isobe
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Naoko Chayahara
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Naomi Kiyota
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toru Mukohara
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan.,Department of Breast and Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yukari Tsubata
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Takamasa Hotta
- Division of Medical Oncology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Shimane University, Shimane, Japan
| | - Kenji Tamura
- Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Noboru Yamamoto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan.,Department of Experimental Therapeutics, National Cancer Center Hospital, Shimane, Tokyo
| | - Hironobu Minami
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Japan
| |
Collapse
|
|
10
|
Sara JD, Kaur J, Khodadadi R, Rehman M, Lobo R, Chakrabarti S, Herrmann J, Lerman A, Grothey A. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol 2018; 10:1758835918780140. [PMID: 29977352 PMCID: PMC6024329 DOI: 10.1177/1758835918780140] [Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 04/25/2018] [Indexed: 12/15/2022] Open
Abstract
Fluoropyrimidines such as 5-fluorouracil (5-FU) form the foundation of a wide variety of chemotherapy regimens. 5-FU is in fact the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. As with all chemotherapy, balancing the potential benefits of therapy against the risks of drug-related toxicity is crucial when clinicians and patients make shared decisions about treatment. 5-FU is the second most common chemotherapeutic drug associated with cardiotoxicity after anthracyclines, which can manifest as chest pain, acute coronary syndrome/myocardial infarction or death. Nevertheless a widespread appreciation of 5-FU-related cardiotoxicity and its implications is lacking amongst clinicians. In this review, we outline the incidence, possible risk factors, and likely pathophysiological mechanisms that may account for 5-FU-related cardiotoxicity and also highlight potential management strategies for this poorly understood clinical entity.
Collapse
Affiliation(s)
- Jaskanwal D Sara
- Department of Cardiovascular Diseases, Mayo College of Medicine, 200 First Street SW, Rochester, MN 55905-0001, USA
| | - Jasvinder Kaur
- Kent Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Maidstone, Kent, UK
| | - Ryan Khodadadi
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Muneeb Rehman
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Ronstan Lobo
- Department of Internal Medicine, Mayo College of Medicine, Rochester, MN, USA
| | - Sakti Chakrabarti
- Department of Medical Oncology, Mayo College of Medicine, Rochester, MN, USA
| | - Joerg Herrmann
- Department of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN, USA
| | - Amir Lerman
- Department of Cardiovascular Diseases, Mayo College of Medicine, Rochester, MN, USA
| | - Axel Grothey
- Department of Medical Oncology, Mayo College of Medicine, Rochester, MN, USA
| |
Collapse
|
|
11
|
Harada K, Ferdous T, Ueyama Y. Therapeutic strategies with oral fluoropyrimidine anticancer agent, S-1 against oral cancer. JAPANESE DENTAL SCIENCE REVIEW 2017; 53:61-77. [PMID: 28725297 PMCID: PMC5501734 DOI: 10.1016/j.jdsr.2016.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Revised: 10/21/2016] [Accepted: 11/07/2016] [Indexed: 02/06/2023] Open
Abstract
Oral cancer has been recognized as a tumor with low sensitivity to anticancer agents. However, introduction of S-1, an oral cancer agent is improving treatment outcome for patients with oral cancer. In addition, S-1, as a main drug for oral cancer treatment in Japan can be easily available for outpatients. In fact, S-1 exerts high therapeutic effects with acceptable side effects. Moreover, combined chemotherapy with S-1 shows higher efficacy than S-1 alone, and combined chemo-radiotherapy with S-1 exerts remarkable therapeutic effects. Furthermore, we should consider the combined therapy of S-1 and molecular targeting agents right now as these combinations were reportedly useful for oral cancer treatment. Here, we describe our findings related to S-1 that were obtained experimentally and clinically, and favorable therapeutic strategies with S-1 against oral cancer with bibliographic considerations.
Collapse
Affiliation(s)
- Koji Harada
- Department of Oral and Maxillofacial Surgery, Yamaguchi University Graduate School of Medicine, 1-1-1, Minamikogushi, Ube 755-8505, Japan
| | | | | |
Collapse
|
|
12
|
Kudo M, Moriguchi M, Numata K, Hidaka H, Tanaka H, Ikeda M, Kawazoe S, Ohkawa S, Sato Y, Kaneko S, Furuse J, Takeuchi M, Fang X, Date Y, Takeuchi M, Okusaka T. S-1 versus placebo in patients with sorafenib-refractory advanced hepatocellular carcinoma (S-CUBE): a randomised, double-blind, multicentre, phase 3 trial. Lancet Gastroenterol Hepatol 2017; 2:407-417. [PMID: 28497756 DOI: 10.1016/s2468-1253(17)30072-9] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Revised: 02/21/2017] [Accepted: 02/21/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Unresectable advanced hepatocellular carcinoma is a heterogeneous disease, for which sorafenib is the first targeted agent approved for first-line therapy, and treatment options for patients with sorafenib-refractory advanced hepatocellular carcinoma are limited. We assessed the efficacy and safety of S-1, a chemotherapeutic agent based on fluorouracil, in patients with sorafenib-refractory advanced hepatocellular carcinoma. METHODS We did a randomised, double-blind, placebo-controlled, phase 3 study done at 57 sites in Japan. Patients with advanced hepatocellular carcinoma who were ineligible for surgical or local-regional therapy and judged refractory to sorafenib (ie, had progressed on sorafenib or had discontinued sorafenib because of adverse events) were randomly assigned (2:1) to receive oral S-1 (weight-banded 80 mg/m2 [80-120 mg per day]), or placebo, twice per day for 28 days consecutively, followed by a minimum 14 day drug-free period. This cycle was repeated until disease progression or the patient became intolerant to the study treatment. Patients were stratified by site and presence or absence of extrahepatic metastasis or vascular invasion. The primary endpoint was overall survival, assessed in the full analysis set (ie, all patients who were treated with study drug except any individuals who were found not to have hepatocellular carcinoma or who were found to have active double cancer). Patients, medical staff, investigators, and the sponsor were masked to treatment assignment. Blinding was maintained even after study treatment concluded. This study is registered with JapicCTI, number JapicCTI-090920, and has been completed. FINDINGS Between Oct 26, 2009, and Aug 22, 2012, we screened 399 patients. 65 patients were excluded due to not meeting criteria (n=61), declining to participate (n=3), or other reasons (n=1). 334 patients were randomly assigned to receive either S-1 (n=223) or placebo (n=111). One patient in the S-1 group did not receive treatment, and was thus excluded from analyses. At data cutoff, median follow-up was 32·4 months (IQR 24·0-34·7) in the S-1 group and 32·9 months (23·7-39·5) in the placebo group. Median overall survival was 11·1 months (95% CI 9·7-13·1) in the S-1 group and 11·2 months (9·2-12·8) in the placebo group (hazard ratio 0·86, 95% CI 0·67-1·10; p=0·220). The most frequently reported adverse events were skin hyperpigmentation (123 [55%] of 222 patients in the S-1 group vs nine [8%] of 111 patients in the placebo group), decreased appetite (104 [47%] vs 21 [19%]), fatigue (102 [46%] vs 20 [18%]), diarrhoea (77 [35%] vs 14 [13%]), and increased blood bilirubin (77 [35%] vs 14 [13%]). Serious adverse events were reported in 90 (41%) of 222 patients in the S-1 group and 24 (22%) of 111 patients in the placebo group. Five treatment-related deaths were reported in the S-1 group. INTERPRETATION S-1 did not prolong overall survival in patients with sorafenib-refractory advanced hepatocellular carcinoma. Further research is needed to identify subgroups of patients who might benefit from S-1. FUNDING Taiho Pharmaceuticals.
Collapse
Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine, Osaka, Japan.
| | - Michihisa Moriguchi
- Department of Gastroenterology, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Diagnostic Radiology, Shizuoka Cancer Center Hospital, Shizuoka, Japan
| | - Kazushi Numata
- Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Hisashi Hidaka
- Department of Gastroenterology, Kitasato University Hospital, Kanagawa, Japan
| | - Hironori Tanaka
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan; Department of Gastroenterology and Hepatology, Takarazuka Municipal Hospital, Hyogo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Seiji Kawazoe
- Department of Internal Medicine, Saga-ken Medical Centre KOSEIKAN, Saga, Japan
| | - Shinichi Ohkawa
- Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Yokohama, Japan
| | - Yozo Sato
- Department of Diagnostic and Interventional Radiology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Hospital, Ishikawa, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan
| | | | - Xuemin Fang
- Department of Clinical Medicine, Kitasato University School of Pharmacy, Tokyo, Japan
| | | | - Masahiro Takeuchi
- Department of Clinical Medicine, Kitasato University School of Pharmacy, Tokyo, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| |
Collapse
|
|
13
|
Mahlberg R, Lorenzen S, Thuss-Patience P, Heinemann V, Pfeiffer P, Möhler M. New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin. Chemotherapy 2016; 62:62-70. [PMID: 27643822 DOI: 10.1159/000443984] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 01/12/2016] [Indexed: 11/19/2022]
Abstract
Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events. Pharmacokinetic studies showed differences in Asian and Caucasian patients; therefore, a new non-Asian study program was initiated, which led to the pivotal phase 3 trial First-Line Advanced Gastric Cancer Study (FLAGS). In FLAGS, 1,053 patients with advanced gastric cancer from 24 non-Asian countries were enrolled. S-1 plus cisplatin showed no overall survival (OS) benefit when compared to 5-FU plus cisplatin. The primary endpoint superior OS was not met but better tolerability was shown. A post hoc noninferiority OS and safety analysis showed that S-1 plus cisplatin has the same efficacy as 5-FU plus cisplatin but a more favorable safety profile. This led to the approval of S-1 in combination with cisplatin in gastric cancer in Europe in 2011. This article reviews the mode of action of S-1, pivotal study results from an EU point of view, and future perspectives.
Collapse
Affiliation(s)
- Rolf Mahlberg
- First Department of Medicine, Mutterhaus der Borromäerinnen, Trier, Germany
| | | | | | | | | | | |
Collapse
|
|
14
|
Kasai T, Nakamura Y, Fukuda M, Kitazaki T, Nagashima S, Takatani H, Nakano H, Nakatomi K, Ikeda T, Yamaguchi H, Tsukamoto K, Oka M, Kohno S. A Phase II Study of S-1 for Previously Untreated Elderly Patients with Advanced Non-Small Cell Lung Cancer. Chemotherapy 2015; 61:93-8. [PMID: 26606381 DOI: 10.1159/000441486] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Accepted: 10/05/2015] [Indexed: 11/19/2022]
Abstract
BACKGROUND S-1, a novel oral fluoropyrimidine, is active in the treatment of non-small cell lung cancer (NSCLC). However, data on S-1 for elderly patients with NSCLC are insufficient. METHODS Eligibility criteria were no prior chemotherapy, stage IIIB or IV NSCLC, performance status 0-1, age >70 years, and adequate hematological, hepatic, and renal functions. Patients received S-1 (40 mg/m(2) twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. The primary end point was the tumor response rate. RESULTS Thirty-two patients were enrolled and 31 patients were evaluable for response. The patients' median age was 80 years (range: 71-88). The response rate was 22.6% (95% CI: 11-38). Neutropenia, anemia, thrombocytopenia, febrile neutropenia, and diarrhea of grade ≥ 3 occurred in 6, 6, 10, 3, and 3%, respectively. CONCLUSIONS In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity.
Collapse
|
|
15
|
Chua C, Tan IB, Yamada Y, Rha SY, Yong WP, Ong WS, Tham CK, Ng M, Tai DWM, Iwasa S, Lim HY, Choo SP. Phase II study of trastuzumab in combination with S-1 and cisplatin in the first-line treatment of human epidermal growth factor receptor HER2-positive advanced gastric cancer. Cancer Chemother Pharmacol 2015; 76:397-408. [PMID: 26099969 DOI: 10.1007/s00280-015-2811-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 06/13/2015] [Indexed: 12/13/2022]
Abstract
PURPOSE The use of trastuzumab, a monoclonal antibody targeting the HER2 protein, in combination with 5-fluorouracil/platinum-based chemotherapy improves survival in patients with HER2-positive advanced gastric cancer. In addition, TS-one (S-1)/platinum is also used as a standard of care in Asian countries. However, little is known about the combination of S-1/cisplatin chemotherapy and trastuzumab in patients with HER2-positive advanced gastric/gastroesophageal junction (GEJ) cancer. METHODS We conducted a single-arm, two-stage, open-label, multicenter phase II study. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 mg/kg and 6 mg/kg on day 1 of subsequent cycles. Cisplatin was administered intravenously at 60 mg/m(2) on day 1 of each cycle after trastuzumab. S-1 was administered orally [based on body surface area (BSA)] twice a day for 14 days in a 3-weekly cycle. Patients with BSA of <1.25 received a total of 80 mg of S-1, those with BSA ≥1.5 received 120 mg, and the remaining received 100 mg daily in two divided doses. RESULTS All evaluable patients experienced tumor reduction during the trial. The primary end point (overall survival rate) was 59.3 %, with a clinical benefit rate of 66.7 %. Median progression-free survival was 7.4 months; 62.6 % patients were free from disease progression at 6 months. Median overall survival was 14.6 months, and the median time to treatment failure was 6.0 months. CONCLUSION The combination of trastuzumab with S-1 and cisplatin demonstrated good activity, was generally well tolerated, and is a feasible treatment option in the first-line treatment of HER2-positive advanced gastric/GEJ cancers.
Collapse
Affiliation(s)
- Clarinda Chua
- Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
16
|
Survival prolongation after treatment failure of first-line chemotherapy in patients with advanced gastric cancer: combined analysis of the Japan Clinical Oncology group trials JCOG9205 and JCOG9912. Gastric Cancer 2015; 17:522-8. [PMID: 24162387 DOI: 10.1007/s10120-013-0309-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Accepted: 09/26/2013] [Indexed: 02/07/2023]
Abstract
BACKGROUND Two randomized phase III trials of first-line chemotherapy for advanced gastric cancer (JCOG9205 and JCOG9912) conducted by the Japan Clinical Oncology Group used 5-fluorouracil continuous infusion (5-FUci) as the control arm. New active agents (e.g., S-1, irinotecan, and taxanes) were introduced as second-line chemotherapy in the late 1990s after JCOG9205. This combined analysis evaluated whether patients in the 5-FUci arm of JCOG9912 exhibited better survival after adjusting for baseline factors and also investigated the cause of survival prolongation. PATIENTS AND METHODS The subjects were patients assigned to the 5-FUci arms who met the eligibility criteria of both JCOG9205 and JCOG9912. Overall survival (OS), time to treatment failure (TTF), and survival after treatment failure in the first-line chemotherapy (OS-TTF) were compared after adjusting baseline characteristics using the Cox proportional hazard model. Second-line chemotherapy details were also reviewed. RESULTS The combined analysis included 89 and 230 patients in JCOG9205 and JCOG9912, respectively. After adjusting baseline characteristics, TTF was similar between groups (HR 0.95; 95 % CI, 0.73-1.26). However, both OS (HR, 0.74; 95 % CI, 0.56-0.99) and OS-TTF (HR, 0.76; 95 % CI, 0.57-1.01) were longer in JCOG9912. More patients in JCOG9912 received second-line chemotherapy (83 vs. 52 %) with new drugs (77 vs. 10 %) than in JCOG9205. OS-TTF was substantially prolonged in patients who received second-line chemotherapy (HR, 0.66; 95 % CI, 0.46-0.95). CONCLUSION OS and OS-TTF were longer in JCOG9912 than JCOG9205. Second-line chemotherapy with new drugs is a potential reason for the observed prolongation of survival.
Collapse
|
|
17
|
Yamatsuji T, Fujiwara Y, Matsumoto H, Hato S, Namikawa T, Hanazaki K, Takaoka M, Hayashi J, Shigemitsu K, Yoshida K, Urakami A, Uno F, Nishizaki M, Kagawa S, Ninomiya M, Fujiwara T, Hirai T, Nakamura M, Haisa M, Naomoto Y. Feasibility of oral administration of S-1 as adjuvant chemotherapy in gastric cancer: 4-week S-1 administration followed by 2-week rest vs. 2-week administration followed by 1-week rest. Mol Clin Oncol 2015; 3:527-532. [PMID: 26137261 DOI: 10.3892/mco.2015.500] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 09/13/2014] [Indexed: 12/22/2022] Open
Abstract
In 2006, the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) demonstrated that S-1 is an effective adjuvant therapy for gastric cancer. Following that study, S-1 has been used as the standard adjuvant therapy for gastric cancer in Japan. However, the 1-year completion rate was only 65.8% in the ACTS-GC study and feasibility remains a critical issue. We conducted a study to evaluate the feasibility of 2 weekly administration regimens of S-1 as adjuvant chemotherapy in gastric cancer. The criteria for eligibility included histologically proven stage II (excluding T1), IIIA or IIIB gastric cancer with D2 lymph-node dissection. The patients were randomly assigned to either arm A (S-1 administration for 4 weeks followed by 2 weeks of rest) or arm B (S-1 administration for 2 weeks followed by 1 week of rest). In each arm, treatment was continued for 12 months unless recurrence or severe adverse events were observed. The primary endpoint was feasibility (protocol treatment completion rate). The secondary endpoints were safety, relapse-free survival and overall survival. A total of 47 patients were assigned to arms A or B between May, 2008 and February, 2010. During the first interim analysis, the protocol treatment completion rates in arms A and B were 83 and 100%, respectively at 6 months and 49 and 89%, respectively, at 12 months (P=0.0046). Therefore, S-1 administration for 2 weeks followed by 1 week rest was more feasible as adjuvant chemotherapy in gastric cancer. Grade 3 adverse events in arm A included fatigue (8.0%), anorexia (8.0%), nausea (4.0%), vomiting (4.0%) and hand-foot syndrome (4.0%), whereas none were observed in arm B. There were no reported grade 4 adverse events in either arm. In conclusion, the 2-week S-1 administration followed by 1-week rest regimen appears to be a more feasible oral administration regimen for S-1 as adjuvant chemotherapy in gastric cancer.
Collapse
Affiliation(s)
- Tomoki Yamatsuji
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Yasuhiro Fujiwara
- Department of Surgery, Hiroshima City Hospital, Hiroshima, Hiroshima 730-8518, Japan ; Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Hideo Matsumoto
- Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Shinji Hato
- Department of Surgery, Shikoku Cancer Center, National Hospital Organization, Matsuyama, Ehime 791-0280, Japan
| | - Tsutomu Namikawa
- Department of Surgery, Kochi University Medical School, Kochi, Kochi 783-8505, Japan
| | - Kazuhiro Hanazaki
- Department of Surgery, Kochi University Medical School, Kochi, Kochi 783-8505, Japan
| | - Munenori Takaoka
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Jiro Hayashi
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Kaori Shigemitsu
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Kazuhiro Yoshida
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Atsushi Urakami
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Futoshi Uno
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Masahiko Nishizaki
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Shunsuke Kagawa
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Motoki Ninomiya
- Department of Surgery, Hiroshima City Hospital, Hiroshima, Hiroshima 730-8518, Japan
| | - Toshiyoshi Fujiwara
- Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Toshihiro Hirai
- Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Masafumi Nakamura
- Department of Digestive Surgery, Kawasaki Medical School, Kurashiki, Okayama 701-0192, Japan
| | - Minoru Haisa
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| | - Yoshio Naomoto
- Department of General Surgery, Kawasaki Medical School, Okayama, Okayama 700-8505, Japan
| |
Collapse
|
|
18
|
Yang J, Zhou Y, Min K, Yao Q, Xu CN. S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: A meta-analysis. World J Gastroenterol 2014; 20:11886-11893. [PMID: 25206296 PMCID: PMC4155382 DOI: 10.3748/wjg.v20.i33.11886] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy and tolerability of S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer (AGC).
METHODS: We extracted reported endpoints, including overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), objective response rate (ORR) and adverse effects, from randomized controlled trials identified in PubMed, the Cochrane library, Science Direct, EMBASE and American Society of Clinical Oncology meetings. Stata software was used to calculate the pooled values.
RESULTS: Seven randomized controlled trials involving 2176 patients were included in this meta-analysis. Compared to non-S-1-based regimens, the use of S-1-based regimens were associated with an increase in ORR (RR = 1.300; 95%CI: 1.028-1.645); OS (HR = 0.89; 95%CI: 0.81-0.99; P = 0.025), TTF (HR = 0.83; 95%CI: 0.75-0.92; P = 0.000), and a lower risk of febrile neutropenia (RR = 0.225; P = 0.000) and stomatitis (RR = 0.230; P = 0.032). OS, PFS and TTF were prolonged, especially in the Asian population. In subgroup analysis, statistically significant increases in ORR (RR = 1.454; P = 0.029), OS (HR = 0.895; P = 0.041) and TTF (HR = 0.832; P = 0.000) were found when S-1-based chemotherapy was compared to 5-fluorouracil (5-FU)-based chemotherapy. The incidence of leukopenia (RR = 0.584; P = 0.002) and stomatitis (RR = 0.230; P = 0.032) was higher in the 5-FU-based arm. S-1-based regimens had no advantage in ORR, OS, PFS, TTF and grade 3 or 4 adverse events over capecitabine-based regimens.
CONCLUSION: S-1-based chemotherapy may be a good choice for AGC because of longer survival times, better tolerance and more convenient use.
Collapse
|
|
19
|
Chisaki Y, Noda S, Hira D, Morita SY, Yano Y, Terada T. Reduction in gastrointestinal toxicity by gastric secretion inhibitors during S-1 monotherapy for patients with gastric cancer. Biol Pharm Bull 2014; 37:1158-61. [PMID: 24989007 DOI: 10.1248/bpb.b14-00025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The purpose of this study was to retrospectively examine the effect of concomitant administration of gastric secretion inhibitors or gastrectomy on the frequency of gastrointestinal toxicity caused by 5-fluorouracil (5-FU) in gastric cancer patients receiving chemotherapy with S-1. In 62 gastric cancer patients treated with S-1 alone, data relating to the occurrence of gastrointestinal toxicity (diarrhea, vomiting, and nausea) and possible contributing factors were retrospectively collected, and logistic regression analysis was performed. Time-to-event data relating to the occurrence of gastrointestinal toxicity were also collected, and the effect of gastric secretion inhibitors on the time-to-event profiles was examined using a log-rank test. Logistic regression analysis suggested that the frequency of gastrointestinal toxicity was significantly reduced by the administration of gastric secretion inhibitors (p=0.01; odds ratio, 0.197; 95% confidence interval (CI), 0.056-0.694) and that gastrointestinal toxicity correlated with the estimated glomerular filtration rate (p=0.04; odds ratio, 0.956; 95% CI, 0.916-0.997). The median time-to-event of gastrointestinal toxicity was 85 d for patients that received gastric secretion inhibitors, which was significantly different from the 42 d for patients that did not receive the inhibitors (p=0.02, log-rank test). No clear effect of gastrectomy was found in the present study. The prophylactic use of gastric secretion inhibitors in gastric cancer patients treated with S-1 may decrease and delay the occurrence of gastrointestinal toxicity.
Collapse
|
|
20
|
Terazawa T, Iwasa S, Takashima A, Nishitani H, Honma Y, Kato K, Hamaguchi T, Yamada Y, Shimada Y. Impact of adding cisplatin to S-1 in elderly patients with advanced gastric cancer. J Cancer Res Clin Oncol 2013; 139:2111-6. [PMID: 24129809 DOI: 10.1007/s00432-013-1537-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2013] [Accepted: 10/04/2013] [Indexed: 01/09/2023]
Abstract
PURPOSE We retrospectively examined the efficacy and safety of S-1 alone or S-1 plus cisplatin (SP) for elderly patients with advanced gastric cancer because the benefit of adding cisplatin in these patients still remains unclear. PATIENTS AND METHODS Among 175 patients aged 70 years or older who received S-1 alone or SP as a first-line therapy between April 2000 and November 2010 at our institution, 104 patients who met eligibility criteria were examined. We investigated safety and efficacy of S-1 and SP. RESULTS Among these 104 patients, 73 patients received S-1 and 31 patients received SP. The median age was 75 years in the S-1 group and 74 years in the SP group. The response rate was 26.3 % in the S-1 group and 44.0 % in the SP group. Major grade 3 or higher adverse events were observed as follows (S-1 vs. SP): nausea (1.4 vs. 16.1 %), anorexia (16.4 vs. 41.9 %), neutropenia (4.1 vs. 35.5 %), and febrile neutropenia (0 vs. 9.7 %). The median overall survival (OS) was 10.4 months in the S-1 group and 17.8 months in the SP group. Treatment of SP and histology of intestinal type were detected as independent, good prognostic factors in multivariate analysis. CONCLUSION SP might improve OS with some added toxicity compared to S-1 alone in elderly patients with advanced gastric cancer.
Collapse
Affiliation(s)
- Tetsuji Terazawa
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
21
|
Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer. Cancer Chemother Pharmacol 2012; 70:783-9. [PMID: 22960985 DOI: 10.1007/s00280-012-1958-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2012] [Accepted: 08/17/2012] [Indexed: 10/27/2022]
Abstract
PURPOSE We investigated the efficacy and toxicity of a novel oral 5-fluorouracil (5-FU) formulation (S-1), administered according to a tailored dose regimen. METHODS S-1 was administered orally for 28 days, followed by 14 days of no treatment, in 23 patients who received a tailored dose of S-1, adjusted on the basis of individual creatinine clearance and body surface area. In 8 of the patients, pharmacokinetic study was performed on the 6 points on 7th day after S-1 administration. RESULTS Of the 23 patients enrolled in this study, 2 (8.7 %) had a partial response and 14 (60.9 %) had stable disease. The disease control rate was 69.6 % (16/23) (95 % confidence interval, 50.8-88.4 %). Grade 3/4 hematologic and non-hematologic toxicities were minor. In the pharmacokinetic study group, the maximum plasma concentration (C (max)) and the area under the plasma concentration curve of 5-FU at all 6 points after administration of the tailored S-1 dose regimen were similar to the values reported in a previous study describing cancer patients with normal renal function who received a standard dose of S-1 (80 mg/m(2)/day). CONCLUSIONS Our results suggest that tailored S-1 monotherapy is safe and therapeutically useful as first-line treatment for elderly patients with advanced and recurrent non-small cell lung cancer.
Collapse
|
|
22
|
Koo DH, Ryu MH, Ryoo BY, Lee SS, Moon JH, Chang HM, Lee JL, Kim TW, Kang YK. Three-week combination chemotherapy with S-1 and cisplatin as first-line treatment in patients with advanced gastric cancer: a retrospective study with 159 patients. Gastric Cancer 2012; 15:305-12. [PMID: 22160244 DOI: 10.1007/s10120-011-0117-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Accepted: 10/31/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND Doses and schedules of the combination of S-1 and cisplatin for the treatment of advanced gastric cancer (AGC) have not been standardized. We therefore evaluated the efficacy and feasibility of a 3-week schedule of S-1 and cisplatin in patients with AGC, as well as assessing factors prognostic of patient outcomes. METHODS A total of 159 patients with AGC were treated with S-1 (40 mg/m(2) bid on days 1-14) and cisplatin (60 mg/m(2) IV on day 1) between January 2004 and December 2008. RESULTS Median follow-up duration was 20.0 months (range, 11.4-48.5 months), during which time 129 patients (81.1%) died. Patients received a median 6 cycles of chemotherapy (range, 1-19 cycles). Among the 59 patients with measurable disease, 1 achieved a complete response (1.7%) and 24 (40.7%) had partial responses, giving an overall response rate of 42.4% (95% CI, 23.0-61.8%). The median progression-free survival (PFS) was 5.8 months (95% CI, 4.8-6.9 months), and the median overall survival (OS) was 11.3 months (95% CI, 9.6-13.0 months). Multivariate analysis showed that initial metastasis, bone metastasis, and liver metastasis were independent prognostic factors for reduced PFS, whereas poor performance status, initial metastasis, and bone metastasis were prognostic for reduced OS. Application of a previous prognostic model showed that observed PFS and OS survival curves for patients in various risk groups differed significantly (P < 0.001 each). CONCLUSIONS A 3-week regimen of S-1 plus cisplatin was active and well tolerated as first-line treatment in patients with AGC. Disease status and bone metastasis were the most important prognostic factors.
Collapse
Affiliation(s)
- Dong Hoe Koo
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 86 Asanbyeongwon-gil, Songpa-gu, Seoul, 138-736, Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
23
|
Comparison of safety and efficacy of S-1 monotherapy and S-1 plus cisplatin therapy in elderly patients with advanced gastric cancer. Int J Clin Oncol 2011; 18:10-6. [PMID: 22020563 DOI: 10.1007/s10147-011-0335-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Accepted: 09/23/2011] [Indexed: 01/22/2023]
Abstract
BACKGROUND Although S-1 plus cisplatin (SP) therapy is recognized as the standard treatment for advanced gastric cancer (AGC) in Japan, its safety and efficacy in elderly patients have not been investigated sufficiently. METHODS We retrospectively reviewed the data of 58 patients with AGC selected from 82 consecutive patients who were ≥70 years old and were treated with SP or S-1 monotherapy as the first-line therapy. In SP, S-1 (40 mg/m(2), bid) was administered for 3 weeks and cisplatin (60 mg/m(2)) on day 8, every 5 weeks. In S-1 monotherapy, S-1 (40 mg/m(2), bid) was administered for 4 weeks, every 6 weeks. RESULTS SP and S-1 was administered in 21 and 37 patients, respectively. There were some differences in patient characteristics between the treatment groups, such as histological type (P = 0.16); the presence of liver metastasis (P = 0.07); and the presence of peritoneal metastasis (P = 0.02). The incidences of grade 3/4 hematological toxicities were 57% (12/21) in the SP and 35% (13/37) in the S-1 group (P = 0.17). Those of non-hematological toxicities were 14% (3/21) and 14% (5/37) for anorexia, 10% (2/21) and 14% (5/37) for fatigue, and 5% (1/21) and 5% (2/37) for nausea in the SP and S-1 groups, respectively. Median progression-free survival and median overall survival in the SP and S-1 groups were 5.0 and 5.2 months, and 14.4 and 10.9 months, respectively. CONCLUSION SP and S-1 therapy were both feasible in elderly patients, though there is the risk of a high incidence of hematological toxicities.
Collapse
|
|
24
|
Yoda S, Soejima K, Yasuda H, Naoki K, Kawada I, Watanabe H, Nakachi I, Satomi R, Nakayama S, Ikemura S, Terai H, Sato T, Morosawa M, Asano K. A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients. Cancer Chemother Pharmacol 2010; 67:717-22. [PMID: 21152917 DOI: 10.1007/s00280-010-1539-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 11/24/2010] [Indexed: 02/06/2023]
Abstract
BACKGROUND This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment. METHODS Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25-1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1-14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥ 3 neutropenia with fever over 38°C, grade ≥ 3 thrombocytopenia, or grade ≥ 3 major nonhematological toxicities. RESULTS Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose. CONCLUSION The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.
Collapse
Affiliation(s)
- Satoshi Yoda
- Department of Pulmonary Medicine, School of Medicine, Keio University, Shinjuku-ku, Tokyo, 160-8582, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Safety and efficacy of S-1 monotherapy in elderly patients with advanced gastric cancer. Gastric Cancer 2010; 13:245-50. [PMID: 21128060 DOI: 10.1007/s10120-010-0566-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Accepted: 07/06/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although S-1 is effective against advanced gastric cancer (AGC), its efficacy in elderly patients has not yet been investigated sufficiently. We assessed the efficacy and safety of S-1 monotherapy in elderly patients with AGC. METHODS We conducted a retrospective review of the data of 153 patients with unresectable/recurrent gastric adenocarcinoma who received S-1 monotherapy as first-line chemotherapy at our institution. S-1 was administered orally twice daily at the dose of 40 mg/m², on days 1-28, every 6 weeks. We categorized the patients into three groups, the young (≤65 years old), the middle-aged (66-75 years old), and the elderly (≥76 years old); and the drug toxicity, objective responses, progression-free survivals, and overall survivals were compared among the three groups. RESULTS The incidence of leukopenia of grade 3 or greater in the three groups was 7%, 5%, and 13%, and that of anemia was 9%, 18%, and 27%, respectively. In regard to nonhematological toxicities, the incidence of nausea of grade 3 or greater was 3%, 5%, and 13%; that of fatigue was 5%, 11%, and 20%; and that of anorexia was 5%, 6%, and 27%, respectively. As for the treatment efficacy, the objective response rates, median progressionfree survivals, and overall survivals in the young, middle-aged, and elderly groups were 53%, 46%, and 33%; 7.8, 5.6, and 3.9 months; and 16.9, 17.1; and 7.7 months, respectively. CONCLUSION Although S-1 monotherapy showed moderate efficacy in elderly (≥76 years) patients with AGC, patients in this age group showed higher incidences of severe toxicities than the younger patients.
Collapse
|
|
26
|
Rino Y, Yukawa N, Murakami H, Wada N, Yamada R, Hayashi T, Sato T, Ohshima T, Masuda M, Imada T. A Phase II Study of S-1 Monotherapy as a First-line Combination Therapy of S-1 Plus Cisplatin as a Second-line Therapy, and Weekly Paclitaxel Monotherapy as a Third-line Therapy in Patients with Advanced Gastric Carcinoma: A Second Report. CLINICAL MEDICINE INSIGHTS-ONCOLOGY 2010; 4:1-10. [PMID: 20567630 PMCID: PMC2883242 DOI: 10.4137/cmo.s3920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND We have previousy reported on a Phase II study of S-1 monotherapy as a first line, combination therapy of S-1 plus cisplatin as a second line, and weekly paclitaxel monotherapy as a third line therapy in patients with advanced gastric carcinomas. The median survival time (MST) of patients over the whole course of treatment was not previously calculated because 12 out of 19 patients had not yet succumbed. Since then, we have calculated the MST for this study and herein report our findings. PATIENTS AND METHODS Between 2002 and 2005, 19 patients were enrolled in this study. Chemotherapy consisted of either 60 mg/m(2) of S-1 for 4 weeks at 6-week intervals, a combination of 60 mg/m(2) S-1 for 3 weeks and 60 mg/m(2) cisplatin on day 8 at 5-week intervals, or 60 mg/m(2) paclitaxel at days 1, 8, and 15, at 4-week intervals. The regimens were repeated until the occurrence of unacceptable toxicities, disease progression, or patient noncompliance. The primary end point was the overall survival. RESULTS The median survival time was 774 days. The response rates were 33.3% (3/9), 12.5% (1/8), and 0% (0/4) after the first, second, and third line chemotherapies, respectively. The major adverse hematological toxicity was leukopenia, which reached grades 3-4 in all lines of chemotherapy investigated. In addition, the major adverse non-hematological toxicity was anorexia, which reached grade 3-4 in second line chemotherapy, and no deaths were attributable to the adverse effects of the drugs. CONCLUSION This sequential therapy was an effective treatment for advanced gastric cancer with acceptable toxic side-effects. We considered this therapy to be effective because of the smooth transition to the next regimen.
Collapse
Affiliation(s)
- Yasushi Rino
- Department of Surgery, School of Medicine, Yokohama City University
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
27
|
Sakuma K, Hosoya Y, Arai W, Haruta H, Ui T, Kurashina K, Saito S, Hirashima Y, Yokoyama T, Zuiki T, Hyodo M, Nagai H, Yasuda Y, Shirasaka T. Alternate-day treatment with S-1 in patients with gastric cancer: a retrospective study of strategies for reducing toxicity. Int J Clin Oncol 2010; 15:166-71. [PMID: 20195683 DOI: 10.1007/s10147-010-0036-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2009] [Accepted: 09/28/2009] [Indexed: 12/29/2022]
Abstract
BACKGROUND In patients with adverse events of S-1, the dose is generally reduced or the treatment cycle is shortened. Whether the therapeutic effectiveness of modified regimens is similar to that of the standard dosage remains unclear. METHODS We retrospectively studied patients with gastric cancer who received S-1 on alternate days. RESULTS A total of 266 patients received S-1 on alternate days. In 116 patients, S-1 was initially given at the standard dosage but was switched to alternate-day treatment because of toxicity within 28 days on average. The other 150 patients initially received alternate-day treatment because of poor general condition. In the adjuvant chemotherapy group (n = 96), the 3-year survival rate was 88% in patients with stage II, 73% in stage IIIA, and 67% in stage IIIB who underwent D2 lymph-node dissection. In the palliative surgery group (n = 96), the response rate was 13%, with a median survival time (MST) of 624 days. In patients with unresectable/recurrent disease (n = 74), the response rate was 25%, with an MST of 338 days. Among the 116 patients who initially received treatment on consecutive days, 100% had grade 1, 53% had grade 2, and 5.2% had grade 3 adverse events. When S-1 was switched to alternate-day treatment, toxicity decreased in all patients. In the 266 patients who received alternate-day treatment, 8% had grade 1, 6% had grade 2, and 0% had grade 3 adverse events. CONCLUSION Alternate-day treatment with S-1 may have milder adverse events without compromising therapeutic effectiveness.
Collapse
Affiliation(s)
- Kazuya Sakuma
- Department of Surgery, Jichi Medical University, 3311-1 Shimotsuke, Tochigi, 329-0498, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abe S, Tsuji Y, Tsushima T, Kogawa T, Abe M, Onodera Y, Mizushima T, Kukitsu T, Sumiyoshi T, Yoshizaki N, Ishii T, Kondo H. Efficacy and Feasibility of Combination Chemotherapy with S-1 and Cisplatin (2 Weeks Regimen) for Advanced Gastric Cancer. Jpn J Clin Oncol 2010; 40:302-6. [DOI: 10.1093/jjco/hyp177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
|
|
29
|
Sakuramoto S, Yamashita K, Watanabe M. Newly emerging standard chemotherapies for gastric cancer and clinical potential in elderly patients. World J Gastrointest Oncol 2009; 1:47-54. [PMID: 21160774 PMCID: PMC2999089 DOI: 10.4251/wjgo.v1.i1.47] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Revised: 07/29/2009] [Accepted: 08/05/2009] [Indexed: 02/05/2023] Open
Abstract
With the increase in average life expectancy, the rate of occurrence of gastric cancer in elderly patients is also rising. While many clinical trials have been conducted to examine the effect of chemotherapy treatment on gastric cancer, age limits for eligible subjects have prevented the establishment of standards for chemotherapy in elderly patients with gastric cancer. As of March 2009, evidence-based standard chemotherapy regimens were established. In the Western world, debates centered on the ECF (Epirubicin/cisplatin/5-FU) or DCF (Docetaxel/cisplatin/5-FU) regimens based on the phase III randomized controlled trial at the Royal Marsden Hospital (RMH) or the V325 study, respectively. The JCOG9912 and SPIRITS trials emerged from Japan indicating attractive regimens that include S-1 for advanced gastric cancer patients. Using these active anticancer drugs, the trials that studied the efficacy of adjuvant therapies or surgical approaches, such as the Int-116/MAGIC/ACTS-GC trials, have actually succeeded in demonstrating the benefits of adjuvant therapies in gastric cancer patients. For cases of gastric cancer in elderly patients, treatment policies should consider these studies while analyzing not only the therapeutic effects but also drug toxicity, individual general health conditions, and social factors to select treatments that emphasize quality of life.
Collapse
Affiliation(s)
- Shinichi Sakuramoto
- Shinichi Sakuramoto, Keishi Yamashita, Masahiko Watanabe, Department of Surgery, Kitasato University Hospsital, Kitasato 1-15-1, Sagamihara, Kanagawa 228-8555, Japan
| | | | | |
Collapse
|
|
30
|
Phase I/II and pharmacokinetic study of S-1 and oxaliplatin in previously untreated advanced gastric cancer. Cancer Chemother Pharmacol 2009; 65:473-80. [PMID: 19551382 DOI: 10.1007/s00280-009-1052-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Accepted: 06/08/2009] [Indexed: 01/16/2023]
Abstract
BACKGROUND We aimed to determine the maximum-tolerated dose (MTD) of S-1 when given with oxaliplatin, to evaluate S-1 pharmacokinetics, and to determine the efficacy and safety of this regimen as a first-line treatment for advanced gastric cancer (AGC). METHODS Oxaliplatin was fixed at a dose of 130 mg/m2 on day 1 (D1). S-1 was administered from D1 to D14 of a 3-week cycle, and escalated by 10 mg/m2 per day from 70 mg/m2 per day up to 100 mg/m2 per day. Pharmacokinetic analyses were performed following a single dose of S-1 on D-5 and D1 of the first cycle. RESULTS In phase I (n=18), MTD was not defined. In phase II (n=47) with the planned maximum dose, partial response was achieved in 26 patients (55.3%) and stable disease in 14 patients (29.8%). The median time to progression was 6.6 months (95% CI 4.0-9.2 months) and the median overall survival was 12.5 months (95% CI 9.2-15.9 months). Frequent grade 3/4 toxicities included thrombocytopenia (39%), neutropenia (28%), anemia (17%), and leukopenia (13%). There was one grade 5 febrile neutropenia during the first cycle. CONCLUSIONS The pharmacokinetics of S-1 was not influenced by oxaliplatin. S-1/Oxaliplatin combination therapy is highly active against AGC and has a favorable toxicity profile.
Collapse
|
|
31
|
Saif MW, Syrigos KN, Katirtzoglou NA. S-1: a promising new oral fluoropyrimidine derivative. Expert Opin Investig Drugs 2009; 18:335-48. [PMID: 19243284 DOI: 10.1517/13543780902729412] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
S-1 is an oral fluoropyrimidine that is designed to improve the antitumor activity of 5-fluorouracil (5-FU) concomitantly with an intent to reduce its toxicity. S-1 consists of tegafur, a prodrug of 5-FU combined with two 5-FU biochemical modulators:5-chloro-2,4-dihydroxypyridine (gimeracil or CDHP), a competitive inhibitor of dihydropyrimidine dehydrogenase and oteracil potassium which inhibits phosphorylation of 5-FU in the gastrointestinal tract decreasing serious gastrointestinal toxicities,including nausea, vomiting, stomatitis and diarrhea. Being an oral agent, S-1 offers convenience of administration and prevents complications of central venous access such as infection, thrombosis and bleeding. S-1 has shown efficacy in both gastrointestinal as well non-gastrointestinal malignancies. The authors review the current literature and provide their expert opinion on the incorporation of S-1 in the treatment of solid malignancies [corrected].
Collapse
Affiliation(s)
- Muhammad Wasif Saif
- Yale University School of Medicine, Division of Medical Oncology, 333 Cedar Street, FMP 116 New Haven, CT 06520, USA.
| | | | | |
Collapse
|
|
32
|
Lee SJ, Cho SH, Yoon JY, Hwang JE, Bae WK, Shim HJ, Chung IJ. Phase II study of S-1 monotherapy in paclitaxel- and cisplatin-refractory gastric cancer. Cancer Chemother Pharmacol 2009; 65:159-66. [PMID: 19479256 DOI: 10.1007/s00280-009-1019-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 04/26/2009] [Indexed: 10/20/2022]
Abstract
PURPOSE S-1 is a fourth-generation oral fluoropyrimidine that was developed to mimic the effects achieved with protracted continuous infusion of 5-fluorouracil (5-FU). This phase II study evaluated the efficacy and safety of S-1 salvage chemotherapy in patients with paclitaxel- and cisplatin-refractory gastric cancer. The primary end point was progression-free survival; secondary end points were overall survival, safety, and clinical benefit. METHODS Patients were eligible for the study if they had histologically documented gastric adenocarcinoma previously treated with paclitaxel and cisplatin, age > or = 18 years, Eastern Clinical Oncology Group performance status < or =2, adequate organ function, and no evidence of gastrointestinal obstruction or passage disturbance. Patients were treated with a dose of S-1 based on body surface area (BSA) as follows: BSA < 1.25 m(2), 80 mg/day; 1.25 < or = BSA < 1.5 m(2), 100 mg/day; BSA > or= 1.5 m(2), 120 mg/day. The total dose was divided in two and administered twice daily for 4 weeks followed by a 2-week rest period. RESULTS Of the 53 patients enrolled in this study, 49 were evaluable. A total of 190 chemotherapy cycles were administered, and the median number of cycles was 2. Five patients (9.4%) had a partial response, and 18 (34%) had stable disease. Median progression-free survival and overall survival were 4.9 and 10.4 months, respectively. Grade 3/4 hematological toxicities included neutropenia in six patients (11%) but no cases of febrile neutropenia were found. Most of the non-hematological toxicities were diarrhea, asthenia, and mucositis, but none reached grade 3 or grade 4 in severity. Improvement of pain was observed in 17 patients (32.1%). CONCLUSIONS S-1 monotherapy provides active and safe salvage chemotherapy for patients with advanced gastric cancer who have been previously treated with paclitaxel and cisplatin.
Collapse
Affiliation(s)
- Sung-Ji Lee
- Division of Hemato-Oncology, Department of Internal Medicine, Center for Biomedical Human Resources, Chonnam National University Medical School, Kwangju, Korea
| | | | | | | | | | | | | |
Collapse
|
|
33
|
|
|
34
|
Arai W, Hosoya Y, Haruta H, Kurashina K, Saito S, Hirashima Y, Yokoyama T, Zuiki T, Sakuma K, Hyodo M, Yasuda Y, Nagai H, Shirasaka T. Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo. Int J Clin Oncol 2008; 13:515-20. [PMID: 19093179 DOI: 10.1007/s10147-008-0780-4] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2007] [Accepted: 03/13/2008] [Indexed: 11/27/2022]
Abstract
BACKGROUND The toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required. METHODS We used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments. RESULTS In vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment. CONCLUSION Experimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.
Collapse
Affiliation(s)
- Wataru Arai
- Department of Surgery, Jichi Medical University, 3311-1 Shimotsuke, Tochigi, 329-0498, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Affiliation(s)
- Masahiko Nishiyama
- Translational Research Center, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan.
| |
Collapse
|
|
36
|
Affiliation(s)
- Masahiko Nishiyama
- Translational Research Center, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka, Saitama 350-1298, Japan.
| |
Collapse
|
|
37
|
Rino Y, Yukawa N, Wada N, Suzuki M, Murakami H, Yamada T, Nakayama H, Yamamoto N, Sato T, Yamada R, Ohshima T, Masuda M, Imada T. Phase II Study of S-1 Monotherapy as a First-line, Combination Therapy of S-1 plus Cisplatin as a Second-line, and Weekly Paclitaxel Monotherapy as a Third-line Therapy in Patients with Advanced Gastric Carcinoma: Phase II Study of S-1, S-1 plus Cisplatin, and Weekly Paclitaxel in Patients with Advanced Gastric Carcinoma. Clin Med Oncol 2008; 2:375-83. [PMID: 21892302 PMCID: PMC3161668 DOI: 10.4137/cmo.s610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Background We conducted a pilot phase II study to evaluate the efficacy and safety of S-1 as a first-line, S-1 plus cisplatin as a second-line, and weekly paclitaxel as a third-line therapy for advanced gastric cancer. Patients and methods Between 2002 and 2005, 19 patients were enrolled in this study. Chemotherapy consisted of either 60 mg/m2 of S-1 for 4 weeks at 6 weeks interval, a combination of 60 mg/m2 S-1 for 3 weeks and 60 mg/m2 cisplatin on day 8 at 5 weeks interval, or 60 mg/m2 paclitaxel at day 1, 8, 15, at 4 weeks interval. The regimen was repeated until the occurrence of unacceptable toxicities, disease progression, or patient refusal. The primary end point was the overall survival. Results The response rates were 33.3%, 12.5%, and 0% after the first, second, and third line chemotherapy, respectively. The mean overall survival time was 994 days. The median survival time could not be calculated because 12 out of 19 patients were still alive when the study was concluded. Regarding hematological toxicity, the major adverse effect was leukopenia, which reached grades 3–4 in all lines of chemotherapy investigated. In addition, regarding non-hematological toxicities, the major adverse effect was anorexia, which reached grade 3–4 in the second line chemotherapy, and no deaths were attributable to the adverse effects of the drugs. Conclusion This sequential therapy was an effective treatment for advanced gastric cancer with acceptable toxic side-effects. We considered this sequential therapy to be effective because of the smooth switch to the next regimen.
Collapse
Affiliation(s)
- Yasushi Rino
- Department of Surgery, School of Medicine, Yokohama City University
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
38
|
Uedo N, Narahara H, Ishihara R, Takiuchi H, Goto M, Fujitani K, Hirao M, Tsujinaka T, Imano M, Furukawa H, Tsukuma H, Taguchi T. Phase II study of a combination of irinotecan and S-1 in patients with advanced gastric cancer (OGSG0002). Oncology 2008; 73:65-71. [PMID: 18334851 DOI: 10.1159/000120630] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2007] [Accepted: 09/04/2007] [Indexed: 01/26/2023]
Abstract
BACKGROUND/AIMS To investigate the efficacy and safety of the combination therapy of irinotecan (CPT-11) plus S-1 in patients with advanced gastric cancer at the dose recommended by a previous phase I study. METHODS A total of 23 patients received 80 mg/m(2) of CPT-11 on days 1 and 15, and S-1 at a dose level set on the basis of the body surface area (BSA): 40 (BSA <1.25 m(2)), 50 (BSA > or =1.25 to <1.5 m(2)) or 60 mg (BSA > or =1.5 m(2)) b.i.d. was given from days 1-21. RESULTS The overall response rate was 47.8% (11 of 23, 95% confidence interval, CI: 27.4-68.2%). The median time to progression (TTP) was 210 days (95% CI: 145-322 days) and the median survival time was 394 days (95% CI: 241-484 days). The incidence of grade 3 or 4 hematological and non-hematological toxicity was 17.4 and 8.7%. The most common hematological toxicity was anemia and the most common non-hematological toxicity was diarrhea. CONCLUSION The combination therapy of CPT-11 and S-1 provided prolonged TTP with low toxicity, and the results warrant a further phase III study to define the efficacy in improvement of survival in patients with advanced gastric cancer.
Collapse
Affiliation(s)
- Noriya Uedo
- Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka,
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
39
|
S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. Lancet Oncol 2008; 9:215-21. [PMID: 18282805 DOI: 10.1016/s1470-2045(08)70035-4] [Citation(s) in RCA: 1398] [Impact Index Per Article: 82.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. METHODS In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. FINDINGS 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. INTERPRETATION S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.
Collapse
|
|
40
|
Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. Safety evaluation of oral fluoropyrimidine S-1 for short- and long-term delivery in advanced gastric cancer: analysis of 3,758 patients. Cancer Chemother Pharmacol 2007; 61:335-43. [DOI: 10.1007/s00280-007-0595-4] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2007] [Accepted: 09/04/2007] [Indexed: 12/27/2022]
|
|
41
|
Kim WY, Nakata B, Hirakawa K. Alternative pharmacokinetics of S-1 components, 5-fluorouracil, dihydrofluorouracil and alpha-fluoro-beta-alanine after oral administration of S-1 following total gastrectomy. Cancer Sci 2007; 98:1604-8. [PMID: 17683513 PMCID: PMC11159371 DOI: 10.1111/j.1349-7006.2007.00573.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
We studied whether total gastrectomy for gastric cancer would affect the pharmacokinetics of 5-fluorouracil (5-FU) and its degradation products, such as dihydrouracil (FUH(2)) and alpha-fluoro-beta-alanine (FBAL), after oral administration of the fluorouracil derivative S-1, composed of tegafur, 5-chloro-2,4-dihydroxypyridine (CDHP; a dihydropyrimidine dehydrogenase inhibitor) and potassium oxonate. Blood and urine samples were obtained, both preoperatively and at least 2 weeks postoperatively, from six patients with advanced gastric cancers who were undergoing total gastrectomy. Plasma levels of tegafur, 5-FU, CDHP, potassium oxonate, FUH(2) and FBAL were measured prior to and at 1, 2, 4, 6 and 10 h after oral administration of 40 mg/m(2) S-1. The total amounts of 5-FU, FUH(2) and FBAL excreted into urine during the 24-h period after S-1 administration were also measured. Total gastrectomy significantly increased the maximum concentration and the area under the curve until 10 h after administration (AUC(1-10h)) of plasma 5-FU. The plasma AUC(1-10h) of CDHP was significantly higher than the preoperative value. In terms of clinical efficacy, the higher AUC(1-10h) of 5-FU after total gastrectomy may be beneficial to S-1 administered as adjuvant chemotherapy, and might be caused by the higher postoperative AUC(1-10h) of CDHP relative to preoperative values. However, the dose of S-1 for patients who have undergone total gastrectomy might be diminished to avoid severe adverse events and to continue the treatment for a long period.
Collapse
Affiliation(s)
- Woo Young Kim
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan
| | | | | |
Collapse
|
|
42
|
Takayama T, Sato Y, Sagawa T, Okamoto T, Nagashima H, Takahashi Y, Ohnuma H, Kuroiwa G, Miyanishi K, Takimoto R, Matsunaga T, Kato J, Yamaguchi K, Hirata K, Niitsu Y. Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Br J Cancer 2007; 97:851-6. [PMID: 17848958 PMCID: PMC2360407 DOI: 10.1038/sj.bjc.6603957] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The aim of this dose escalation study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs) and preliminary efficacy of docetaxel, S-1 and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Seventeen patients received oral S-1 (40 mg m−2 bid) on days 1–14, intravenous cisplatin (60 mg m−2) and docetaxel (60, 70 or 80 mg m−2 depending on DLT) on day 8 every 3 weeks. The MTD of this combination was presumed to be docetaxel 70 mg m−2. At this dose level, 40% of the patients (two of five) developed grade 4 neutropenia and 20% (one of five) exhibited grade 3 nausea during the first course. Therefore, the recommended dose of docetaxel was defined as 60 mg m−2. The DLT was neutropenia. The response rate (RR) was 88.2% (15 of 17), consisting of one complete response and 14 partial responses. There were two stable diseases but no progressive disease. Of these 15 responders, four (23.5%) with high VEGF expression showed rapid tumour regression and achieved downstaging, leading to subsequent curative gastrectomy. Three of these have been disease free for about 3 years, suggesting a complete cure. In conclusion, this regimen was tolerable and showed a quite high RR, with an appreciable downstaging rate in metastatic gastric cancer.
Collapse
Affiliation(s)
- T Takayama
- Fourth Department of Internal Medicine, Sapporo Medical University, School of Medicine, Sapporo, Japan.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y, Fukushima M. Analysis of risk factors for severe adverse effects of oral 5-fluorouracil S-1 in patients with advanced gastric cancer. Gastric Cancer 2007; 10:129-34. [PMID: 17577624 DOI: 10.1007/s10120-007-0422-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2007] [Accepted: 04/15/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND S-1 is an oral fluoropyrimidine that promises better and accessible treatment. This article identifies the risk factors for severe adverse events of S-1 from nationwide survey data. METHODS Advanced gastric cancer patients scheduled to receive S-1 monotherapy (80 mg/day for days 1-28, every 6 weeks) were registered throughout Japan between 1999 and 2000 (n = 3758). Univariate and multivariate analyses were performed to explore the risk factors for severe adverse events. RESULTS A multivariate analysis revealed that grade 3 or 4 neutropenia was significantly associated with baseline renal function [odds ratios (ORs) corresponding to creatinine clearance (ml/min) ranges of 50-79, 30-49, and <30 in reference to >80 increased to 1.21, 1.79, and 2.43, respectively], and the estimated incidence probability of grade 3 or 4 neutropenia ranged from 5.0% to 33.7% depending on the initial status of renal function and baseline neutrophil count. Some prior chemotherapeutic drug use may be implicated in the experience of adverse events; decreases in hemoglobin, nausea/vomiting, and hyperbilirubinemia were observed to be influenced by the previous use of irinotecan (OR = 3.07, P = 0.003), mitomycin (OR = 2.28, P = 0.004), and cisplatin (OR = 1.60, P = 0.007), respectively. CONCLUSION These findings identified possible risk factors for severe adverse events of S-1 and the patient subgroups at potentially higher risk from its administration. The results will facilitate safer administration of S-1 and thus promote enhanced tolerability and efficacy.
Collapse
Affiliation(s)
- Takeharu Yamanaka
- Cancer Biostatics Laboratory, Institute for Clinical Research, National Kyushu Cancer Center, 3-1-1 Notame, Fukuoka, Japan
| | | | | | | | | | | |
Collapse
|
|
44
|
Jeung HC, Rha SY, Shin SJ, Ahn JB, Noh SH, Roh JK, Chung HC. A phase II study of S-1 monotherapy administered for 2 weeks of a 3-week cycle in advanced gastric cancer patients with poor performance status. Br J Cancer 2007; 97:458-63. [PMID: 17653073 PMCID: PMC2360346 DOI: 10.1038/sj.bjc.6603902] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Systemic chemotherapy for gastric cancer is often associated with treatment-related toxicity, which is particularly severe in patients with a poor performance status. In this paper, we describe the first study to evaluate S-1 monotherapy as an option for advanced gastric cancer patients who are not candidates for combination chemotherapy due to poor clinical condition. Fifty-two patients with Eastern Cooperative Oncology Group (ECOG) performance scale 2-3, whose general condition had made use of combination chemotherapy impossible, were enrolled. S-1 was administered to 30 patients as second- or third-line therapy. The initial dose of S-1 was 35 mg m(-2), administered b.i.d for 14 days every 3 weeks. With a median follow-up period of 33 weeks, the median progression-free survival, and overall survival were 11 weeks (95% CI, 8-14) and 33 weeks (95% CI, 19-47), respectively. The overall 1-year survival rate was 29% by intent-to-treat analysis. The overall response rate was 12% (95% CI, 3-21), and the percentage of stable disease was 35%, resulting in the disease control rate of 47% (95% CI, 32-60). Significant drug-related toxicity included grade 3 diarrhoea (14%), anorexia (14%), fatigue (10%), neutropenia (10%), and leucopenia (6%). In conclusion, this study indicated the modest activity of S-1 in gastric cancer patients with poor performance status.
Collapse
Affiliation(s)
- H-C Jeung
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - S Y Rha
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - S J Shin
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - J B Ahn
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - S H Noh
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - J K Roh
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - H C Chung
- Cancer Metastasis Research Center, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Yonsei Cancer Center, Yonsei University College of Medicine, 134 Shinchon-Dong, Seodaemun-Ku, CPO Box 8044, Seoul 120-752, Korea. E-mail:
| |
Collapse
|
|
45
|
Hosokawa A, Sugiyama T, Ohtsu A, Doi T, Hattori S, Kojima T, Yano T, Minashi K, Muto M, Yoshida S. Long-term outcomes of patients with metastatic gastric cancer after initial S-1 monotherapy. J Gastroenterol 2007; 42:533-8. [PMID: 17653648 DOI: 10.1007/s00535-007-2059-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Accepted: 02/24/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND S-1, an oral fluoropyrimidine, has been shown to have excellent activity against gastric cancer in two phase II studies and is widely used in Japan. However, the long-term outcomes of patients after S-1 monotherapy for metastatic gastric cancer are unclear. The aim of this study was to investigate the long-term outcomes in metastatic gastric cancer patients who had initially received S-1 monotherapy. METHODS Ninety-two previously untreated patients with advanced gastric cancer received S-1 monotherapy as first-line chemotherapy at the National Cancer Center Hospital East, Kashiwa, Japan, and then the long-term outcomes and characteristics of long-term survivors were analyzed retrospectively. Multivariate analysis of prognostic factors was performed by the Cox proportional hazard method. RESULTS With a median follow-up of 3.1 years, the median progression-free survival time was 4.6 months. The median survival time was 11.9 months, with 1-, 2- and 3-year survival rates of 49.1%, 22.8%, and 9.8%, respectively. Multivariate analysis showed that good performance status (P = 0.0004) and only one metastatic site (P = 0.0048) were significant independent prognostic factors. Among 48 patients with a single metastatic site, 22 with peritoneal metastasis had longer survival times (median survival, 24 months) than patients with metastasis at other sites. Among the nine 3-year survivors, six had peritoneal metastases alone. CONCLUSIONS The survival outcomes after S-1 monotherapy are promising, especially in patients with good performance status and a single metastatic site. Our findings suggest that, among patients with a single metastatic site, those with peritoneal metastases alone have a chance for long-term survival.
Collapse
Affiliation(s)
- Ayumu Hosokawa
- Department of Internal Medicine, Faculty of Medicine, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
46
|
Lee JL, Kang HJ, Kang YK, Ryu MH, Chang HM, Kim TW, Sohn HJ, Kim H, Lee JS. Phase I/II study of 3-week combination of S-1 and cisplatin chemotherapy for metastatic or recurrent gastric cancer. Cancer Chemother Pharmacol 2007; 61:837-45. [PMID: 17579864 DOI: 10.1007/s00280-007-0541-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Accepted: 06/01/2007] [Indexed: 11/24/2022]
Abstract
PURPOSE To define the maximum-tolerated dose (MTD) of S-1, given daily for 2 weeks followed by a 1-week rest, with a fixed dose of cisplatin on the initial day, and to determine the activity and safety of this regimen at the recommended dose (RD) when used as first line treatment of advanced gastric cancer (AGC). PATIENTS AND METHODS Cisplatin was fixed at a dose of 60 mg/m2 on day 1 (D1) and the starting dose of S-1 was 60 mg/m2/day (30 mg/m2 bid) (level I) on D1 to D14, every 3 weeks. The dose of S-1 was increased by 5 mg/m2 bid up to 100 mg/m2/day (level V) unless the MTD was achieved. RESULTS Sixty-two eligible patients were enrolled. MTD was set at level V with two of three patients developing grade 3 diarrhea or febrile neutropenia. The RD was determined at level IV (90 mg/m2/day). After the first 20 patients were enrolled in phase II, the protocol was amended; the S-1 dose was reduced to 80 mg/m2/day (N=23) because of poor bone marrow recovery. The objective response was observed in 20 of 42 evaluable patients (48%). SD was achieved in 15 (36%). The median PFS was 5.3 months (95% CI, 4.6-6.0 months) with a median OS of 10.0 months (95% CI, 5.1-14.8 months). Grade 3-4 toxicities included neutropenia (33%), anemia (31%), and anorexia (24%). CONCLUSIONS The 3-week combination of cisplatin plus S-1 is active against AGC with favorable toxicitiy profiles. The phase II schedule or doses may need further refinements.
Collapse
Affiliation(s)
- Jae-Lyun Lee
- Division of Oncology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Poongnap-dong, Songpa-gu, Seoul, 138-736, South Korea
| | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Jeung HC, Rha SY, Kim HK, Lim HY, Kim S, Kim SY, Gong SJ, Park CH, Ahn JB, Noh SH, Chung HC. Multi‐Institutional Phase II Study of S‐1 Monotherapy in Advanced Gastric Cancer with Pharmacokinetic and Pharmacogenomic Evaluations. Oncologist 2007; 12:543-54. [PMID: 17522242 DOI: 10.1634/theoncologist.12-5-543] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
This study describes the first phase II study of S-1, a novel oral fluoropyrimidine, in a non-Japanese Asian population with advanced gastric cancer. S-1 was administered twice daily for 28 days every 6 weeks. A pharmacokinetic study was performed on day 28 of cycles 1 and 3. Genomic DNA from peripheral mononuclear cells was analyzed using a cDNA microarray-based comparative genomic hybridization (CGH) method. Thirty-one patients were initially given a dose of 35 mg/m(2) twice daily (bid) (group 1); then, the protocol was amended by increasing the dose to 40 mg/m(2) bid for an additional 31 patients (group 2) because of good tolerability to S-1. The overall response rate was 19.3% (95% confidence interval, 9.2%-29.5%). Over a median follow-up duration of 265 days, the median time to progression and overall survival time were 126 and 264 days, respectively. The 1-year survival rate was 34%. There was no grade 4 toxicity and the major adverse event was anemia. Pharmacokinetic parameters were similar to those of the previous Japanese reports. Microarray CGH identified 18 genes with copy number changes that were associated with hemoglobin reduction with S-1 treatment. A logistic regression analysis, integrating one clinical parameter (initial hemoglobin level) combined with three genetic copy number variations (HIST1H2BL, C10orf127, and XPNPEP2), provided a predictive model for the development of severe hemoglobin reduction. In conclusion, this study showed the feasibility of using S-1 at 35 mg/m(2) bid in gastric cancer. We suggest that the pharmacogenomic markers identified in this study may be potential candidates for predicting anemia after S-1 treatment.
Collapse
Affiliation(s)
- Hei-Cheul Jeung
- Yonsei University College of Medicine, Seodaemun-Ku, CPO Box 8044, Seoul, 120-752, Korea
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Nakata B, Tsuji A, Mitachi Y, Yamamitsu S, Hirata K, Takeuchi T, Shirasaka T, Hirakawa K. Moderate Neutropenia with S-1 Plus Low-dose Cisplatin May Predict a More Favourable Prognosis in Advanced Gastric Cancer. Clin Oncol (R Coll Radiol) 2006; 18:678-83. [PMID: 17100153 DOI: 10.1016/j.clon.2006.07.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
AIMS The effects of haematological adverse events on the prognosis of patients with gastric cancer were investigated. MATERIALS AND METHODS We retrospectively analysed the association between haematological adverse events and prognosis in 23 patients with far advanced or recurrent gastric cancer treated with a JFMC27-9902 regimen consisting of an oral fluorouracil derivative S-1 plus low-dose cisplatin. RESULTS The patients who suffered grade 2-3 neutropenia (n = 10; median survival time [MST] 679 days) were found to have significantly more favourable prognoses than patients who developed grade 0-1 (n = 10; MST 271 days) or grade 4 neutropenia (n = 3; MST 408 days) (P = 0.0039 and 0.0112, respectively), although no significant differences were found among the clinicopathological factors of any grade groups. With respect to anaemia or thrombocytopenia, there were no significant differences among the MSTs of the groups stratified by toxicity grade. Multivariate survival analysis revealed that grade 2-3 neutropenia is an independent predictor of a more favourable prognosis (hazard ratio = 38.693, P = 0.0004). CONCLUSIONS These results suggest that S-1 plus low-dose cisplatin against gastric cancer may contribute to long survival when it induces moderate neutropenia.
Collapse
Affiliation(s)
- B Nakata
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Inokuchi M, Yamashita T, Yamada H, Kojima K, Ichikawa W, Nihei Z, Kawano T, Sugihara K. Phase I/II study of S-1 combined with irinotecan for metastatic advanced gastric cancer. Br J Cancer 2006; 94:1130-5. [PMID: 16570038 PMCID: PMC2361252 DOI: 10.1038/sj.bjc.6603072] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
A dose-escalation study of irinotecan (CPT-11) combined with S-1, an oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was administered orally at 80 mg m−2 day−1 from day 1 to 14 of a 28-day cycle and CPT-11 was given intravenously on day 1 and 8 at an initial dose of 70 mg m−2 day−1, stepping up to 100 mg m−2. The treatment was repeated every 4 weeks, unless disease progression was observed. In the phase I portion, the MTD of CPT-11 was presumed to be 100 mg m−2, because 66.6% of patients (two of three) developed DLTs. All three patients at the initial RD of CPT-11 (90 mg m−2) experienced grade 4 haematological or grade 3 nonhaematological toxicities at second course, followed by the dose reduction of CPT-11 from the third course. Considering safety and the ability to continue treatment, the final RD was determined to be 80 mg m−2. In the phase II portion, 42 patients including seven patients in the final RD phase I portion were evaluated. The median treatment course was five (range: 1–13). The incidences of severe (grade 3–4) haematological and nonhaematological toxicities were 19 and 10%, respectively, but all were manageable. The RR was 62% (26 of 42, 95% confidence interval: 47.2–76.6%), and the median survival time was 444 days. Our phase I/II trial showed S-1 combined with CPT-11 is effective for AGC and is well tolerated, with acceptable toxicity.
Collapse
Affiliation(s)
- M Inokuchi
- Department of Esophagogastric Surgery, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo, and Mutsugi Clinic, Tokyo 113-8519, Japan.
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Tsukuda M, Kida A, Fujii M, Kono N, Yoshihara T, Hasegawa Y, Sugita M. Randomized scheduling feasibility study of S-1 for adjuvant chemotherapy in advanced head and neck cancer. Br J Cancer 2005; 93:884-9. [PMID: 16189518 PMCID: PMC2361656 DOI: 10.1038/sj.bjc.6602804] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The purpose of this study was to determine the feasible adjuvant therapy administration schedule of S-1 for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Patients receiving definitive treatments were randomly assigned to either arm A (51 cases) receiving oral S-1 of 2-week administration followed by 1-week rest for 6 months, or arm B receiving S-1 of 4-week administration followed by 2-week rest for 6 months. Planned treatment was given in 40% of patients in arm A and 29% in arm B. The cumulative rates of the relative total administration dose of S-1 at 100% were 54.9% (95% CI: 40.1–69.7%) in arm A and 34.3% (95% CI: 21.1–47.4%) in arm B, respectively (P=0.054). Adverse events were recorded in 41 patients (82.0%) in arm A and 48 patients (94.1%) in arm B (P=0.060). The incidences of diarrhoea (10 vs 28%; P<0.05) and skin toxicities (18 vs 37%; P<0.05) were significantly higher in arm B. One-year disease-free survival was similar in both arms: arm A 81.2% (95% CI: 70.0–92.4%); arm B 77.0% (95% CI: 65.0–89.0%). The schedule of 2-week administration followed by 1-week rest seems to be more feasible for oral 6-month administration of S-1 in adjuvant chemotherapy of locoregionally advanced SCCHN.
Collapse
Affiliation(s)
- M Tsukuda
- Department of Biology and Function in the Head and Neck, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan.
| | | | | | | | | | | | | |
Collapse
|