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Tokuyama N, Ikeda S, Ishida R, Futai R, Tobimatsu K, Kodama Y. Impaired Consciousness Due to Hyperammonemia During S-1 Administration for Unresectable Pancreatic Cancer. Intern Med 2025; 64:695-698. [PMID: 39048368 PMCID: PMC11949670 DOI: 10.2169/internalmedicine.3771-24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 05/28/2024] [Indexed: 07/27/2024] Open
Abstract
A 71-year-old woman diagnosed with unresectable locally advanced pancreatic cancer was initially treated with gemcitabine and nab-paclitaxel as first-line therapy. The tumor exhibited no significant progression; however, after 12 cycles, the patient developed drug-induced interstitial pneumonia, leading to the discontinuation of gemcitabine and nab-paclitaxel therapy. Following recovery from pneumonia, S-1 therapy was initiated as second-line treatment. During S-1 therapy, she was hospitalized because of impaired consciousness and was subsequently diagnosed with hyperammonemia induced by S-1. Although rarely reported, S-1-induced hyperammonemia is potentially a significant adverse effect. Here, we herein report the case of a patient with pancreatic cancer.
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Affiliation(s)
- Nagahiro Tokuyama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
| | - Sayaka Ikeda
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
| | - Ryosuke Ishida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
| | - Ryoko Futai
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
| | - Kazutoshi Tobimatsu
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
| | - Yuzo Kodama
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Japan
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Kawashima Y, Ishimoto O, Miyauchi E, Sakakibara T, Harada T, Usui K, Inoue A, Sugawara S. Phase II trial of daily S-1 combined with weekly irinotecan in previously treated patients with advanced or recurrent squamous cell lung cancer: North Japan lung cancer group 1101. Thorac Cancer 2023; 14:2804-2810. [PMID: 37589158 PMCID: PMC10518229 DOI: 10.1111/1759-7714.15076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/01/2023] [Accepted: 08/03/2023] [Indexed: 08/18/2023] Open
Abstract
BACKGROUND This phase II trial was designed to evaluate the efficacy and safety of S-1 combined with weekly irinotecan as a second- or third-line treatment for patients with advanced or recurrent squamous cell lung cancer. METHODS Patients with a body surface area <1.25, 1.25-1.50, and >1.50 m2 received oral S-1 on days 1-14 at 80, 100, and 120 mg/day, respectively, and irinotecan on days 1 and 8 at 70 mg/m2 every 3 weeks. The primary endpoint was the overall response rate, and the secondary endpoints were progression-free survival, overall survival, and the incidence and severity of adverse effects. RESULTS Between September 2011 and December 2014, 30 patients were enrolled in this study. The overall response rate was 6.7% (95% confidence interval [CI]: 0.8%-22.1%), and the disease control rate was 73.3%. The median progression-free survival was 3.0 months (95% CI: 2.5-3.4 months), and the median overall survival was 10.5 months (95% CI: 5.6-13.7 months). Grade 3/4 treatment-related adverse events were reported in ≥10% of the patients, including leukopenia (21%), neutropenia (21%), anemia (17%), anorexia (10%), and hypokalemia (10%). CONCLUSIONS Although the treatment-related adverse events were manageable, the combination of weekly irinotecan and S-1 did not have the expected effect.
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Affiliation(s)
- Yosuke Kawashima
- Department of Pulmonary MedicineSendai Kousei HospitalSendaiJapan
| | - Osamu Ishimoto
- Department of Pulmonary MedicineSendai Kousei HospitalSendaiJapan
- Okino Medical ClinicSendaiJapan
| | - Eisaku Miyauchi
- Department of Respiratory MedicineTohoku University Graduate School of MedicineSendaiJapan
| | | | - Toshiyuki Harada
- Department of Respiratory MedicineJCHO Hokkaido HospitalSapporoJapan
| | - Kazuhiro Usui
- Division of RespirologyNTT Medical Center TokyoTokyoJapan
| | - Akira Inoue
- Department of Palliative MedicineTohoku University Graduate School of MedicineSendaiJapan
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3
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Zhang M, Liu C, Zhou H, Wang W, Wang L, Shi B, Xue X. Meta of classical chemotherapy compared with high-dose chemotherapy and autologous stem cell rescue in newly diagnosed medulloblastoma after radiotherapy. Medicine (Baltimore) 2022; 101:e29372. [PMID: 35905255 PMCID: PMC9333539 DOI: 10.1097/md.0000000000029372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND High-dose chemotherapy combined with autologous stem cell rescue (HDCT + ASCR) has been used to treat newly diagnosed medulloblastoma, but there was no high-level evidence to support its efficacy. METHODS Databases were retrieved, and patients were divided into 2 groups: group A was radiotherapy combined with HCDT + ASCR, and group B was classical radiotherapy and chemotherapy. The clinical benefit rate, progression-free survival (PFS), overall survival (OS) and toxicities data were extracted. RESULTS 22 clinical trials met the inclusion criteria, 416 in group A and 2331 in group B. There was no difference in CBR between 2 groups (80.0% vs 71.5%, P.262). The 3-year PFS (3-y PFS) of group A was significantly better than group B (79.0% vs 69.5%, P = .004). The analysis found that there was no difference between the 2 groups of the standard risk group or the high-risk group. In the standard risk group, the 5-y PFS of group A was significantly better than group B (83.6% vs75.6%, P = .004). Comparison of 3-y OS and 5-y OS between 2 groups of all MB patients showed no difference (P = .086; P = .507), stratified analysis was the same result. The gastrointestinal toxicity in group A was significantly higher than that in group B (P = .016), and the level 3/4 ototoxicity in high-risk group A was higher than that in group B (P = .001). CONCLUSIONS HDCT + ASCR can prolong 3-year PFS significantly, and prolong 5-y PFS significantly in the standard risk group, but increase gastrointestinal toxicity significantly for newly diagnosed medulloblastoma.
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Affiliation(s)
- Mengting Zhang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Oncology, Handan Central Hospital, Handan, Hebei, China
| | - Chunmei Liu
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huandi Zhou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Center of Metabolic Diseases and Cancer Research (CMCR), Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wenyan Wang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lixin Wang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Baojun Shi
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoying Xue
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- *Correspondence: Xiaoying Xue, Department of Radiotherapy, The Second Hospital Of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei, China (e-mail: )
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4
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ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer. Cancer Chemother Pharmacol 2019; 84:1229-1239. [DOI: 10.1007/s00280-019-03959-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 09/05/2019] [Indexed: 01/09/2023]
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Tsuchiya T, Matsumoto K, Miyazaki T, Yamaguchi H, Yamazaki T, Sano I, Fukuoka J, Nakamura Y, Yamasaki N, Nagayasu T. Concurrent chemoradiotherapy using cisplatin and S-1, followed by surgery for stage II/IIIA non-small cell lung cancer. Gen Thorac Cardiovasc Surg 2019; 67:537-543. [PMID: 30673966 DOI: 10.1007/s11748-018-01058-3] [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: 11/22/2018] [Accepted: 12/25/2018] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Because chemoradiotherapy using cisplatin and S-1, an oral fluoropyrimidine, is effective for unresectable non-small cell lung cancer (NSCLC), an induction setting was used in a multicenter phase II study (Clinical trial number: UMIN000008205). The correlations of relapse and clinicopathological factors were analyzed. METHODS We defined locally advanced NSCLC as pathologically proven chest wall invasion or hilar and/or mediastinal lymph node metastases by endobronchial ultrasound-guided transbronchial needle aspiration. The patients received two courses of S-1 administration for 14 days and intravenous cisplatin injection on day 8. A total dose of 40 Gy radiotherapy was concurrently received. Surgical resection was performed after completion of the treatment. RESULTS Of the 23 eligible patients, 18 had stage IIIA and 5 had stage IIB NSCLC. Twenty of the eligible patients (87.0%) completed the regimen. Six (26.1%) complete responses were identified and 12 cases (52.2%) were histopathologically downstaged by induction chemoradiotherapy (ICRT). The 3-year overall survival rate was 58.1% and relapse-free survival (RFS) rate was 52.0%, respectively. Among several clinicopathological parameters, univariate RFS analysis identified that only downstaging was significantly associated with longer RFS times (p = 0.003). The radiological response did not reflect pathological response. When the variables of preoperative pathologically proven N2 metastasis, pathological ICRT effectiveness, and downstaging were included in the Cox proportional hazard modes, only the parameter of downstaging displayed significant hazard ratio (hazard ratio 0.13, p = 0.010). CONCLUSION This protocol is considered an option among preoperative therapies and has obvious benefits for pathologically downstaged cases. CLINICAL TRIAL NUMBER UMIN000008205. TRIAL REGISTRATION DATE June 19, 2012.
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Affiliation(s)
- Tomoshi Tsuchiya
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan. .,Clinical Oncology Center, Nagasaki University Hospital, Nagasaki, Japan.
| | - Keitaro Matsumoto
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takuro Miyazaki
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Hiroyuki Yamaguchi
- Second Department of Internal Medicine, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takuya Yamazaki
- Department of Radiology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Isao Sano
- Department of Surgery, The Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
| | - Junya Fukuoka
- Department of Pathology, Nagasaki University Hospital, Nagasaki, Japan
| | - Yoichi Nakamura
- Department of Internal Medicine, Tochigi Cancer Center, Utsunomiya, Japan
| | - Naoya Yamasaki
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
| | - Takeshi Nagayasu
- Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8501, Japan
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Okamoto T, Yano T, Shimokawa M, Takeo S, Yamazaki K, Sugio K, Takenoyama M, Nagashima A, Tsukamoto S, Hamatake M, Yokoyama H, Ueda H, Motohiro A, Tagawa T, Shoji F, Kometani T, Saito G, Fukuyama Y, Toyokawa G, Osoegawa A, Emi Y, Maehara Y. A phase II randomized trial of adjuvant chemotherapy with S-1 versus S-1 plus cisplatin for completely resected pathological stage II/IIIA non-small cell lung cancer. Lung Cancer 2018; 124:255-259. [PMID: 30268470 DOI: 10.1016/j.lungcan.2018.08.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 07/03/2018] [Accepted: 08/17/2018] [Indexed: 12/25/2022]
Abstract
OBJECTIVES Platinum-based combination chemotherapy is the standard postoperative adjuvant treatment for pathological stage II/III non-small cell lung cancer (NSCLC). Oral S-1 therapy has good efficacy and relatively low toxicity for the treatment of advanced NSCLC. We investigated whether long-term S-1 monotherapy is also useful as an adjuvant therapy after surgery in patients with NSCLC. PATIENTS AND METHODS We conducted a phase II randomized open-label multi-institutional study in patients with pathological stage II/IIIA NSCLC (7th TNM classification) who underwent complete resection from 2009 to 2013. The primary endpoint, the 2-year disease-free survival (DFS) rate, was evaluated using the Bayesian method. Eligible patients were randomly assigned to two arms: oral S-1 monotherapy (S-1 arm) and S-1 plus cisplatin combination therapy followed by S-1 (S-1 plus cisplatin arm) both for a total of 1 year. RESULTS A total of 70 and 71 patients were enrolled in S-1 arm and S-1 plus cisplatin arm, respectively. The 2-year DFS rates were 52% (95% confidence interval [CI], 0.40-0.63) and 61% (95% CI, 0.48-0.70) for S-1 arm and S-1 plus cisplatin arm, respectively. Both arms met the primary endpoint. Neither DFS nor OS was significantly different between the arms (log-rank test: P = 0.1695 and P = 0.8684, respectively). The main G3/4 adverse events were loss of appetite and anemia (S-1 vs. S-1 plus cisplatin: 4.3% vs. 11.6% and 0% vs. 5.8%, respectively). The treatment completion rate did not differ between the two arms (S-1 vs. S-1 plus cisplatin: 45.7%, 95% CI, 41.9-66.3% vs. 43.5% 95% CI, 44.0-68.4%). CONCLUSIONS Long-term adjuvant chemotherapy with S-1 was a feasible and promising treatment for patients with completely resected NSCLC, regardless of cisplatin addition. S-1 monotherapy should be investigated further, based on its low toxicity and practical convenience.
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Affiliation(s)
- Tatsuro Okamoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan.
| | - Tokujiro Yano
- Department of General Thoracic Surgery, National Hospital Organization Beppu Medical Center, Beppu, Japan
| | | | - Sadanori Takeo
- Department of Thoracic Surgery and Clinical Research Institute, National Hospital Organization Kyushu Medical Center Hospital, Fukuoka, Japan
| | - Koji Yamazaki
- Department of Thoracic Surgery and Clinical Research Institute, National Hospital Organization Kyushu Medical Center Hospital, Fukuoka, Japan; Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | - Kenji Sugio
- Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan; Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan
| | | | - Akira Nagashima
- Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
| | - Shuichi Tsukamoto
- Department of Thoracic Surgery, Steel Memorial Yawata Hospital, Kitakyushu, Japan
| | - Motoharu Hamatake
- Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan; Department of Surgery, Hiroshima Red Cross Hospital and Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Hideki Yokoyama
- Department of Thoracic Surgery, Matsuyama Red Cross Hospital, Matsuyama, Japan
| | - Hitoshi Ueda
- Department of Surgery, National Hospital Organization Fukuoka Hospital, Fukuoka, Japan
| | - Akira Motohiro
- Department of Thoracic Surgery, Oita Red Cross Hospital, Oita, Japan
| | - Tetsuzo Tagawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Thoracic Surgery, Oita Red Cross Hospital, Oita, Japan
| | - Fumihiro Shoji
- Department of Thoracic Surgery, Oita Red Cross Hospital, Oita, Japan; Department of Thoracic Surgery, Kyushu Center Hospital, Fukuoka, Japan
| | - Takuro Kometani
- Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan; Department of Thoracic Surgery, National Hospital Organization Oita Medical Center, Oita, Japan
| | - Genkichi Saito
- Department of Thoracic Surgery, Kyushu Center Hospital, Fukuoka, Japan
| | - Yasuro Fukuyama
- Department of Thoracic Surgery, Nakatsu Municipal Hospital, Nakatsu, Japan
| | - Gouji Toyokawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Atsushi Osoegawa
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Thoracic and Breast Surgery, Oita University Faculty of Medicine, Oita, Japan
| | - Yasunori Emi
- Department of Surgery, Saiseikai Fukuoka General Hospital, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Zhao D, Feng JF, Wang XH. A retrospective study of concurrent radiotherapy plus S-1 for treating advanced non-small cell lung cancer. Medicine (Baltimore) 2018; 97:e10740. [PMID: 29851779 PMCID: PMC6392540 DOI: 10.1097/md.0000000000010740] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
We investigated the efficacy of concurrent radiotherapy plus S-1 (CRS) for treating unresectable stage III advanced non-small-cell lung cancer (ANSCLC).Seventy five ANSCLC patients were included in this retrospective study. Of those, 40 patients were assigned to an intervention group, and received S-1 (orally at 40 mg/m) twice daily for 14 consecutive days. Then, concurrent radiotherapy was administered in 2 Gy fractions, 5 times weekly for a total dose of 60 Gy. The other 35 patients were assigned to a control group, and underwent concurrent radiotherapy (the same as the intervention group) and cisplatin (60 mg/m on day 1 (CRC). The outcome measurements included overall response rate (ORR), overall survival (OS), progression-free survival (PFS), and toxicity.The 3-year ORR was 60.7% and 43.9% for intervention group and control group, respectively (P = .031). The median OS was 34.1 months and 25.3 months in the intervention and control groups, respectively (P = .041). The median PFS was 31.5 months for intervention group, while it was 22.4 months for control group (P = .048). No significant difference in toxicity was found between the 2 groups.The results demonstrated that the efficacy of CRS was superior to the CRC in ANSCLC patients with similar toxicity.
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Affiliation(s)
- Dejun Zhao
- Department of Respiratory Medicine, The People's Hospital of Fuyang
| | - Jun-fei Feng
- Department of Respiratory Medicine, Hangzhou Fuyang Hospital of Traditional Chinese Medicine, Hangzhou, China
| | - Xue-hui Wang
- Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
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Yang L, Yang S, Liu Y, Li J, Hu X, Wang Y, Zhang Y, Wang Y. Combination TS-1 plus EGFR-tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer after progression on first-line or further EGFR-TKIs: A phase II, single-arm trial. Thorac Cancer 2018; 9:693-698. [PMID: 29655198 PMCID: PMC5983211 DOI: 10.1111/1759-7714.12632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 02/26/2018] [Accepted: 02/26/2018] [Indexed: 12/27/2022] Open
Abstract
Background EGFR‐tyrosine kinase inhibitors (TKIs) combined with TS‐1 might overcome EGFR‐TKI resistance, which has been indicated by several preclinical studies. We investigated the synergistic efficacy and safety of the combination therapy of EGFR‐TKIs and TS‐1 in non‐small cell lung cancer (NSCLC) patients with acquired resistance to previous EGFR‐TKI therapy. Methods This was a phase II, single‐arm and single‐center prospective study. Stage IIIB–IV NSCLC patients with acquired resistance to prior EGFR‐TKI treatment were enrolled. All patients were administered combination therapy of TS‐1 and continuing EGFR‐TKIs in this study. The primary endpoints were progression‐free survival (PFS), while overall survival (OS), disease control rate (DCR), and safety were secondary endpoints. Results A total of 42 patients with acquired resistance to EGFR‐TKIs were eligible for this study. The median PFS for all patients was five months (95% confidence interval [CI] 3.6–5.4). The OS and DCR were 31.9 (95% CI 17.8–46.0) months and 69.0% (29/42), respectively. No grade 4 toxicity or grade 3 hematologic toxicity was observed in this study. One patient (2%) experienced grade 3 elevated total serum bilirubin. Conclusion The combination treatment of TS‐1 and EGFR‐TKIs was effective and well tolerated by patients who had experienced prior EGFR‐TKI treatment failure. Our results need to be validated by larger prospective clinical trials.
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Affiliation(s)
- Lu Yang
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Sheng Yang
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yutao Liu
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Junling Li
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xingsheng Hu
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yalei Wang
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Zhang
- Medical Oncology Department, Tianjin Haihe Hospital, Tianjin, China
| | - Yan Wang
- Medical Oncology Department, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Honma Y, Togo S, Shimizu K, Tulafu M, Hayashi T, Uekusa T, Tominaga S, Kido K, Fujimoto Y, Nanba Y, Takamochi K, Oh S, Suzuki K, Takahashi K. Expression of thymidylate synthase predicts clinical outcomes of S-1-based chemotherapy in squamous cell lung cancer. Oncol Lett 2017; 14:3319-3326. [PMID: 28927083 PMCID: PMC5587968 DOI: 10.3892/ol.2017.6610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 01/09/2017] [Indexed: 11/06/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) patients with squamous cell carcinoma (SCC) histology have limited chemotherapeutic options. Treatment with S-1 combined with carboplatin (CBDCA) has been shown to provide a significant survival benefit in SCC patients compared with treatment with combined CBDCA and paclitaxel. The aim of the present study was to investigate the association between the expression of molecular markers related to the pharmacological action of S-1, including thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT) and dihydropyrimidine dehydrogenase (DPD), and the clinical efficacy of S-1-based chemotherapy in SCC patients. The immunohistochemical expression of TS, OPRT and DPD were retrospectively analyzed in tumor biopsy and resection specimens from patients with advanced SCC (n=32). Immunohistochemical H-scores were calculated and their association with S-1/CBDCA response was evaluated. Median progression-free survival time was significantly longer in patients with low TS H-scores than in those with high TS H-scores (162.5 vs. 97 days; P=0.004); by contrast, overall survival time was not observed to differ significantly between these groups (P=0.185). In the multivariate analysis, low TS expression was a significant positive factor for progression-free survival rate (hazard ratio, 0.40; P=0.021). A low TS H-score was also associated with an increased response to S-1-based chemotherapy compared with a high TS H-score (P=0.002). This indicates that SCC patients with low TS expression can benefit significantly from S-1-based chemotherapy, and that H-score measurement of intratumoral TS expression may represent a useful predictive biomarker for response to S-1-based chemotherapy by patients with SCC-type NSCLC.
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Affiliation(s)
- Yuichiro Honma
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Shinsaku Togo
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazue Shimizu
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Miniwan Tulafu
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Takuo Hayashi
- Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Toshimasa Uekusa
- Department of Pathology, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, Kawasaki, Kanagawa 211-8510, Japan
| | - Shigeru Tominaga
- Department of Respiratory Medicine, Juntendo University Urayasu Hospital, Urayasu, Chiba 279-0021, Japan
| | - Kenji Kido
- Department of Respiratory Medicine, Juntendo University Nerima Hospital, Tokyo 177-8521, Japan
| | - Yuichi Fujimoto
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Yukiko Nanba
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazuya Takamochi
- Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Shiaki Oh
- Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kenji Suzuki
- Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Kazuhisa Takahashi
- Department of Respiratory Medicine, Juntendo University Faculty of Medicine & Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan.,Research Institute for Diseases of Old Ages, Juntendo University Graduate School of Medicine, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Kaira K, Yanagitani N, Sunaga N, Imai H, Ono A, Koga Y, Hisada T, Ishizuka T, Yamada M. Prospective exploratory study of gemcitabine and S-1 against elderly patients with advanced non-small cell lung cancer. Oncol Lett 2017; 14:1123-1128. [PMID: 28693283 DOI: 10.3892/ol.2017.6259] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2016] [Accepted: 03/03/2017] [Indexed: 11/06/2022] Open
Abstract
A prospective study was conducted to investigate the efficacy of a combined regimen of gemcitabine and S-1 for the treatment of elderly patients (>70 years) with advanced non-small cell lung cancer (NSCLC) as a first-line setting based on the dosage recommended in a previous phase I study. Chemotherapy-naïve patients with advanced NSCLC received gemcitabine plus S-1. S-1 (40 mg/m2) was administered orally twice daily for 14 days while gemcitabine (1,000 mg/m2) was administered on days 1 and 15 of each cycle, and this regimen was repeated every 4 weeks. A total of 20 patients were included in the present study. Of these, 8 patients achieved an overall response rate of 40.0%, and the overall disease control rate was 65.0%. According to the histological type, the response rate in patients with NSCLC and adenocarcinoma was 38.5%, and that for non-adenocarcinoma was 42.9%. Progression-free survival and median survival times were 6.4 months and 17.8 months, respectively. Grade 3 or 4 hematological toxicities observed were leukopenia (29%) and neutropenia (24%), while febrile neutropenia was not observed in any patient. The only non-hematological adverse event observed was grade 3 skin rash (10%). Therefore, the combination of gemcitabine and S-1 may be a promising and feasible regimen in the first-line setting for elderly patients with advanced NSCLC.
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Affiliation(s)
- Kyoichi Kaira
- Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.,Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Noriko Yanagitani
- Department of Thoracic Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan
| | - Noriaki Sunaga
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan.,Oncology Center, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Hisao Imai
- Department of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Gunma 373-8550, Japan
| | - Akihiro Ono
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Yasuhiko Koga
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Takeshi Hisada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
| | - Tamotsu Ishizuka
- Third Department of Internal Medicine, University of Fukui, Yoshida, Fukui 910-1193, Japan
| | - Masanobu Yamada
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma University Hospital, Maebashi, Gunma 371-8511, Japan
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Matsubara T, Nishida T, Tomimaru Y, Yamamoto M, Hayashi S, Nakajima S, Fukui K, Dono K, Adachi S, Ioka T, Kanai M, Inada M. Histological complete response in a patient with advanced biliary tract cancer treated by gemcitabine/cisplatin/S-1 combination chemotherapy: A case report. Mol Clin Oncol 2017; 5:757-761. [PMID: 28101354 PMCID: PMC5228213 DOI: 10.3892/mco.2016.1065] [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: 08/23/2016] [Accepted: 10/13/2016] [Indexed: 12/30/2022] Open
Abstract
A 68-year-old woman was referred to our hospital with increased levels of biliary enzymes. On imaging, the patient was diagnosed with unresectable intrahepatic biliary tract cancer (BTC) with invasion of the portal vein and para-aortic lymph node metastasis (cT3N1M1, cStage IVb) and underwent endoscopic biliary drainage for the biliary stricture prior to therapy. The patient was subsequently enrolled in a phase III randomized trial (UMIN000014371/NCT02182778) and randomly assigned to receive gemcitabine/cisplatin/S-1 (GCS) combination therapy intravenously at doses of 1,000 or 25 mg/m2 on day 1 and orally twice daily at a dose of 80 mg/m2 on days 1–7 every 2 weeks. After 12 cycles of scheduled therapy without uncontrollable adverse effects, the patient achieved a good partial response with chemotherapy. Computed tomography (CT) revealed a marked reduction of the primary and metastatic lesions. In addition,18F-fluorodeoxyglucose-positron emission tomography/CT revealed diminishing abnormal uptake and no macroscopic evidence of factors adversely affecting tumor resectability. Therefore, the patient underwent extended right hepatic lobectomy, lymph node dissection and left hepaticojejunostomy. Finally, histological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. We herein present the case of a patient with intrahepatic BTC who achieved a pathologically complete response following combination chemotherapy with GCS.
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Affiliation(s)
- Tokuhiro Matsubara
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Tsutomu Nishida
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Yoshito Tomimaru
- Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Masashi Yamamoto
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Shiro Hayashi
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Sachiko Nakajima
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Koji Fukui
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Keizo Dono
- Department of Surgery, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Shiro Adachi
- Department of Pathology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
| | - Tatsuya Ioka
- Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-0025, Japan
| | - Masashi Kanai
- Department of Clinical Oncology and Pharmacogenomics, Kyoto University Hospital, Kyoto 606-8507, Japan
| | - Masami Inada
- Department of Gastroenterology, Toyonaka Municipal Hospital, Toyonaka, Osaka 560-8565, Japan
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Feng J, Xu J, Wang X, Zhao D. S-1 plus cisplatin with concurrent radiotherapy versus cisplatin alone with concurrent radiotherapy in Chinese patients with nonsmall-cell lung cancer: A multicentre randomized controlled trial. Medicine (Baltimore) 2016; 95:e4557. [PMID: 27603346 PMCID: PMC5023868 DOI: 10.1097/md.0000000000004557] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND The aim of this study was to investigate the efficacy and safety of S-1 plus cisplatin combined with concurrent radiotherapy (SCCCR) versus cisplatin alone combined with concurrent radiotherapy (CCCR) in Chinese patients with unresectable stage III nonsmall-cell lung cancer (NSCLC). METHODS Between January 2012 and December 2014, 72 eligible Chinese patients with NSCLC were included and randomly divided into 2 groups, each having 36 patients. Patients in the SCCCR group received S-1 plus cisplatin with concurrent, radiotherapy. The other 36 patients in the CCCR group were administered cisplatin with concurrent radiotherapy. The primary outcome was the overall response rate. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and adverse events. RESULTS The 3-year overall response rates for the SCCCR and CCCR groups were 60.1% and 53.3%, respectively (P = 0.041). The median OS was 35.1 (range, 6.5-47.2) months and 24.6 (range, 2.8-24.3) months for the SCCCR and CCCR groups, respectively (P = 0.016). The median PFS for the SCCCR and CCCR groups was 31.4 (range, 5.6-39.3) months and 22.3 (range, 2.4-36.5) months, respectively (P = 0.023). The toxicity profiles were similar for both groups. CONCLUSION The efficacy and safety of SCCCR was more encouraging compared to those of CCCR in Chinese NSCLC patients. In addition, the toxicities in both groups were tolerable.
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Affiliation(s)
| | - Jinquan Xu
- Department of Cardiovascular Medicine, Hangzhou Fuyang Hospital of Traditional Chinese Medicine, Hangzhou
| | - Xuehui Wang
- Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin
- Correspondence: Xuehui Wang, Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin 150040, China (e-mail: ); Dejun Zhao, Department of Respiratory Medicine, The People's Hospital of Fuyang, No. 400 Jinqiaobei Road, Hangzhou 311400, China (e-mail: )
| | - Dejun Zhao
- Department of Respiratory Medicine, The People's Hospital of Fuyang, Hangzhou, China
- Correspondence: Xuehui Wang, Department of Respiratory Medicine, First Affiliated Hospital of Heilongjiang University of Chinese Medicine, No. 24, Heping Road, Xiangfang District, Harbin 150040, China (e-mail: ); Dejun Zhao, Department of Respiratory Medicine, The People's Hospital of Fuyang, No. 400 Jinqiaobei Road, Hangzhou 311400, China (e-mail: )
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Suzuki S, Karayama M, Inui N, Fujisawa T, Enomoto N, Nakamura Y, Kuroishi S, Matsuda H, Yokomura K, Koshimizu N, Toyoshima M, Imokawa S, Asada K, Masuda M, Yamada T, Watanabe H, Suda T. Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer. Invest New Drugs 2016; 34:490-6. [DOI: 10.1007/s10637-016-0365-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 05/26/2016] [Indexed: 11/24/2022]
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Wang T, Zhang SF, Qiu MQ, Li QL. Efficacy and safety of S-1 (tegafur, gimeracil, and oteracil potassium) concurrent with 3-dimensional conformal radiotherapy for newly diagnosed squamous cell carcinoma of the lung in elderly patients. Cancer Radiother 2016; 20:181-6. [DOI: 10.1016/j.canrad.2015.12.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 11/20/2015] [Accepted: 12/02/2015] [Indexed: 11/30/2022]
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15
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Wang Y, Xing D, Zhao M, Wang J, Yang Y. The Role of a Single Angiogenesis Inhibitor in the Treatment of Recurrent Glioblastoma Multiforme: A Meta-Analysis and Systematic Review. PLoS One 2016; 11:e0152170. [PMID: 27007828 PMCID: PMC4805294 DOI: 10.1371/journal.pone.0152170] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/09/2016] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Currently, the standard treatment for newly diagnosed glioblastoma multiforme (GBM) is maximal safe surgical resection followed by radiation therapy with concurrent and adjuvant temozolomide. However, disease recurs in almost all patients, and the optimal salvage treatment for recurrent GBM remains unclear. We conducted a systematic review and meta-analysis of published clinical trials to assess the efficacy and toxicities of angiogenesis inhibitors alone as salvage treatment in these patients. METHODS Trials published between 1994 and 2015 were identified by an electronic search of public databases (MEDLINE, EMBASE, Cochrane library). Demographic data, treatment regimens, objective response rate (ORR), median progression-free survival (PFS), median overall survival (OS), 6-months PFS rate, 1-year OS and grade 3/4 toxicities were extracted. We also compared the main outcomes of interest between bevacizumab and other angiogenesis inhibitors. All analyses were performed using Comprehensive Meta Analysis software (Version 2.0). RESULTS A total of 842 patients were included for analysis: 343 patients were treated with bevacizumab, 386 with other angiogenesis inhibitors and 81 with thalidomide. The pooled ORR, 6-months PFS, and 1-year OS for recurrent GBM patients receiving angiogenesis inhibitors was 20.1%, 19.5% and 29.3%, respectively. The use of single agent bevacizumab in recurrent GBM significantly improved ORR and 6-months PFS when compared to other angiogenesis inhibitors [relative risk (RR) 2.93, 95% CI 1.38-6.21; p = 0.025; and RR 2.36 95% CI 1.46-3.82; p<0.001, respectively], while no significant difference in 1-year OS was found between the two groups (p = 0.07). when compared to thalidomide, bevacizumab treatment in recurrent GBM significantly improved ORR (RR 6.8, 95%CI: 2.64-17.6, p<0.001), but not for 6-months PFS (p = 0.07) and 1-year OS (p = 0.31). As for grade 3/4 toxicities, the common toxicity was hypertension with pooled incidence of 12.1%, while high-grade thromboembolic events (2.2%), hemorrhage (5.1%) and GI perforation (2.8%) associated with angiogenesis inhibitors were relatively low. CONCLUSIONS In comparison with other angiogenesis inhibitors and thalidomide, the use of single agent bevacizumab as salvage treatment for recurrent GBM patients improve ORR and 6-months PFS, but not for 1-year OS.
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Affiliation(s)
- Yawei Wang
- Department of Electromyography, Tianjin Hospital, Tianjin, China
| | - Dan Xing
- Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University, Beijing, China
| | - Meng Zhao
- Clinical laboratory, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
| | - Jie Wang
- Department of Orthopedics, Tianjin Hospital, Tianjin, China
| | - Yang Yang
- Department of Orthopedics, Tianjin Hospital, Tianjin, China
- * E-mail:
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16
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Iwamoto Y, Mitsudomi T, Sakai K, Yamanaka T, Yoshioka H, Takahama M, Yoshimura M, Yoshino I, Takeda M, Sugawara S, Kawaguchi T, Takahashi T, Ohta M, Ichinose Y, Atagi S, Okada M, Saka H, Nakagawa K, Nakanishi Y, Nishio K. Randomized Phase II Study of Adjuvant Chemotherapy with Long-term S-1 versus Cisplatin+S-1 in Completely Resected Stage II–IIIA Non–Small Cell Lung Cancer. Clin Cancer Res 2015; 21:5245-52. [DOI: 10.1158/1078-0432.ccr-14-3160] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 07/12/2015] [Indexed: 11/16/2022]
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Watanabe A, Kida M, Miyazawa S, Iwai T, Okuwaki K, Kaneko T, Yamauchi H, Takezawa M, Imaizumi H, Koizumi W. Phase I trial of combination chemotherapy with gemcitabine, cisplatin, and S-1 in patients with advanced biliary tract cancer. World J Gastroenterol 2015; 21:5979-5984. [PMID: 26019463 PMCID: PMC4438033 DOI: 10.3748/wjg.v21.i19.5979] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the dose-limiting toxicities (DLTs) and determine the maximum-tolerated dose (MTD) and recommended dose (RD) of combination chemotherapy with gemcitabine, cisplatin and S-1 which is an oral fluoropyrimidine pro-drug in patients with advanced biliary tract cancer.
METHODS: Patients with histologically or cytologically confirmed unresectable or recurrent biliary tract cancer were enrolled. The planned dose levels of gemcitabine (mg/m2), cisplatin (mg/m2), and S-1 (mg/m2 per day) were as follows: level -1, 800/20/60; level 0, 800/25/60; level 1, 1000/25/60; and level 2, 1000/25/80. In each cycle, gemcitabine and cisplatin were administered intravenously on days 1 and 15, and S-1 was administered orally twice daily on days 1 to 7 and days 15 to 21, every 4 wk.
RESULTS: Twelve patients were enrolled, and level 0 was chosen as the starting dose. None of the first three patients had DLTs at level 0, and the dose was escalated to level 1. One of six patients had DLTs (grade 4 febrile neutropenia, leucopenia, and neutropenia; grade 3 thrombocytopenia) at level 1. We then proceeded to level 2. None of three patients had DLTs during the first cycle. Although the MTD was not determined, level 2 was designated at the RD for a subsequent phase II study.
CONCLUSION: The RD was defined as gemcitabine 1000 mg/m2 (days 1, 15), cisplatin 25 mg/m2 (days 1, 15), and S-1 80 mg/m2 per day (days 1-7, 15-21), every 4 weeks. A phase II study is planned to evaluate the effectiveness of combination chemotherapy with gemcitabine, cisplatin, and S-1 in advanced biliary tract cancer.
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18
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Kubota K, Sakai H, Katakami N, Nishio M, Inoue A, Okamoto H, Isobe H, Kunitoh H, Takiguchi Y, Kobayashi K, Nakamura Y, Ohmatsu H, Sugawara S, Minato K, Fukuda M, Yokoyama A, Takeuchi M, Michimae H, Gemma A, Kudoh S. A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol 2015; 26:1401-8. [PMID: 25908605 PMCID: PMC4478975 DOI: 10.1093/annonc/mdv190] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 04/13/2015] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Platinum-based two-drug combination chemotherapy has been standard of care for patients with advanced nonsmall-cell lung cancer (NSCLC). The primary aim was to compare overall survival (OS) of patients with advanced NSCLC between the two chemotherapy regimens. Secondary end points included progression-free survival (PFS), response, safety, and quality of life (QoL). PATIENTS AND METHODS Patients with previously untreated stage IIIB or IV NSCLC, an Eastern Cooperative Oncology Group performance status of 0-1 and adequate organ function were randomized to receive either oral S-1 80 mg/m(2)/day on days 1-21 plus cisplatin 60 mg/m(2) on day 8 every 4-5 weeks, or docetaxel 60 mg/m(2) on day 1 plus cisplatin 80 mg/m(2) on day 1 every 3-4 weeks, both up to six cycles. RESULTS A total of 608 patients from 66 sites in Japan were randomized to S-1 plus cisplatin (n = 303) or docetaxel plus cisplatin (n = 305). OS for oral S-1 plus cisplatin was noninferior to docetaxel plus cisplatin [median survival, 16.1 versus 17.1 months, respectively; hazard ratio = 1.013; 96.4% confidence interval (CI) 0.837-1.227]. Significantly higher febrile neutropenia (7.4% versus 1.0%), grade 3/4 neutropenia (73.4% versus 22.9%), grade 3/4 infection (14.5% versus 5.3%), and grade 1/2 alopecia (59.3% versus 12.3%) were observed in the docetaxel plus cisplatin than in the S-1 plus cisplatin. There were no differences found in PFS or response between the two arms. QoL data investigated by EORTC QLQ-C30 and LC-13 favored the S-1 plus cisplatin. CONCLUSION Oral S-1 plus cisplatin is not inferior to docetaxel plus cisplatin and is better tolerated in Japanese patients with advanced NSCLC. CLINICAL TRIAL NUMBER UMIN000000608.
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Affiliation(s)
- K Kubota
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo
| | - H Sakai
- Department of Thoracic Oncology, Saitama Cancer Center, Kita-adachi-gun
| | - N Katakami
- Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe
| | - M Nishio
- Department of Thoracic Medical Oncology, Cancer Institute Hospital of JFCR, Tokyo
| | - A Inoue
- Clinical Research, Innovation and Education Center, Tohoku University Hospital, Sendai
| | - H Okamoto
- Department of Respiratory Medicine and Medical Oncology, Yokohama Municipal Citizen's Hospital, Hodogaya-ku
| | - H Isobe
- Department of Medical Oncology, KKR Sapporo Medical Center, Sapporo
| | - H Kunitoh
- Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo
| | - Y Takiguchi
- Department of Medical Oncology, Graduate School of Medicine, Chiba University, Chiba
| | - K Kobayashi
- Department of Respiratory Medicine, Saitama Medical University International Medical Center, Saitama
| | - Y Nakamura
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki
| | - H Ohmatsu
- Division of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa
| | - S Sugawara
- Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai
| | - K Minato
- Department of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota
| | - M Fukuda
- Department of Respiratory Medicine, National Hospital Organization Nagasaki Medical Center, Omura
| | - A Yokoyama
- Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata
| | - M Takeuchi
- Department of Clinical Medicine (Biostatistics and Pharmaceutical Medicine), Kitasato University School of Pharmacy, Tokyo
| | - H Michimae
- Department of Clinical Medicine (Biostatistics and Pharmaceutical Medicine), Kitasato University School of Pharmacy, Tokyo
| | - A Gemma
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo
| | - S Kudoh
- Double-Barred Cross Hospital Japan Anti-Tuberculosis Association, Tokyo, Japan
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Yao L, Xu S, Xu J, Yang C, Wang J, Sun D. S-1 plus cisplatin with concurrent radiotherapy versus cisplatin alone with concurrent radiotherapy for stage III non-small cell lung cancer: a pilot randomized controlled trial. Radiat Oncol 2015; 10:10. [PMID: 25572571 PMCID: PMC4311504 DOI: 10.1186/s13014-014-0306-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 12/15/2014] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND We investigated the efficacy and safety of S-1 and cisplatin with concurrent thoracic radiation (SCCR) over cisplatin alone plus concurrent thoracic radiation (CCR) for unresectable stage III non-small-cell lung cancer (NSCLC). METHODS Between January 2009 and November 2011, 40 eligible patients with NSCLC were included and divided randomly into two groups. Twenty patients received SCCR with S-1 (orally at 40 mg/m(2) per dose, b.i.d.) on days 1 through 14, cisplatin (60 mg/m(2) on day 1) every 4 weeks for two cycles, and radiotherapy (60 Gy/30 fractions over 6 weeks) beginning on day 1. Twenty subjects received CCR (cisplatin and radiotherapy, the same as for SCCR). RESULTS The 3-year overall response rate was 59.3% and 52.4% for the SCCR and CCR groups, respectively, and the difference was statistically significant, while the median overall survival was 33 months (range, 4-41 months) and 24 months (range, 2-37 months), respectively (P = 0.048). The median progression-free survival was 31 months for SCCR (range, 5-39 months), whereas it was 20 months (range, 2-37 months) for CCR (P = 0.037). The toxicity profile was similar in both groups. CONCLUSION In summary, we demonstrated that S-1 and cisplatin with concurrent thoracic radiation was more effective than cisplatin plus radiotherapy in NSCLC patients with acceptable toxicity. TRIAL REGISTRATION Chinese Clinical Trials Register: ChiCTR-TRC-13003997 .
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Affiliation(s)
- Lei Yao
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Shidong Xu
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Jianyu Xu
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Chaoyang Yang
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Junfeng Wang
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
| | - Dawei Sun
- Department of Chest Surgery, Third Affiliated Hospital of Harbin Medical University, Haping Road No.150, Nangang District, Harbin, Heilongjiang Province, 150081, China.
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A multi-institution phase II study of gemcitabine/cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002). Cancer Chemother Pharmacol 2014; 75:293-300. [DOI: 10.1007/s00280-014-2648-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Accepted: 12/02/2014] [Indexed: 01/15/2023]
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Tang Y, Wang W, Teng XZ, Shi L. Efficacy of S-1 plus nedaplatin compared to standard second-line chemotherapy in EGFR-negative lung adenocarcinoma after failure of first-line chemotherapy. Tumour Biol 2014; 35:8945-51. [PMID: 24899263 DOI: 10.1007/s13277-014-2155-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2014] [Accepted: 05/26/2014] [Indexed: 11/25/2022] Open
Abstract
For patients with advanced non-small cell lung adenocarcinoma that fail to respond to first-line chemotherapy and that do not involve epidermal growth factor receptor (EGFR) mutations, previous empirical analysis showed that a single second-line chemotherapy agent may be inadequate for the control of further tumor development. This study examines the combination of S-1 drugs and nedaplatin that has no cross-resistance to first-line treatments; 179 cases of IIIb-IV stage non-small-cell lung adenocarcinoma that failed to respond to first-line chemotherapy were included, and these subjects did not have mutated EGFRs. In the present study, S-1 plus nedaplatin chemotherapy was better than standard second-line chemotherapy options in the treatment of advanced lung adenocarcinoma that did not involve EGFR mutations and that failed to respond to first-line chemotherapy. Additionally, the combination of S-1 and nedaplatin seemed to be well tolerated, making this chemotherapy technique a potentially strong candidate for the treatment of advanced non-small-cell lung adenocarcinoma.
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Affiliation(s)
- Yu Tang
- Department of Oncology, Liaoning Cancer Hospital & Institute, 44 Xiaoheyan Road, Dadong District, Shenyang, 110042, Liaoning, China,
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Hisamatsu Y, Murakami H, Akamatsu H, Kimura M, Mori K, Imai H, Ono A, Shukuya T, Taira T, Kenmotsu H, Naito T, Endo M, Nakajima T, Takahashi T, Yamamoto N. Differences in the efficacy of S-1 monotherapy according to histological type in pretreated patients with advanced non-small cell lung cancer. Thorac Cancer 2014; 5:121-5. [PMID: 26766988 DOI: 10.1111/1759-7714.12071] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Accepted: 07/29/2013] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND S-1 is a novel antimetabolic agent that inhibits thymidylate synthase. The expression of thymidylate synthase is higher in squamous (Sq) non-small cell lung cancer (NSCLC) than in non-Sq NSCLC. The aim of this retrospective study was to assess the efficacy of S-1 monotherapy for advanced NSCLC according to the histological subtype. METHODS We reviewed the clinical records of patients with advanced NSCLC treated with S-1 monotherapy as second- or third-line therapy between May 2005 and July 2012 at the Shizuoka Cancer Center. RESULTS A total of 71 patients were included in this retrospective study. Patient characteristics were similar in the Sq NSCLC (n = 15) and non-Sq NSCLC (n = 56) groups, except with regard to gender and smoking status. The overall response rates were 0% (95% confidence interval [CI] 0-17%) for Sq NSCLC and 11% (95% CI 3-19%) for non-Sq NSCLC (P = 0.33). For Sq NSCLC and non-Sq NSCLC, the median progression-free survival times were 2.1 and 2.8 months (P = 0.02), respectively, and the median overall survival times were 6.1 and 10.1 months (P = 0.01), respectively. CONCLUSION S-1 monotherapy may be more effective in patients with non-Sq NSCLC than in those with Sq NSCLC.
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Affiliation(s)
- Yasushi Hisamatsu
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan; Department of Medical Oncology, Oita University Hospital Oita, Japan
| | - Haruyasu Murakami
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Hiroaki Akamatsu
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Madoka Kimura
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Keita Mori
- Division of Clinical Trial Coordination office, Shizuoka Cancer Center Shizuoka, Japan
| | - Hisao Imai
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Akira Ono
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Takehito Shukuya
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan; Department of Respiratory Medicine, School of Medicine, Juntendo University Tokyo, Japan
| | - Tetsuhiko Taira
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | | | - Tateaki Naito
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan
| | - Masahiro Endo
- Division of Diagnostic Radiology, Shizuoka Cancer Center Shizuoka, Japan
| | - Takashi Nakajima
- Division of Diagnostic Pathology, Shizuoka Cancer Center Shizuoka, Japan
| | | | - Nobuyuki Yamamoto
- Division of Thoracic Oncology, Shizuoka Cancer Center Shizuoka, Japan; The Third Department of Internal Medicine, Wakayama Medical University Wakayama, Japan
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Mochinaga K, Tsuchiya T, Nagasaki T, Arai J, Tominaga T, Yamasaki N, Matsumoto K, Miyazaki T, Nanashima A, Hayashi T, Tsukamoto K, Nagayasu T. High Expression of Dihydropyrimidine Dehydrogenase in Lung Adenocarcinoma is Associated With Mutations in Epidermal Growth Factor Receptor: Implications for the Treatment of Non–Small-Cell Lung Cancer Using 5-Fluorouracil. Clin Lung Cancer 2014; 15:136-144.e4. [DOI: 10.1016/j.cllc.2013.09.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 09/08/2013] [Accepted: 09/10/2013] [Indexed: 11/17/2022]
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Kaira K, Tomizawa Y, Yoshino R, Yoshii A, Matsuura M, Iwasaki Y, Koga Y, Ono A, Nishioka M, Kamide Y, Hisada T, Ishizuka T, Shirai K, Ebara T, Saitoh JI, Nakano T, Sunaga N. Phase II study of oral S-1 and cisplatin with concurrent radiotherapy for locally advanced non-small-cell lung cancer. Lung Cancer 2013; 82:449-54. [PMID: 24099666 DOI: 10.1016/j.lungcan.2013.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2013] [Revised: 09/06/2013] [Accepted: 09/11/2013] [Indexed: 10/26/2022]
Abstract
PURPOSE To determine the efficacy and safety of oral S-1 in combination with cisplatin and thoracic radiotherapy in patients with unresectable stage III non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS S-1 (50mg/m(2)) was administered orally twice daily for 14 days, with cisplatin (40 mg/m(2)) on days 1 and 8 of each cycle every 3 weeks, for 2-4 cycles. Thoracic radiation therapy was administered in 2 Gy fractions five times weekly for a total dose of 60 Gy. The primary endpoint was the response rate, and secondary endpoints included progression-free survival, overall survival and safety. RESULTS Forty-one patients were enrolled in this study. The objective response rate was 87.8% (98% CI: 77.8-97.8%). The median progression-free survival was 467 days (15.4 months), and the median survival time was 904 days (29.7 months). The overall survival rates at 1- and 2-years were 85.7% and 52.9%, respectively. Hematological toxicities included grade 3/4 neutropenia (17%) and grade 3/4 leukopenia (27%). No grade 3 febrile neutropenia was detected, and grade 3/4 non-hematological toxicities were also mild. A grade 3 gastrointestinal hemorrhage was observed in one patient. CONCLUSIONS The combination of oral S-1 plus cisplatin with concurrent radiotherapy is a promising treatment with a high efficacy and lower toxicity in patients with locally advanced NSCLC.
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Affiliation(s)
- Kyoichi Kaira
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan.
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Takeda K. Clinical development of S-1 for non-small cell lung cancer: a Japanese perspective. Ther Adv Med Oncol 2013; 5:301-11. [PMID: 23997830 DOI: 10.1177/1758834013500702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
For more than a decade, S-1 has been investigated aggressively against non-small cell lung cancer (NSCLC) in Japan. Recently, two randomized phase III trials of S-1 combined with cisplatin (CDDP) or carboplatin (CBDCA) compared with the standard platinum doublet chemotherapy were reported. S-1 and CDDP was noninferior to CDDP and DTX in terms of overall survival (OS) (median survival time [MST] 16.1 versus 17.1 months, respectively; hazard ratio [HR] 1.013; 96.4% confidence interval [CI] 0.837-1.227). Noninferiority of S-1 and CBDCA compared with CBDCA and paclitaxel was also confirmed for OS (MST 15.2 versus 13.3 months, respectively; HR 0.928; 99.2% CI 0.671-1.283). The noninferiority design employed an upper CI limit of HR<1.322 in the former trial and HR<1.33 in the latter. S-1 combined with CDDP or CBDCA was thought to be one of the standard platinum doublet regimens in the first-line setting for patients with advanced NSCLC in Japan. Some additional interesting phase I and II studies have been published in Japan. They include studies of S-1 as first-line chemotherapy when combined with nonplatinum agents; as second-line chemotherapy; within chemoradiotherapy for locally advanced disease; and in the postoperative adjuvant setting. This review will also describe the use of S-1 for the treatment of NSCLC in these settings.
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Affiliation(s)
- Koji Takeda
- Department of Clinical Oncology, Osaka City General Hospital, 2-13-22, Miyakojimahondori, Miyakojima-ku, Osaka, 534-0021, Japan
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Yamaguchi M, Toyokawa G, Ohba T, Sasaki T, Kometani T, Hamatake M, Hirai F, Taguchi K, Yamanaka T, Seto T, Takenoyama M, Sugio K, Ichinose Y. Preoperative concurrent chemoradiotherapy of S-1/cisplatin for stage III non-small cell lung cancer. Ann Thorac Surg 2013; 96:1783-9. [PMID: 23998404 DOI: 10.1016/j.athoracsur.2013.06.036] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Revised: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 10/26/2022]
Abstract
BACKGROUND Concurrent chemoradiotherapy using S-1 containing tegafur, an oral 5-FU prodrug, plus cisplatin has been reported to show promising efficacy against locally advanced non-small cell lung cancer with acceptable toxicity. The purpose of this study is to assess the impact of this induction treatment followed by surgery on survival for those patients. METHODS Potentially resectable locally advanced non-small cell lung cancer patients were eligible. The concurrent phase consisted of S-1 (orally at 40 mg/m² twice a day on days 1 to 14 and 22 to 36) and cisplatin (60 mg/m² on days 1 and 22) with radiation of 40 Gy/20 fractions beginning on day 1 followed by surgical resection. RESULTS Forty-two consecutive patients, between June 2005 and February 2011, were retrospectively analyzed. The median age was 59 (42 to 77) years, there were 34 males and 8 females, 26 cStage IIIA and 16 IIIB, each 21 adenocarcinomas and others. There were 26 partial responses and 16 stable disease cases after current induction treatment without uncontrollable toxicity. Of the 42 patients, 39 underwent surgical resection; 27 underwent a lobectomy and 12 pneumonectomies. One patient died due to thoracic empyema 65 days after surgery. The median follow-up time was 32.0 months. Three- and 5-year disease-free survival rates in all 39 resected patients were 52.0% and 44.0%, respectively, and 3- and 5-year overall survival rates were 77.4% and 61.7%, respectively. CONCLUSIONS Concurrent chemoradiotherapy using S-1 plus cisplatin followed by surgery may provide a better prognosis for locally advanced non-small cell lung cancer patients. Further prospective clinical investigation should be required.
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Affiliation(s)
- Masafumi Yamaguchi
- Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan
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Tsuya A, Kurata T, Tamiya A, Okamoto I, Ueda S, Sakai D, Sugimoto N, Matsumoto K, Goto I, Yamamoto N, Fukuoka M, Nakagawa K. A phase II study of cisplatin /S-1 in patients with carcinomas of unknown primary site. Invest New Drugs 2013; 31:1568-72. [PMID: 23975509 DOI: 10.1007/s10637-013-0014-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 08/13/2013] [Indexed: 12/01/2022]
Abstract
BACKGROUND Carcinomas of unknown primary site (CUPs) are heterogeneous tumors associated with a poor prognosis. This phase II trial was designed to evaluate the efficacy and safety of a novel combination chemotherapy of S-1 and cisplatin (CDDP) in patients with CUP. PATIENTS AND METHODS Patients with previously untreated CUPs were eligible for this trial. The treatment schedule consisted of oral S-1 (40 mg/m(2)) twice a day on days 1-21, and intravenous CDDP (60 mg/m(2)) on day 8. This schedule was repeated every 5 weeks. RESULTS A total of 46 patients were enrolled. The overall response rate and the disease control rate were 41.3% and 80.4%, respectively. The median overall survival time was 17.4 months. Grade 3/4 neutropenia, thrombocytopenia, and febrile neutropenia occurred in 28.3%, 13.0%, and 2.2% of the patients, respectively. CONCLUSION CDDP plus S-1 combination chemotherapy is well tolerated and active first-line empiric therapies for patients with CUP.
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Affiliation(s)
- Asuka Tsuya
- Division of thoracic Oncology, Shizuoka Cancer Center, 1007 Shimonagakubo Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan,
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Kaira K, Tomizawa Y, Yoshino R, Miura Y, Yoshii A, Iwasaki Y, Koga Y, Ono A, Hisada T, Minato K, Sato K, Kazama T, Ishihara S, Kohyama K, Fueki N, Saito R, Sunaga N. Phase II study of oral S-1 plus cisplatin with bevacizumab for advanced non-squamous non-small cell lung cancer. Lung Cancer 2013; 82:103-8. [PMID: 23927884 DOI: 10.1016/j.lungcan.2013.07.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Revised: 07/02/2013] [Accepted: 07/11/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND We conducted a phase II study to evaluate the efficacy and safety of S-1 plus cisplatin with bevacizumab followed by maintenance bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Chemotherapy-naïve patients received S-1 plus cisplatin with bevacizumab. S-1 (80 mg/m(2)) was administered orally twice daily for 14 days, cisplatin (60 mg/m(2)) on day 1, and bevacizumab (15 mg/kg) on day 1 and every 3 weeks for 4-6 cycles. Patients with an objective response or stable disease received maintenance bevacizumab every 3 weeks until disease progression. RESULTS Thirty patients were enrolled in this study. The median number of chemotherapy was four (range, 1-6 cycles), and the median number of bevacizumab alone was three (range, 1-31 cycles). The grade 3/4 toxicities were neutropaenia (23%), thrombocytopaenia (10%), febrile neutropaenia (3%), hypertension (17%), pneumonia (7%), and bowel perforation (3%). The objective response rate was 71% (95% CI, 55-88%) for a disease control rate of 100%. The median progression-free and overall survival times were 7.0 months and 20.0 months, respectively. CONCLUSIONS S-1 plus cisplatin with bevacizumab is an active and well-tolerated regimen in patients with chemotherapy-naïve non-squamous NSCLC.
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Affiliation(s)
- Kyoichi Kaira
- Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511, Japan.
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Sugawara S, Maemondo M, Tachihara M, Inoue A, Ishimoto O, Sakakibara T, Usui K, Watanabe H, Matsubara N, Watanabe K, Kanazawa K, Ishida T, Saijo Y, Nukiwa T. Randomized phase II trial of uracil/tegafur and cisplatin versus vinorelbine and cisplatin with concurrent thoracic radiotherapy for locally advanced unresectable stage III non-small-cell lung cancer: NJLCG 0601. Lung Cancer 2013; 81:91-6. [DOI: 10.1016/j.lungcan.2013.04.010] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 03/14/2013] [Accepted: 04/08/2013] [Indexed: 11/16/2022]
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Komazaki Y, Sakashita H, Furuiye M, Fujie T, Tamaoka M, Sumi Y, Miyazaki Y, Kojima K, Jin Y, Inase N. Feasibility study of adjuvant chemotherapy of S-1 and carboplatin for completely resected non-small cell lung cancer. Chemotherapy 2013; 59:35-41. [PMID: 23816760 DOI: 10.1159/000351101] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2012] [Accepted: 03/26/2013] [Indexed: 11/19/2022]
Abstract
BACKGROUND The purpose of this study was to evaluate the feasibility and compliance of adjuvant chemotherapy of S-1 plus carboplatin for patients with completely resected non-small cell lung cancer (NSCLC) of pathological stage IB-IIIB. METHODS S-1 was given orally at a dose of 80 mg/m²/day for 2 weeks, followed by a 2-week period of no treatment. Carboplatin was given intravenously on day 8 at an area under the curve of 6. This regimen was repeated for four to six 28-day courses. RESULTS Seventeen patients were enrolled in this study. Fourteen of them completed at least 4 cycles of chemotherapy. Nine patients had grade 2 and three patients had grade 3 thrombocytopenia, respectively. Severe nonhematologic toxicities were uncommon. Treatment was delayed in a few patients because of prolonged thrombocytopenia. CONCLUSION We concluded that the regimen was feasible and tolerable for patients with completely resected NSCLC as adjuvant chemotherapy.
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Affiliation(s)
- Yoshitoshi Komazaki
- Department of Integrated Pulmonology, Tokyo Medical and Dental University, Tokyo, Japan
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A pilot feasibility study for cisplatin plus S-1 for the treatment for advanced or recurrent cervical cancer. Cancer Chemother Pharmacol 2013; 71:1369-74. [DOI: 10.1007/s00280-013-2137-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 03/07/2013] [Indexed: 01/09/2023]
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Harada H, Nishio M, Murakami H, Ohyanagi F, Kozuka T, Ishikura S, Naito T, Kaira K, Takahashi T, Horiike A, Nishimura T, Yamamoto N. Dose-escalation study of three-dimensional conformal thoracic radiotherapy with concurrent S-1 and cisplatin for inoperable stage III non-small-cell lung cancer. Clin Lung Cancer 2013; 14:440-5. [PMID: 23540866 DOI: 10.1016/j.cllc.2013.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 12/31/2012] [Accepted: 01/29/2013] [Indexed: 12/28/2022]
Abstract
PURPOSE To determine the recommended dose (RD) in concurrent conformal radiotherapy with S-1 and cisplatin chemotherapy for inoperable stage III non-small-cell lung cancer. PATIENTS AND METHODS Eligible patients with inoperable stage III non-small-cell lung cancer, age ≥ 20 years, performance status 0-1 received 4 cycles of intravenous cisplatin (60 mg/m(2), day 1) and oral S-1 (80, 100, or 120 mg based on body surface area, days 1-14) repeated every 4 weeks. Radiation doses were 66, 70, and 74 Gy for arms 1, 2, and 3, respectively. RESULTS A total of 24 patients were enrolled in our study, including 6 in arm 1, 6 in arm 2, and 12 in arm 3. The patients consisted of 14 men and 10 women, with a median age of 63 years (range, 44-73 years). The median follow-up was 27.3 months (range, 8.5-42.6 months) for all patients and 33.9 months (range, 15.2-42.6 months) for those still alive. Grade 3 febrile neutropenia, lung toxicities, and heart toxicities occurred in 2, 2, and 2 patients, respectively. Dose-limiting toxicity occurred in 2, none, and 1 patient in arms 1, 2, and 3, respectively. The median survival was not reached, and the 2-year survival rate was 70% (95% CI, 51%-89%). Two-year local relapse-free survival and distant metastasis-free survival were 74% (95% CI, 56%-92%) and 45% (95% CI, 25%-65%), respectively. CONCLUSIONS High-dose radiotherapy with S-1 and cisplatin is feasible, and 74 Gy was determined as the recommended dose.
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Affiliation(s)
- Hideyuki Harada
- Division of Radiation Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
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Nagao A, Abu Lila AS, Ishida T, Kiwada H. Abrogation of the accelerated blood clearance phenomenon by SOXL regimen: promise for clinical application. Int J Pharm 2012; 441:395-401. [PMID: 23174409 DOI: 10.1016/j.ijpharm.2012.11.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2012] [Revised: 10/26/2012] [Accepted: 11/11/2012] [Indexed: 12/14/2022]
Abstract
We recently proposed an S-1 combined with oxaliplatin (SOXL) regimen, a combination treatment consisting of oral metronomic S-1 dosing and intravenous administration of oxaliplatin (l-OHP) containing PEGylated liposomes, which showed potent antitumor activity in vivo. PEGylated liposomes induce what is referred to as the "accelerated blood clearance (ABC) phenomenon" upon repeated administration and consequently lose their long-circulating characteristics. This phenomenon seems to pose an impediment for the clinical application and use of PEGylated liposomal formulations. In the present study, l-OHP-containing PEGylated liposomes in the SOXL regimen significantly attenuated the ABC phenomenon in a dose-dependent manner through suppression of the anti-PEG IgM response, which allowed an enhanced hepatic uptake of subsequently injected test PEGylated liposomes. In tumor-bearing mice, the abrogation of the ABC phenomenon restored intratumor accumulation of subsequently injected PEGylated liposomes. Consequently, the therapeutic efficacy of the SOXL regimen over the combination of the free form of the drugs was credited not only with the selective delivery of drugs to the tumor tissue but also with ensuring an adequate accumulation of subsequent doses within the tumor tissue. The SOXL regimen we proposed may hold promise as a safe and effective treatment regimen for advanced colorectal cancer.
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Affiliation(s)
- Ai Nagao
- Department of Pharmacokinetics and Biopharmaceutics, Institute of Health Biosciences, The University of Tokushima, Tokushima, Japan
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Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer. Cancer Chemother Pharmacol 2012; 70:691-7. [PMID: 22941346 DOI: 10.1007/s00280-012-1957-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2012] [Accepted: 08/17/2012] [Indexed: 10/27/2022]
Abstract
PURPOSE This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC). METHODS The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40 mg/m(2) twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle. RESULTS In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90 mg/m(2) (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80 mg/m(2) of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8 % (90 % confidence interval (CI): 6.1-25.5 %), and the median progression-free and overall survival times were 4.5 months (95 % CI: 3.5-5.0) and 15.0 months (95 % CI: 9.5-20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9 % of the patients, thrombocytopenia in 5.1 % and nausea in 7.7 %. CONCLUSION Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.
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Kim HS, Kim HR, Kim GM, Kim HS, Koh YW, Kim SH, Choi EC, Hong YK, Sung JH, Kim SM, Kim JH, Cho BC. The efficacy and toxicity of S-1 and cisplatin as first-line chemotherapy in recurrent or metastatic head and neck squamous cell carcinoma. Cancer Chemother Pharmacol 2012; 70:539-46. [PMID: 22868340 DOI: 10.1007/s00280-012-1933-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Accepted: 07/20/2012] [Indexed: 11/24/2022]
Abstract
PURPOSE To assess the clinical activity and toxicity of a combination chemotherapy regimen of S-1 and cisplatin in patients with recurrent and/or metastatic head and neck squamous cell carcinoma (HNSCC) in a retrospective study. METHODS A total of 49 patients were treated in an outpatient setting with S-1 80 mg/m(2) on days 1-14 and with cisplatin 70 mg/m(2) on day 1 every 3 weeks for a maximum of six cycles as a first-line palliative chemotherapy. Patients who achieved complete response (CR), partial response (PR) or stable disease (SD) after six cycles received S-1 monotherapy as a maintenance therapy. RESULTS The median patient age was 55 years (range 33-79), 89.8 % were male, and the Eastern Cooperative Oncology Group performance status distribution was 0/1/2 (20.4 %/73.5 %/6.1 %). Of the 43 evaluable patients, 2 (4.1 %) achieved CR and 20 (40.8 %) had a PR, for an overall response rate of 44.9 %. Thirteen patients (26.6 %) had SD. The median number of chemotherapy treatments was 4 (range 1-18). Nine patients received maintenance S-1 monotherapy after six cycles of combination chemotherapy. With a mean 10.5 months (range 1.3-25.1) of follow-up, the median progression-free and overall survival were 4.5 (95 % CI, 3.7-5.3 months) and 10.8 months (95 % CI, 5.9-15.6 months), respectively. The main grade 3-4 toxicities were neutropenia (37 %), anemia (16 %) and general weakness (8 %). Other toxicities, including nausea/vomiting, mucositis and neuropathy, were mostly grade 1-2 and easily manageable. CONCLUSIONS The combination of S-1/cisplatin therapy had a favorable efficacy with manageable toxicity as a first-line chemotherapy regimen for advanced head and neck squamous cell carcinoma patients.
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Affiliation(s)
- Han Sang Kim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea
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S-1 plus cisplatin with concurrent radiotherapy for locally advanced non-small cell lung cancer: a multi-institutional phase II trial (West Japan Thoracic Oncology Group 3706). J Thorac Oncol 2012; 6:2069-75. [PMID: 22052226 DOI: 10.1097/jto.0b013e3182307e5a] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To evaluate the combination chemotherapy using oral antimetabolite S-1 plus cisplatin (SP) with concurrent thoracic radiotherapy (RT) followed by the consolidation SP for locally advanced non-small cell lung cancer. PATIENTS AND METHODS Patients with stage III non-small cell lung cancer, 20 to 74 years of age, and Eastern Cooperative Oncology Group performance status 0 to 1 were eligible. The concurrent phase consisted of full dose S-1 (orally at 40 mg/m/dose twice daily, on days 1-14) and cisplatin (60 mg/m on day 1) repeated every 4 weeks for two cycles with RT delivered beginning on day 1 (60 Gy/30 fractions over 6 weeks). After SP-RT, patients received an additional two cycles of SP as the consolidation phase. RESULTS Fifty-five patients were registered between November 2006 and December 2007. Of the 50 patients for efficacy analysis, the median age was 64 years; male/female 40/10; Eastern Cooperative Oncology Group performance status 0/1, 21/29; clinical stage IIIA/IIIB 18/32; and adenocarcinoma/others 20/30. There were 42 clinical responses including one complete response with an objective response rate of 84% (95% confidence interval [CI], 71-93%). The 1- and 2-year overall survival rates were 88% (95% CI, 75-94%) and 70% (95% CI, 55-81%), respectively. The median progression-free survival was 20 months. Of the 54 patients for safety analysis, common toxicities in the concurrent phase included grade 3/4 neutropenia (26%), thrombocytopenia (9%), and grade 3 esophagitis (9%) and febrile neutropenia (9%). In one patient, grade 3 pneumonitis was observed in the consolidation phase. There were two treatment-related deaths caused by infection in the concurrent phase. CONCLUSIONS SP-RT showed a promising efficacy against locally advanced NCSLC with acceptable toxicity.
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Phase I trial of oral S-1 combined with gemcitabine and cisplatin for advanced biliary tract cancer (KHBO1002). Cancer Chemother Pharmacol 2012; 69:1181-8. [DOI: 10.1007/s00280-011-1818-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Accepted: 12/28/2011] [Indexed: 01/16/2023]
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Phase II trial of S-1 as second-line therapy in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011; 6:790-5. [PMID: 21325974 DOI: 10.1097/jto.0b013e3182103b51] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE Currently available agents for the treatment of advanced stage non-small cell lung cancer (NSCLC) have limited efficacy. S-1 is a novel formulation of oral fluoropyrimidine shown to be tolerable and active in patients with NSCLC in Japan. We conducted a multicenter phase II study in previously treated patients with NSCLC to evaluate the efficacy of single-agent S-1 in a predominantly non-Asian population. PATIENTS AND METHODS Patients with advanced NSCLC and previously treated with only one line of chemotherapy received oral S-1 at 30 mg/m every 12 hours for 14 consecutive days followed by a 7-day rest until meeting discontinuation criteria. The primary end point was to evaluate the overall response rate. RESULTS Fifty-seven patients were accrued from 21 centers across the United States. Overall response rates and stable disease according to independent review were 7.1% and 48.2%, respectively, with a disease control rate of 55.3%. Progression-free survival was 2.9 months, median overall survival 7.3 months, and 1-year survival 31.6%. There were no significant differences in survival according to histologic subtype. The treatment was well tolerated, with the most common treatment-related side effects being nausea (54%) and diarrhea (49%). CONCLUSION Single-agent S-1 is well tolerated and has activity comparable with the other agents approved for use in recurrent/relapsed NSCLC.
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An Open-Label, Multicenter, Three-Stage, Phase II Study of S-1 in Combination with Cisplatin as First-Line Therapy for Patients with Advanced Non-small Cell Lung Cancer. J Thorac Oncol 2011; 6:1400-6. [PMID: 21673602 DOI: 10.1097/jto.0b013e31820d7805] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
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Long-term administration of second-line chemotherapy with S-1 and gemcitabine for platinum-resistant non-small cell lung cancer: a phase II study. J Thorac Oncol 2011; 6:156-60. [PMID: 21107293 DOI: 10.1097/jto.0b013e3181f7c76a] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Standard second-line chemotherapies for non-small cell lung cancer (NSCLC) have been established but have limited clinical relevance. S-1 is a recently developed agent with potential activity against NSCLC. METHODS Patients with confirmed NSCLC recurrence after previous single- or two-regimen chemotherapy with platinum, performance status of 0 to 1, adequate organ functions, and measurable lesions were treated with S-1 (60 mg/m/d, twice a day) on days 1 to 14 and gemcitabine (1000 mg/m) on days 8 and 15, which were repeated every 3 weeks until tumor progression. RESULTS Treatment was administered for a median of 4 courses (range, 1-13) over a median of 125-day period in 34 patients. The overall response rate was 23.5% (no complete response and eight partial response; 95% confidence interval: 9.1-38.0%). The median progression-free and overall survival times were 6.6 and 19.9 months, respectively. The 1- and 2-year survival rates were 58.8 and 30.9%, respectively. Toxicity was mild during the entire treatment period, except for three grade 3 interstitial pneumonia. CONCLUSION The primary end point was met with the relatively high overall response rate. Randomized phase III studies for elucidating survival outcome of the regimen are warranted.
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Tomimoto H, Hanibuchi M, Ogushi F, Okano Y, Shinohara T, Doi H, Yamamoto A, Takeuchi E, Yamamoto A, Azuma M, Tada H, Kanematsu T, Kakiuchi S, Goto H, Yano S, Nishioka Y, Sone S. A multi-institutional phase II study of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer. Oncol Lett 2011; 2:465-470. [PMID: 22866104 DOI: 10.3892/ol.2011.266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2010] [Accepted: 12/23/2010] [Indexed: 11/05/2022] Open
Abstract
S-1 is an oral anticancer fluoropyrimidine agent designed to elevate anticancer activity with a decrease in gastrointestinal toxicity. We conducted a phase II study to evaluate the efficacy and safety of combination chemotherapy with S-1 plus cisplatin in patients with advanced non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients were treated with S-1 administered orally at 40 mg/m(2) twice a day for 21 consecutive days, and cisplatin (60 mg/m(2)) infused intravenously on day 8, repeated every 5 weeks. Of the 44 patients enrolled in the study, 40 were assessable for efficacy and safety. The median number of cycles administered was 3 (range 1-9 cycles). Among the 40 assessable patients, 7 partial responses were observed, with an overall response rate (RR) of 17.5% [95% confidence interval (CI), 5.2-29.8]. Patients with squamous cell carcinoma showed a significantly higher RR (55.5%) than those with adenocarcinoma (9.1%) or other types of NSCLC (0%). The median progression-free survival was 4.3 months (95% CI, 3.4-4.9), the median survival time was 17.9 months (95% CI, 15.0-20.8), and the 1- and 2-year survival rates were 63.3 and 27.3%, respectively. Major grade 3-4 hematologic toxicities were leukocytopenia (7.5%), neutropenia (5.0%), anemia (15.0%) and thrombocytopenia (2.5%). No grade 4 non-hematologic toxicity or treatment-related death occurred. These results suggest that combination chemotherapy with S-1 plus cisplatin is a promising therapeutic candidate for patients with advanced NSCLC, particularly squamous cell carcinoma.
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Affiliation(s)
- Hideki Tomimoto
- Department of Medical Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503
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Katsumata N, Hirai Y, Kamiura S, Sugiyama T, Kokawa K, Hatae M, Nishimura R, Ochiai K. Phase II study of S-1, an oral fluoropyrimidine, in patients with advanced or recurrent cervical cancer. Ann Oncol 2011; 22:1353-1357. [PMID: 21345941 PMCID: PMC3101364 DOI: 10.1093/annonc/mdq602] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Background: S-1 is an oral fluoropyrimidine. This phase II study was designed to evaluate the efficacy and safety of S-1 in patients with advanced or recurrent uterine cervical cancer. Patients and methods: S-1 35 mg/m2 was given twice daily for 28 days repeated every 6 weeks. Eligible patients were women aged 20–74 years, who had Eastern Cooperative Oncology Group performance status of zero or one, who had stage IVB or recurrent uterine cervical cancer, and who had received no more than one platinum-containing chemotherapy regimen for stage IVB or recurrent disease. The primary end point was overall response rate (ORR) determined by RECIST. Results: A total of 37 patients were enrolled in the trial and 36 were eligible. The median number of cycles administered was 4. The confirmed ORR was 30.6% (95% confidence interval 15.5% to 45.6%). The response rate for patients who had received platinum-based treatment including chemoradiotherapy was 31.8% (7 of 22). After a median follow-up duration of 25 months, the median time to progression and the median survival time were 5.2 and 15.4 months, respectively. The most frequent grade 3 or 4 adverse events were anemia (16%), anorexia (16%), and diarrhea (22%). Conclusions: This phase II study of S-1 in cervical cancer suggests a promising response rate and a contribution toward prolonging survival, with modest toxic effects. Phase III studies of S-1 in patients with advanced or recurrent cervical cancer are thus warranted.
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Affiliation(s)
- N Katsumata
- Department of Medical Oncology, National Cancer Center Hospital, Tokyo.
| | - Y Hirai
- Department of Gynecology, Cancer Institute Hospital Ariake, Tokyo
| | - S Kamiura
- Department of Gynecology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka
| | - T Sugiyama
- Department of Obstetrics and Gynecology, Iwate Medical University, Iwate
| | - K Kokawa
- Department of Obstetrics and Gynecology, Wakayama Medical University Hospital, Wakayama
| | - M Hatae
- Department of Obstetrics and Gynecology, Kagoshima City Hospital, Kagoshima
| | - R Nishimura
- Department of Gynecology, Hyogo Cancer Center, Hyogo
| | - K Ochiai
- Department of Obstetrics and Gynecology, The Jikei University, School of Medicine, Tokyo, Japan
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Nagasaki T, Tsuchiya T, Tagawa T, Honda S, Yamasaki N, Miyazaki T, Hidaka S, Hayashi T, Nagayasu T. Analysis of 5-fluorouracil-related enzymes in pulmonary neuroendocrine carcinoma: differences in biological properties compared to epithelial carcinoma. Clin Lung Cancer 2011; 11:412-22. [PMID: 21062732 DOI: 10.3816/clc.2010.n.053] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyl transferase (OPRT), and thymidylate synthase (TS) levels correlate with sensitivity and resistance to 5-fluorouracil (5-FU). Few data are available on these enzymes in pulmonary neuroendocrine carcinoma, because 5-FU appears to have minimal effect on such carcinomas. PATIENTS AND METHODS This study investigated 5-FU-related enzymes in large-cell neuroendocrine carcinoma (LCNEC; n = 31) and small-cell lung carcinoma (SCLC; n = 15), comparing expression levels with epithelial carcinomas including adenocarcinoma (ADC; n = 34) and squamous cell carcinoma (SCC; n = 13) obtained from 93 patients with primary lung tumors. Levels of 5-FU-related enzyme mRNA were analyzed by laser capture microdissection, compared with immunohistochemical findings and correlated with clinicopathologic factors. RESULTS LCNEC and SCLC showed significantly higher TS and OPRT mRNA levels than ADC. SCLC exhibited significantly higher TS mRNA levels than LCNEC (P = .002). LCNEC displayed significantly lower DPD mRNA levels than ADC (P < .001), with a similar tendency in SCLC. SCC showed significantly lower DPD (P < .01) and higher OPRT (P < .001) mRNA levels than ADC. When we divide the data by pathology into epithelial carcinoma and neuroendocrine carcinoma, malignant potentials and prognoses correlated with mRNA levels in epithelial carcinoma, but not in neuroendocrine carcinoma. Immunohistochemically, neuroendocrine carcinomas were immunonegative for DPD. A significant correlation was found between enzymatic mRNA and protein expression for DPD (R = .500) and a weak correlation was observed for TS (R = .294). CONCLUSION Neuroendocrine carcinomas show characteristic patterns of expression for 5-FU-related enzymes, including low DPD mRNA and protein level and high TS mRNA level compared with adenocarcinomas. These results partially explain why 5-FU-based chemotherapy shows minimal efficacy against SCLC. Conversely, clinicopathological data and survival analysis indicates that 5-FU-related enzymes themselves might not affect the malignant potential of neuroendocrine carcinoma. Expressional differences in 5-FU-related enzymes among pathologies may provide valuable information for tailor-made chemotherapy.
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Affiliation(s)
- Toshiya Nagasaki
- Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, Japan
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Tanaka F, Wada H, Fukui Y, Fukushima M. Thymidylate synthase (TS) gene expression in primary lung cancer patients: a large-scale study in Japanese population. Ann Oncol 2011; 22:1791-7. [PMID: 21321092 DOI: 10.1093/annonc/mdq730] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Previous small-sized studies showed lower thymidylate synthase (TS) expression in adenocarcinoma of the lung, which may explain higher antitumor activity of TS-inhibiting agents such as pemetrexed. PATIENTS AND METHODS To quantitatively measure TS gene expression in a large-scale Japanese population (n = 2621) with primary lung cancer, laser-captured microdissected sections were cut from primary tumors, surrounding normal lung tissues and involved nodes. RESULTS TS gene expression level in primary tumor was significantly higher than that in normal lung tissue (mean TS/β-actin, 3.4 and 1.0, respectively; P < 0.01), and TS gene expression level was further higher in involved node (mean TS/β-actin, 7.7; P < 0.01). Analyses of TS gene expression levels in primary tumor according to histologic cell type revealed that small-cell carcinoma showed highest TS expression (mean TS/β-actin, 13.8) and that squamous cell carcinoma showed higher TS expression as compared with adenocarcinoma (mean TS/β-actin, 4.3 and 2.3, respectively; P < 0.01); TS gene expression was significantly increased along with a decrease in the grade of tumor cell differentiation. There was no significant difference in TS gene expression according to any other patient characteristics including tumor progression. CONCLUSION Lower TS expression in adenocarcinoma of the lung was confirmed in a large-scale study.
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Affiliation(s)
- F Tanaka
- Second Department of Surgery, University of Environmental and Occupational Health, Kitakakyushu, Japan.
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Akie K, Oizumi S, Ogura S, Shinagawa N, Kikuchi E, Fukumoto S, Harada M, Kinoshita I, Kojima T, Harada T, Fujita Y, Ohsaki Y, Dosaka-Akita H, Isobe H, Nishimura M. Phase II Study of Irinotecan plus S-1 Combination for Previously Untreated Advanced Non-Small Cell Lung Cancer: Hokkaido Lung Cancer Clinical Study Group Trial (HOT) 0601. Oncology 2011; 81:84-90. [DOI: 10.1159/000331681] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2011] [Accepted: 08/02/2011] [Indexed: 11/19/2022]
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A multi-institution phase I/II trial of triweekly regimen with S-1 plus cisplatin in patients with advanced non-small cell lung cancer. J Thorac Oncol 2010; 5:702-6. [PMID: 20150827 DOI: 10.1097/jto.0b013e3181ce3e22] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION To determine the dose-limiting toxicity and recommended dose (RD) of cisplatin (CDDP) combined with S-1 (tegafur, 5-chloro-2, 4-dihydroxypyridine, and potassium oxonate) for patients with non-small cell lung cancer and to evaluate efficacy and toxicity of this regimen at RD. METHODS Patients with stages III and IV non-small cell lung cancer received 3-week cycles of treatment, each consisting of oral administration of S-1 at 80 mg/m in 2 divided doses per day for 14 consecutive days, intravenous administration of CDDP (60 mg/m, 70 mg/m, or 80 mg/m) on the first day, and no medication during the subsequent 7 days. The primary objective of phase I study was to estimate the maximum tolerable dose and the RD, and the primary end point of phase II study was response. RESULTS RD of CDDP in the analysis of 18 eligible patients was 60 mg/m. Evaluation of efficacy and toxicity at RD in 55 eligible patients showed that partial response was observed in 18 patients (32.7%, 95% confidence interval: 20.7-46.7%). The median survival time was 18.1 months, and the time to disease progression was 3.8 months. Grade 3 or severer adverse events were observed in 27 patients (49.1%). CONCLUSIONS CDDP combined with S-1 showed a satisfactory overall survival time and acceptable toxicity profile. However, the response as the primary end point did not reach the predetermined threshold level.
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Takezawa K, Okamoto I, Tanizaki J, Kuwata K, Yamaguchi H, Fukuoka M, Nishio K, Nakagawa K. Enhanced Anticancer Effect of the Combination of BIBW2992 and Thymidylate Synthase–Targeted Agents in Non–Small Cell Lung Cancer with the T790M Mutation of Epidermal Growth Factor Receptor. Mol Cancer Ther 2010; 9:1647-56. [DOI: 10.1158/1535-7163.mct-09-1009] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Noro R, Miyanaga A, Minegishi Y, Okano T, Seike M, Soeno C, Kataoka K, Matsuda K, Yoshimura A, Gemma A. Histone deacetylase inhibitor enhances sensitivity of non-small-cell lung cancer cells to 5-FU/S-1 via down-regulation of thymidylate synthase expression and up-regulation of p21(waf1/cip1) expression. Cancer Sci 2010; 101:1424-30. [PMID: 20384633 PMCID: PMC11159244 DOI: 10.1111/j.1349-7006.2010.01559.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2009] [Revised: 02/07/2010] [Accepted: 02/24/2010] [Indexed: 11/29/2022] Open
Abstract
It is desirable to find more appropriate therapeutic opportunities in non-small-cell lung cancer (NSCLC) due to the current poor prognosis of affected patients. Recently, several histone deacetylase (HDAC) inhibitors, including suberoylanilide hydroxamic acid (SAHA), have been reported to exhibit antitumor activities against NSCLC. S-1, a novel oral fluorouracil anticancer drug, has been developed for clinical use in the treatment of NSCLC in Japan. Using an MTT assay, we analyzed the growth-inhibitory effect of 5-fluorouracil (5-FU), S-1, and SAHA against three NSCLC cell lines, as well as the breast cancer cell line MCF7 which is known to be highly sensitive to 5-FU. Combined treatment with low-dose SAHA enhanced 5-FU- and S-1-mediated cytotoxicity and resulted in synergistic effects, especially in 5-FU-resistant cells. Both the mRNA and protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT), which are associated with 5-FU sensitivity/response, were analyzed in the cells undergoing treatment. 5-Fluorouracil-resistant lung cancer cells displayed high expression of TS mRNA and protein. Suberoylanilide hydroxamic acid down-regulated TS mRNA and protein expression, as well as repressed the rapid induction of this factor during 5-FU treatment, in all examined cell types. We also examined the status of the Rb-E2F1 pathway, with SAHA up-regulating p21(waf1/cip1) expression via promoter histone acetylation; this, in turn, blocked the Rb-E2F1 pathway. We conclude that combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU/S-1 sensitivity-associated biomarker (TS) by HDAC inhibitor.
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Affiliation(s)
- Rintaro Noro
- Department of Internal Medicine, Nippon Medical School, Tokyo, Japan
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Kaira K, Sunaga N, Yanagitani N, Imai H, Utsugi M, Iwasaki Y, Shimizu K, Iijima H, Tsurumaki H, Tomizawa Y, Hisada T, Ishizuka T, Saito R, Mori M. Phase 2 study of S-1 plus carboplatin in patients with advanced non-small cell lung cancer. Lung Cancer 2010; 68:253-7. [DOI: 10.1016/j.lungcan.2009.06.024] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2009] [Revised: 06/08/2009] [Accepted: 06/30/2009] [Indexed: 10/20/2022]
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