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Sato Y, Okamoto K, Kida Y, Mitsui Y, Kawano Y, Sogabe M, Miyamoto H, Takayama T. Overview of Chemotherapy for Gastric Cancer. J Clin Med 2023; 12:jcm12041336. [PMID: 36835872 PMCID: PMC9959005 DOI: 10.3390/jcm12041336] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 01/22/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Gastric cancer (GC) is one of the most clinically challenging cancers worldwide. Over the past few years, new molecular-targeted agents and immunotherapy have markedly improved GC prognosis. Human epidermal growth factor receptor 2 (HER2) expression is a key biomarker in first-line chemotherapy for unresectable advanced GC. Further, the addition of trastuzumab to cytotoxic chemotherapy has extended the overall survival of patients with HER2-positive advanced GC. In HER2-negative GC, the combination of nivolumab, an immune checkpoint inhibitor, and a cytotoxic agent has been demonstrated to prolong the overall survival of GC patients. Ramucirumab and trifluridine/tipiracil, which are second- and third-line treatments for GC, and trastuzumab deruxtecan, an antibody-drug conjugate for HER2-positive GC, have been introduced in clinics. New promising molecular-targeted agents are also being developed, and combination therapy comprising immunotherapy and molecular-targeted agents is expected. As the number of available drugs increases, it is important to understand the target biomarkers and drug characteristics and select the optimal therapy for each patient. For resectable disease, differences in the extent of standard lymphadenectomy between Eastern and Western countries have led to different standard treatments: perioperative (neoadjuvant) and adjuvant therapy. This review aimed to summarize recent advances in chemotherapy for advanced GC.
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Affiliation(s)
- Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
- Correspondence: ; Tel.: +81-88-633-7124
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Yoshifumi Kida
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Yutaka Kawano
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Masahiro Sogabe
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima 770-8503, Japan
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Two cases of anal squamous cell carcinoma achieving complete response after docetaxel + cisplatin + S-1 (DCS) induction chemotherapy followed by chemoradiation. Clin J Gastroenterol 2022; 16:180-186. [PMID: 36409453 DOI: 10.1007/s12328-022-01736-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 11/10/2022] [Indexed: 11/22/2022]
Abstract
Anal squamous cell carcinoma (ASCC) is an uncommon tumor. However, its incidence is increasing worldwide. Surgical resection of locally advanced cases requires permanent anal prosthesis. Thus, chemoradiotherapy (CRT) is preferred as the first-line treatment; however, high local recurrence rate remains an issue. Here, we describe two cases of locally advanced ASCC treated with docetaxel + cisplatin + S-1 (DCS) followed by CRT with S-1 that showed complete response. The two patients, aged 69 and 65 years, were diagnosed with ASCC (cStage IIIB) at our hospital. Due to extensive lymph node metastases, the patients were treated with triple induction chemotherapy (DCS) followed by CRT with S-1. Positron emission tomography/computed tomography performed six months after starting the treatment showed disappearance of tumors, indicating a complete response. The patients continued to receive S-1 for one year and achieved relapse-free long-term survival since the completion of treatment. Therefore, induction chemotherapy with DCS, prior to CRT with S-1 may benefit patients with locally advanced ASCC.
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Treatment Response Predictors of Neoadjuvant Therapy for Locally Advanced Gastric Cancer: Current Status and Future Perspectives. Biomedicines 2022; 10:biomedicines10071614. [PMID: 35884916 PMCID: PMC9312565 DOI: 10.3390/biomedicines10071614] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/01/2022] [Accepted: 07/04/2022] [Indexed: 12/26/2022] Open
Abstract
Neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) has been recognized as an effective therapeutic option because it is expected to improve the curative resection rate by reducing the tumor size and preventing recurrence of micrometastases. However, for patients resistant to NAC, not only will operation timing be delayed, but they will also suffer from side effects. Thus, it is crucial to develop a comprehensive strategy and select patients sensitive to NAC. However, the therapeutic effect of NAC is unpredictable due to tumor heterogeneity and a lack of predictive biomarkers for guiding the choice of optimal preoperative treatment in clinical practice. This article summarizes the related research progress on predictive biomarkers of NAC for gastric cancer. Among the many investigated biomarkers, metabolic enzymes for cytotoxic agents, nucleotide excision repair, and microsatellite instability, have shown promising results and should be assessed in prospective clinical trials. Noninvasive liquid biopsy detection, including miRNA and exosome detection, is also a promising strategy.
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Hirahara N, Matsubara T, Kaji S, Yamamoto T, Hyakudomi R, Takai K, Ishitobi K, Uchida Y, Tajima Y. Phase II feasibility study of adjuvant chemotherapy with docetaxel/cisplatin/S-1 followed by S-1 for stage III gastric cancer. BMC Cancer 2021; 21:1073. [PMID: 34598694 PMCID: PMC8485556 DOI: 10.1186/s12885-021-08795-4] [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] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 09/16/2021] [Indexed: 02/03/2023] Open
Abstract
BACKGROUND This study aimed to evaluate the feasibility, safety, and efficacy of postoperative adjuvant chemotherapy with docetaxel/cisplatin/S-1 (DCS) following S-1 therapy in patients with stage III gastric cancer after curative gastrectomy. METHODS Patients with stage III gastric cancer who underwent D2 gastrectomy were enrolled. Adjuvant chemotherapy was initiated within 8 weeks of gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy (day 1-14), followed by a 7-day rest period. Cycles 2 and 3 consisted of the following: S-1 (day 1-14) administration, followed by a 14-day rest period, and an intravenous infusion of cisplatin and docetaxel on days 1 and 15. After two cycles, S-1 was administered for up to 1 year. RESULTS Thirty patients were enrolled between 2014 and 2017. Febrile neutropenia of grade 3 or higher was the most common hematological toxicity with 4 patients (13.3%). Other hematological toxicities of grade 3 or higher were as follows: neutropenia in 3 (10.0%), leukopenia in 3 (10.0%), and anemia in 2 (6.7%) patients. Most frequent non-hematological toxicity of grade 3 was anorexia (n = 4, 13.3%) and general fatigue (n = 3, 10.0%); no grade 4 non-hematological toxicities were observed. Twenty-five patients (83.3%) completed two cycles of DCS treatment and 18 (60.0%) completed subsequent S-1 treatment for 1 year. The relative dose intensity of docetaxel and cisplatin was 0.86 and that of S-1 was 0.88. CONCLUSION The DCS regimen can be acceptable as an adjuvant chemotherapy and offers an effective postoperative treatment option for stage III gastric cancer patients. TRIAL REGISTRATION NUMBER UMIN000012785 . DATE OF REGISTRY 08/01/2014.
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Affiliation(s)
- Noriyuki Hirahara
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
| | - Takeshi Matsubara
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Shunsuke Kaji
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Tetsu Yamamoto
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Ryoji Hyakudomi
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Kiyoe Takai
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Kazunari Ishitobi
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Yuki Uchida
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
| | - Yoshitsugu Tajima
- Department of Digestive and General Surgery, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan
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Tchounwou PB, Dasari S, Noubissi FK, Ray P, Kumar S. Advances in Our Understanding of the Molecular Mechanisms of Action of Cisplatin in Cancer Therapy. J Exp Pharmacol 2021; 13:303-328. [PMID: 33776489 PMCID: PMC7987268 DOI: 10.2147/jep.s267383] [Citation(s) in RCA: 178] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 02/23/2021] [Indexed: 12/15/2022] Open
Abstract
Cisplatin and other platinum-based chemotherapeutic drugs have been used extensively for the treatment of human cancers such as bladder, blood, breast, cervical, esophageal, head and neck, lung, ovarian, testicular cancers, and sarcoma. Cisplatin is commonly administered intravenously as a first-line chemotherapy for patients suffering from various malignancies. Upon absorption into the cancer cell, cisplatin interacts with cellular macromolecules and exerts its cytotoxic effects through a series of biochemical mechanisms by binding to Deoxyribonucleic acid (DNA) and forming intra-strand DNA adducts leading to the inhibition of DNA synthesis and cell growth. Its primary molecular mechanism of action has been associated with the induction of both intrinsic and extrinsic pathways of apoptosis resulting from the production of reactive oxygen species through lipid peroxidation, activation of various signal transduction pathways, induction of p53 signaling and cell cycle arrest, upregulation of pro-apoptotic genes/proteins, and down-regulation of proto-oncogenes and anti-apoptotic genes/proteins. Despite great clinical outcomes, many studies have reported substantial side effects associated with cisplatin monotherapy, while others have shown substantial drug resistance in some cancer patients. Hence, new formulations and several combinational therapies with other drugs have been tested for the purpose of improving the clinical utility of cisplatin. Therefore, this review provides a comprehensive understanding of its molecular mechanisms of action in cancer therapy and discusses the therapeutic approaches to overcome cisplatin resistance and side effects.
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Affiliation(s)
- Paul B Tchounwou
- Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Health Disparities Research, Jackson State University, Jackson, MS, USA
| | - Shaloam Dasari
- Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Health Disparities Research, Jackson State University, Jackson, MS, USA
| | - Felicite K Noubissi
- Cellomics and Toxicogenomics Research Laboratory, NIH-RCMI Center for Health Disparities Research, Jackson State University, Jackson, MS, USA
| | - Paresh Ray
- Department of Chemistry and Biochemistry, College of Science, Engineering and Technology, Jackson State University, Jackson, MS, USA
| | - Sanjay Kumar
- Department of Life Sciences, School of Earth, Biological, and Environmental Sciences, Central University of South Bihar, Gaya, India
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Ohnuma H, Sato Y, Onoyama N, Hamaguchi K, Hayasaka N, Sato M, Murase K, Takada K, Miyanishi K, Murakami T, Ito T, Nobuoka T, Takemasa I, Kato J. Survival benefit of conversion surgery after intensive chemotherapy for unresectable metastatic gastric cancer: a propensity score-matching analysis. J Cancer Res Clin Oncol 2021; 147:2385-2396. [PMID: 33534051 DOI: 10.1007/s00432-021-03516-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 01/09/2021] [Indexed: 12/23/2022]
Abstract
PURPOSE The clinical benefit of conversion surgery (CS) for unresectable gastric cancer (GC), whereby unresectable GC responds to chemotherapy and subsequently receives curative-intent surgery, remains unclear. Here, we aimed to clarify the clinical value of CS. METHODS In this retrospective cohort study, we analyzed 175 unresectable GC, who received triple combined chemotherapy between 2004 and 2019. We divided patients into two groups: those who underwent CS and those receiving chemotherapy only (CS and C groups, respectively). Propensity score matching was used to minimize confounding bias. RESULTS Of 175 cases, 61 (34.9%) underwent CS. R0 resection was obtained in 85.2%. After matching, 44 pairs were selected; there were no significant differences in baseline covariants. Group CS had a significantly better median overall survival (OS) (18.8 vs. 46.0 months, p < 0.001), and prolonged progression-free survival (7.4 vs. 25.8 months, p < 0.001). Subgroup analysis of OS showed a favorable trend for CS for almost all subgroups. Multivariate analysis revealed that good ECOG performance status and CS were associated with a longer OS. CONCLUSION The survival benefit of CS was consistently demonstrated in the univariate and multivariate analysis, even in the matched cohort. Additional large-scale trials are needed for further validation.
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Affiliation(s)
- Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoki Onoyama
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Kota Hamaguchi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Naotaka Hayasaka
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Masanori Sato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Kazuyuki Murase
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan
| | - Takeshi Murakami
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tatsuya Ito
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-0061, Japan.
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Hayashi T, Yoshikawa T, Sakamaki K, Nishikawa K, Fujitani K, Tanabe K, Misawa K, Matsui T, Miki A, Nemoto H, Fukunaga T, Kimura Y, Hihara J. Primary results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for advanced gastric cancer. Ann Gastroenterol Surg 2020; 4:540-548. [PMID: 33005849 PMCID: PMC7511564 DOI: 10.1002/ags3.12352] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/28/2020] [Accepted: 05/11/2020] [Indexed: 12/23/2022] Open
Abstract
AIM Neoadjuvant chemotherapy (NAC) is promising to improve the survival of resectable gastric cancer. However, suitable regimen and treatment duration for NAC have not yet been established. METHODS We conducted a randomized phase II trial to compare two and four courses of neoadjuvant S-1/cisplatin (SC) and S-1/cisplatin/docetaxel(DCS) using a two-by-two factorial design for locally resectable advanced gastric cancer. Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous-type cancer received two or four courses of SC or DCS. Then, patients underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was 3-year overall survival. The planned sample size was 120 eligible patients. RESULTS Between October 2011 and September 2014, 132 patients were assigned to CS (n = 66; 33 in 2-courses and 33 in 4-courses) and DCS (n = 66; 33 in 2-courses and 33 in 4-courses). The 3-year OS was 58.1% in CS and 60.0% in DCS with hazard ratio of 0.80 (95% CI, 0.48-1.34), while it was 53.1% in the two courses and 65.0% in the four courses with hazard ratio of 0.72 (95% CI, 0.43-1.22). In the survival analysis by duration in each regimen, the 3-year OS was 58.1% for both two and four courses in CS, while it was 48.5% for two courses of DCS and 71.9% for four courses of DCS. CONCLUSIONS Considering high 3-year OS, four courses DCS has a value to be tested in a future phase III study to confirm superiority of neoadjuvant chemotherapy for locally advanced gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Akira Miki
- Kobe City Medical Center General HospitalKobeJapan
| | | | - Tetsu Fukunaga
- University HospitalSt. Marianna University School of MedicineKawasaki CityJapan
| | | | - Jun Hihara
- Hiroshima City Asa HospitalHiroshimaJapan
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Nakagawa T, Sato Y, Tanahashi T, Mitsui Y, Kida Y, Fujino Y, Hirata M, Kitamura S, Miyamoto H, Okamoto K, Muguruma N, Bando Y, Takayama T. JMJD2A sensitizes gastric cancer to chemotherapy by cooperating with CCDC8. Gastric Cancer 2020; 23:426-436. [PMID: 31677131 DOI: 10.1007/s10120-019-01024-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/14/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Jumonji domain-containing protein 2A (JMJD2A) of the JMJD2 family of histone lysine demethylases has been implicated in tumorigenesis. However, its expression and role in gastric cancer (GC) drug resistance remain unknown. Here, we investigated the role of JMJD2A in GC chemotherapeutic susceptibility and its clinical relevance in GC. METHODS We selected 12 relevant genes from previously identified gene signatures that can predict GC susceptibility to docetaxel, cisplatin, and S-1 (DCS) therapy. Each gene was knocked down using siRNA in GC cell lines, and cell viability assays were performed. JMJD2A expression in GC cell lines and tissues was assessed using qRT-PCR and immunohistochemistry, respectively. A JMJD2A downstream target related to drug susceptibility was examined using whole-gene expression array and immunoprecipitation. RESULTS Among the 12 candidate genes, down-regulation of JMJD2A showed the maximum effect on GC susceptibility to anti-cancer drugs and increased the IC50 values for 5-FU, cisplatin, and docetaxel 15.3-, 2.7-, and 4.0-fold, respectively. JMJD2A was universally expressed in 12 GC cell lines, and its overexpression in GC tissue was positively correlated with tumor regression in 34 DCS-treated patients. A whole-gene expression array of JMJD2A-knockdown GC cells demonstrated a significant decrease in the expression of pro-apoptotic coiled-coil domain containing 8 (CCDC8), a downstream target of JMJD2A. Direct interaction between CCDC8 and JMJD2A was verified using immunoprecipitation. CCDC8 inhibition restored drug resistance to docetaxel, cisplatin, and S-1. CONCLUSIONS Our results indicate that JMJD2A is a novel epigenetic factor affecting GC chemotherapeutic susceptibility, and JMJD2A/CCDC8 is a potential GC therapeutic target.
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Affiliation(s)
- Tadahiko Nakagawa
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
- Department of Health and Nutrition, Faculty of Nursing and Nutrition, The University of Shimane, Shimane, 693-8550, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima, 770-8503, Japan.
| | - Toshihito Tanahashi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Yoshifumi Kida
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Yasuteru Fujino
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Misato Hirata
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
| | - Yoshimi Bando
- Division of Pathology, Tokushima University Hospital, Tokushima, 770-8503, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, 770-8503, Japan
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Hosoda K, Azuma M, Katada C, Ishido K, Niihara M, Ushiku H, Sakuraya M, Washio M, Wada T, Watanabe A, Harada H, Tanabe S, Koizumi W, Yamashita K, Hiki N. A phase I study of docetaxel/oxaliplatin/S-1 (DOS) combination neoadjuvant chemotherapy for patients with locally advanced adenocarcinoma of the esophagogastric junction. Int J Clin Oncol 2020; 25:1090-1097. [PMID: 32124094 DOI: 10.1007/s10147-020-01638-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 02/20/2020] [Indexed: 01/19/2023]
Abstract
BACKGROUND The optimal dose of each drug used in the docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy remains to be clarified for the Japanese population. The purpose of this study was to determine a recommended dose for a combination neoadjuvant DOS chemotherapy for Japanese patients with locally advanced adenocarcinoma of the esophagogastric junction (AEG). METHODS Patients with cT3 or more advanced AEG without distant metastasis were eligible for this study. The planned dosages of docetaxel (mg/m2, day 1), oxaliplatin (mg/m2, day 1), and S-1 (mg/day, days 1-14) were: 50/100/80-120 at level 1, and 60/100/80-120 at level 2, respectively. The treatment cycle was repeated every 3 weeks, and patients were assessed for response to the treatment after 2 and 3 cycles. This study was registered in the UMIN Clinical Trial Registry (UMIN 000022210). RESULTS We enrolled 12 patients with locally advanced AEG in this study. At dose level 1, one of the six patients experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and grade 3 febrile neutropenia. Two of the next six patients also experienced DLT of need for more than 2-week delay of the start of the second cycle due to adverse events at dose level 2. Based on these results, level 2 was considered the recommended dose for this regimen. CONCLUSION Recommended doses of docetaxel (mg/m2), oxaliplatin (mg/m2), and S-1 (mg/day) were 60/100/80-120. This chemotherapy scheme showed good preliminary efficacy with acceptable toxicity warranting a further phase II trial to investigate the efficacy of this regimen.
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Affiliation(s)
- Kei Hosoda
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan.
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikatoshi Katada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Kenji Ishido
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Masahiro Niihara
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Hideki Ushiku
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Mikiko Sakuraya
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Marie Washio
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Takuya Wada
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Akinori Watanabe
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Hiroki Harada
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Satoshi Tanabe
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Wasaburo Koizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Keishi Yamashita
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa, 252-0374, Japan
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Ohe Y, Fushida S, Yamaguchi T, Kinoshita J, Saito H, Okamoto K, Nakamura K, Tajima H, Ninomiya I, Ohta T. Peripheral Blood Platelet-Lymphocyte Ratio Is Good Predictor of Chemosensitivity and Prognosis in Gastric Cancer Patients. Cancer Manag Res 2020; 12:1303-1311. [PMID: 32110104 PMCID: PMC7039245 DOI: 10.2147/cmar.s241069] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 02/05/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction Platelets are one factor promoting tumor development. Conversely, lymphocytes are one factor for immune protection. The peripheral blood platelets–lymphocyte ratio (PLR) is useful as an inflammation/immune indicator to predict postoperative recurrence and prognosis of a variety of malignancies. The peripheral blood neutrophil–lymphocyte ratio (NLR) has also been reported as a useful inflammation/immune indicator. However, there are few studies evaluating the relationship between these peripheral blood indicators and the effectiveness of chemotherapy. Thus, we examined these relationships in gastric cancer patients. Patients and Methods Between 2005 and 2018, 41 gastric cancer patients treated with preoperative DCS therapy (docetaxel, cisplatin, and S-1) therapy followed by gastrectomy were evaluated. Data for peripheral blood tests prior to the initiation of chemotherapy were used. The effectiveness of chemotherapy was determined using Response Evaluation Criteria in Solid Tumors (RECIST) and the pathological response of primary lesions (Ef grade). The relationship between the blood test results and the effectiveness of chemotherapy was evaluated. Results Each optimal cut-off value of peripheral inflammation/immune indicators was calculated through ROC curves. Although the pathological responder (Ef grade 2 or 3) revealed significantly better prognosis than the non-responder (Ef grade 0-1b), no relationship was found between responder according to RECIST and prognosis (P=0.014, P=0.992). In univariate analysis, a low PLR (<180, P=0.005), low NLR (<2.6, P=0.019), high lymphocyte (≥1.43, P=0.019) and high PNI (≥40, P=0.032) were identified as prognostic markers, whereas PLR was the only marker correlated with pathological response (P=0.031). Conclusion PLR obtained prior to chemotherapy might be a useful indicator for predicting chemosensitivity owing to the simplicity of its procedure.
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Affiliation(s)
- Yuka Ohe
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Hiroto Saito
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Koichi Okamoto
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Keishi Nakamura
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Itasu Ninomiya
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
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11
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Shekari N, Asghari F, Haghnavaz N, Shanehbandi D, Khaze V, Baradaran B, Kazemi T. Let-7a Could Serve as A Biomarker for Chemo-Responsiveness to Docetaxel in Gastric Cancer. Anticancer Agents Med Chem 2019; 19:304-309. [PMID: 30543177 DOI: 10.2174/1871520619666181213110258] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 01/14/2018] [Accepted: 11/29/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND MicroRNAs are noncoding RNAs which play critical roles in response to anti-cancer agents. Let-7a and miR-21 are well-known tumor-suppressor and oncomiR miRNAs, respectively. They are involved in tumorigenesis of gastric cancer and have potential to be used as markers in response to the therapy. OBJECTIVE We aimed to study alterations in the expression of Let-7a and miR-21, and their targets in gastric cancer cell lines after treatment with docetaxel. METHODS In order to determine the IC50 of docetaxel, MTT assay was performed in AGS, MKN45 and KATO III gastric cancer cell lines. The expression levels of Let-7a and miR-21 and their target genes, HMGA2 and PDCD4, were determined by reverse-transcription quantitative real-time PCR for both treated and untreated cell lines. RESULTS MTT assay showed higher IC50 concentration of docetaxel in KATO III in comparison with AGS and MKN45, indicating KATO III`s higher resistance to docetaxel. Following the treatment, the expression level of Let-7a was significantly increased in AGS and MKN45, while decreased in KATO III. Expression level of miR- 21 in the three treated cell lines was increased significantly. Not only Let-7a, but also expression level of HMGA2 and PDCD4 genes showed different patterns in KATO III in comparison with AGS and MKN45. CONCLUSION Down-regulation and up-regulation of Let-7a in docetaxel-resistant and sensitive cell lines, respectively indicates its potential usefulness as biomarker for responsiveness of gastric cancer to the therapy with docetaxel and also for predicting patient`s outcome.
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Affiliation(s)
- Najibeh Shekari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Faezeh Asghari
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Navideh Haghnavaz
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Vahid Khaze
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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12
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Zhang F, Huang X, Song Y, Gao P, Zhou C, Guo Z, Shi J, Wu Z, Wang Z. Conversion Surgery for Stage IV Gastric Cancer. Front Oncol 2019; 9:1158. [PMID: 31788445 PMCID: PMC6854003 DOI: 10.3389/fonc.2019.01158] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022] Open
Abstract
The prognosis of stage IV gastric cancer (GC) is poor, with palliative chemotherapy remaining the main therapeutic option. Studies increasingly indicate that patients with unresectable stage IV GC, who undergo gastrectomy with radical intention after responding to several regimens of combined chemotherapy, can achieve good survival outcomes. Thus, surgery aiming at radical resection for unresectable stage IV GC after combined chemotherapy has received increasing attention in recent years. This novel therapeutic strategy was defined as conversion surgery in patients with unresectable stage IV GC and it can associate with significant improved survival when R0 resection can be achieved. Despite the recent advances in conversion surgery for patients with unresectable stage IV GC, selection criteria for combination chemotherapy regimens, indications for conversion surgery, optimal timing to surgery, and postoperative chemotherapy all remain controversial. This article reviews the current state of conversion surgery for unresectable stage IV GC.
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Affiliation(s)
- Fei Zhang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peng Gao
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhexu Guo
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhonghua Wu
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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13
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Yamada Y, Boku N, Mizusawa J, Iwasa S, Kadowaki S, Nakayama N, Azuma M, Sakamoto T, Shitara K, Tamura T, Chin K, Hata H, Nakamori M, Hara H, Yasui H, Katayama H, Fukuda H, Yoshikawa T, Sasako M, Terashima M. Docetaxel plus cisplatin and S-1 versus cisplatin and S-1 in patients with advanced gastric cancer (JCOG1013): an open-label, phase 3, randomised controlled trial. Lancet Gastroenterol Hepatol 2019; 4:501-510. [PMID: 31101534 DOI: 10.1016/s2468-1253(19)30083-4] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 12/27/2022]
Abstract
BACKGROUND We investigated the superiority of docetaxel plus cisplatin and S-1 compared with cisplatin and S-1 in chemotherapy-naive patients with advanced gastric cancer. METHODS In this open-label, phase 3, randomised controlled trial, patients were recruited from 56 hospitals in Japan. We enrolled individuals aged 20-75 years who had unresectable or recurrent gastric cancer, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had received no previous chemotherapy (except adjuvant chemotherapy completed 24 weeks before reccurence), radiotherapy, or hormonal therapy, could take drugs orally, and had adequate organ function. Patients were randomly assigned (1:1) to receive docetaxel plus cisplatin and S-1 (docetaxel 40 mg/m2 and cisplatin 60 mg/m2 on day 1 intravenously, and S-1 40-60 mg twice a day orally for 2 weeks, every 4 weeks) or cisplatin and S-1 (cisplatin 60 mg/m2 intravenously on day 8, and S-1 40-60 mg orally twice a day for 3 weeks, every 5 weeks). Randomisation was done centrally with the minimisation method, with a random component balancing for institution, ECOG performance status (0 vs 1), disease status at enrolment (unresectable vs recurrent), measurable lesion (yes vs no), number of metastatic sites (0-1 vs ≥2), and histological type (differentiated vs undifferentiated). Neither investigators or patients were masked to the study treatment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000007652. FINDINGS Between April 3, 2012, and March 18, 2016, 741 patients were randomly assigned to receive docetaxel plus cisplatin and S-1 (n=370) or cisplatin and S-1 (n=371). Median overall survival was 14·2 months (95% CI 12·9-15·9) in the docetaxel plus cisplatin and S-1 group and 15·3 months (14·2-16·2) in the cisplatin and S-1 group (hazard ratio [HR] 0·99 [95% CI 0·85-1·16]; one-sided stratified log-rank p=0·47). The most common grade 3 or worse adverse events were neutropenia (209 [59%] of 357 patients in the docetaxel plus cisplatin and S-1 group vs 117 [32%] of 365 patients in the cisplatin and S-1 group), leukopenia (120 [34%] vs 60 [16%]), and anorexia (94 [26%] vs 81 [22%]). The deaths of one patient in the cisplatin and S-1 group and in three patients in the docetaxel plus cisplatin and S-1 group were deemed treatment-related. INTERPRETATION The addition of docetaxel to cisplatin and S-1 did not improve overall survival in chemotherapy-naive Japanese patients with advanced gastric cancer. Therefore, cisplatin and S-1 remains the standard first-line chemotherapy. FUNDING Ministry of Health, Labour and Welfare and Japan Agency for Medical Research and Development.
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Affiliation(s)
- Yasuhide Yamada
- Comprehensive Cancer Center, National Center for Global Health and Medicine, Shinjuku-ku, Tokyo, Japan; Department of Medical Oncology, Hamamatsu University School of Medicine, Shizuoka, Japan; Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan.
| | - Narikazu Boku
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Junki Mizusawa
- Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Satoru Iwasa
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Chikusa-ku, Nagoya, Aichi, Japan
| | - Norisuke Nakayama
- Department of Gastroenterology, Kanagawa Cancer Center Hospital, Asahi-ku, Yokohama, Kanagawa, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Minami, Sagamihara, Kanagawa, Japan
| | - Takeshi Sakamoto
- Department of Gastroenterology, Hyogo Cancer Center, Akashi, Hyogo, Japan
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa-shi, Chiba, Japan
| | - Takao Tamura
- Department of Medical Oncology, Kindai University, Faculty of Medicine, Osaka, Japan
| | - Keisho Chin
- Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Koto-ku, Tokyo, Japan
| | - Hiroaki Hata
- Department of Surgery, National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto, Japan
| | - Mikihito Nakamori
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Inamachi, Kitaadachi-gun, Saitama, Japan
| | - Hirofumi Yasui
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
| | - Hiroshi Katayama
- Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Haruhiko Fukuda
- Japan Clinical Oncology Group Data Center and Operations Office, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center Hospital, Asahi-ku, Yokohama, Kanagawa, Japan
| | - Mitsuru Sasako
- Department of Surgery, Hyogo College of Medicine, Fushimi-ku Mukogawa-cho, Nishinomiya-shi, Hyogo, Japan
| | - Masanori Terashima
- Division of Gastric Surgery, Shizuoka Cancer Center, Nagaizumi-cho, Sunto-gun, Shizuoka, Japan
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14
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Okabe H, Hata H, Hosogi H, Ueda S, Ota S, Kinjo Y, Hoshino N, Hisamori S, Tsunoda S, Obama K, Sakai Y. A Phase 2 Study of Induction Chemotherapy Using Docetaxel, Cisplatin, and S-1 for Gastric Cancer with Peritoneal Metastasis (KUGC06). Ann Surg Oncol 2019; 26:1779-1786. [DOI: 10.1245/s10434-019-07229-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Indexed: 01/19/2023]
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15
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Du R, Hu P, Liu Q, Zhang J. Conversion Surgery for Unresectable Advanced Gastric Cancer: A Systematic Review and Meta-Analysis. Cancer Invest 2019; 37:16-28. [PMID: 30632817 DOI: 10.1080/07357907.2018.1551898] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
For patients with unresectable advanced gastric cancer, induction chemotherapy could down-stage primary tumors, resulting in conversion surgery becoming possible. However, the feasibility and therapeutic benefit of conversion surgery remains controversial. Therefore, this meta-analysis aimed to systematically review and investigate the efficacy of conversion surgery followed by chemotherapy for unresectable AGC.
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Affiliation(s)
- Rui Du
- a Department of Oncology , Weifang Medical College , Weifang , China
| | - Pingping Hu
- c Department of Radiation Oncology , Qianfoshan Hospital Affiliated to Shandong University , Jinan , China
| | - Qiqi Liu
- b Department of Oncology , Shandong University School of Medicine , Jinan , China
| | - Jiandong Zhang
- c Department of Radiation Oncology , Qianfoshan Hospital Affiliated to Shandong University , Jinan , China
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16
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Sato Y, Sagawa T, Ohnuma H, Hirakawa M, Takahashi Y, Hamaguchi K, Fujikawa K, Nobuoka T, Okamoto K, Miyamoto H, Muguruma N, Takemasa I, Takayama T. A dose-escalation study of docetaxel, oxaliplatin, and S-1 (DOS) as a first-line therapy for patients with unresectable metastatic gastric cancer. Cancer Chemother Pharmacol 2019; 83:161-167. [PMID: 30406285 DOI: 10.1007/s00280-018-3719-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 10/29/2018] [Indexed: 12/12/2022]
Abstract
PURPOSE The aim of this study was to determine the recommended dose (RD) for a docetaxel/oxaliplatin/S-1 (DOS) regimen in patients with unresectable gastric cancer and to preliminarily evaluate its efficacy. METHODS Previously untreated patients with histologically proven unresectable metastatic gastric cancer were enrolled (n = 16). Docetaxel and oxaliplatin were administered intravenously on day 8 and S-1 was administered orally twice a day on days 1-14. Each cycle was repeated every 3 weeks. Dose-limiting toxicities (DLTs) were evaluated during the first treatment cycle. Three dose escalations of DOS were employed in this study: level 1 (50/100/80 mg/m2), level 2 (50/130/80 mg/m2), and level 3 (60/130/80 mg/m2). RESULTS According to the 3 + 3 dose-escalating schedule, we determined that the RD and maximum tolerated dose for this regimen were level 1 and level 2, respectively. The DLTs were grade 3 diarrhea and febrile neutropenia. The overall response rate was 78% (7/9) for patients with measurable lesions and consisted of two complete responses and five partial responses. Five patients underwent conversion surgery. The median follow-up time was 19 months with median survival time and progression-free survival being 19.6 months and 7.6 months, respectively. CONCLUSIONS The results from this study demonstrated the safety and tolerability of DOS in unresectable metastatic gastric cancer patients and revealed promising preliminary efficacy with a high conversion rate. A phase II trial of DOS regimen using the identified RD is ongoing.
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Affiliation(s)
- Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, 770-8503, Japan.
| | - Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, Hokkaido, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Masahiro Hirakawa
- Department of Medical Oncology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yasuo Takahashi
- Department of Gastroenterology, Hokkaido Cancer Center, Hokkaido, Japan
| | - Kyoko Hamaguchi
- Department of Gastroenterology, Hokkaido Cancer Center, Hokkaido, Japan
| | - Koshi Fujikawa
- Department of Gastroenterology, Hokkaido Cancer Center, Hokkaido, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
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17
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Nie R, Yuan S, Li Y, Chen S, Li S, Yang L, Yang L, Chen Y, Zhou Z. Risk-stratification model to select conversion surgery for advanced gastric cancer patients. Chin J Cancer Res 2019; 31:178-187. [PMID: 30996576 PMCID: PMC6433581 DOI: 10.21147/j.issn.1000-9604.2019.01.13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Objective Conversion surgery is a surgery with a purpose of R0 resection in primary advanced gastric cancer (GC) that responded well to systemic chemotherapy. This study aimed to explore the efficacy of conversion surgery for advanced GC. Methods A total of 618 advanced GC patients receiving systemic chemotherapy were stratified into low-, moderate- and high-risk groups based on a nomogram-predicted probability of overall survival. The survival of conversion surgery and chemotherapy alone groups was compared using the log-rank test and Cox regression analysis after propensity score matching (PSM). Results A nomogram with good discrimination (concordance index: 0.65) and accurate calibration was constructed. After PSM, the median survival time (MST) of conversion surgery was 26.80 months, compared with 16.60 months of chemotherapy alone (P<0.001). Conversion surgery was associated with a longer MST for patients in the low-risk group (30.40 monthsvs. 20.90 months, P=0.013), whereas it was not associated with prolonged survival in the moderate- and high-risk groups (P=0.221 and P=0.131, respectively).
Conclusions Conversion surgery was associated with longer survival, especially for low-risk population.
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Affiliation(s)
- Runcong Nie
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shuqiang Yuan
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yuanfang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Shi Chen
- Department of Gastric Surgery, The 6th Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China
| | - Shuman Li
- Department of Experimental Research (Cancer Institute), Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Lirong Yang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Lifang Yang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Yingbo Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
| | - Zhiwei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China
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18
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Shinkai M, Imano M, Chiba Y, Iwama M, Shiraisi O, Yasuda A, Tsubaki M, Nishida S, Kimura Y, Yasuda T. Phase II trial of neoadjuvant chemotherapy with intraperitoneal paclitaxel, S-1, and intravenous cisplatin and paclitaxel for stage IIIA or IIIB gastric cancer. J Surg Oncol 2018; 119:56-63. [PMID: 30444009 DOI: 10.1002/jso.25295] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 10/23/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND We carried out a phase II trial to evaluate the feasibility and efficacy of neoadjuvant chemotherapy comprising a single intraperitoneal administration of paclitaxel, followed by intravenous administrations of paclitaxel and cisplatin with S-1 for clinical stage III gastric cancer. METHODS Patients with potentially resectable gastric cancer were eligible. A laparoscopic survey was performed to confirm CY0 and P0. Intraperitoneal paclitaxel (60 mg/m 2 ) was administered, followed by systemic chemotherapy. Surgery was performed after two cycles of chemotherapy. The primary endpoint was the response rate of chemotherapy. Secondary endpoints were adverse events, pathological response rate, and overall survival rate. RESULTS Twenty patients were enrolled. Planned cycles were completed in all patients. Grade 3/4 leukopenia and grade 3/4 neutropenia were observed in four (20%) and seven (35%) patients, respectively. The overall response rate was 70% (partial response: 14, stable disease: 5, progressive disease: 1). All patients underwent R0 gastrectomy with D2 lymph-node dissection, with no surgery-related deaths. The pathological response rate was 65% (13 of 20). The 3- and 5-year overall survival rates were 90.0% and 77.1%, respectively. CONCLUSIONS Neoadjuvant chemotherapy including intraperitoneal paclitaxel followed by sequential intravenous paclitaxel and cisplatin with S-1 for resectable advanced gastric cancer is feasible and effective.
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Affiliation(s)
- Masayuki Shinkai
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Motohiro Imano
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Yasutaka Chiba
- Clinical Research Center, Kindai University Hospital, Osakasayama, Japan
| | - Mitsuru Iwama
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Osamu Shiraisi
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Atsushi Yasuda
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Masanobu Tsubaki
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Faculty of Pharmacy, Kindai University, Higashiosaka, Japan
| | - Yutaka Kimura
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
| | - Takushi Yasuda
- Department of Surgery, Faculty of Medicine, Kindai University, Osakasayama, Japan
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19
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Aoyama T, Nishikawa K, Fujitani K, Tanabe K, Ito S, Matsui T, Miki A, Nemoto H, Sakamaki K, Fukunaga T, Kimura Y, Hirabayashi N, Yoshikawa T. Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer. Ann Oncol 2018; 28:1876-1881. [PMID: 28486692 DOI: 10.1093/annonc/mdx236] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Background Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. Methods Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. Results Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. Conclusions Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.
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Affiliation(s)
- T Aoyama
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama
| | - K Nishikawa
- Department of Surgery, Osaka National Hospital
| | - K Fujitani
- Osaka General Medical Center, Department of Surgery, Osaka, Japan
| | - K Tanabe
- Department of Gastrointestinal Surgery, Hiroshima University, Hiroshima
| | - S Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya
| | - T Matsui
- Department of Surgery, Aichi Cancer Center Aichi Hospital, Okazaki
| | - A Miki
- Department of Surgery, Kobe City Medical Center General Hospital, Kobe
| | - H Nemoto
- Department of Surgery, Showa University Fujigaoka Hospital, Yokohama
| | - K Sakamaki
- Department of Biostatistics and Epidemiology, Yokohama City University Medical Center, Yokohama
| | - T Fukunaga
- Department of Surgery, Saint Marianna University, Kawasaki
| | - Y Kimura
- Department of Surgery, Sakai City Hospital, Sakai
| | - N Hirabayashi
- Department of Surgery, Hiroshima City Asa Citizens Hospital, Hiroshima, Japan
| | - T Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama
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Fujimoto D, Goi T, Koneri K, Hirono Y. RPN2 is effective biomarker to predict the outcome of combined chemotherapy docetaxel and cisplatin for advanced gastric cancer. Oncotarget 2018; 9:15208-15218. [PMID: 29632637 PMCID: PMC5880597 DOI: 10.18632/oncotarget.24622] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 02/26/2018] [Indexed: 01/08/2023] Open
Abstract
Preoperative chemotherapy, often using docetaxel and cisplatin, is a famous treatment option for advanced gastric cancer in Japan. But, there are no effective biomarkers that predict the therapeutic outcome on gastric cancer. Ribophorin II (RPN2) silencing, which decreases glycosylation of P-glycoprotein (P-gp) and membrane localization, restores the sensitivity to docetaxel and cisplatin. We inquired whether RPN2 expression in advanced gastric cancer biopsy tissues may be a predictive biomarker for docetaxel and cisplatin combination preoperative chemotherapy. We judged RPN2 expression immunohistochemically in upper endoscopic biopsy tissues from 40 advanced gastric cancer patients, who received the combination preoperative chemotherapy of docetaxel and cisplatin and gastrectomy with D2 resection during 2008-2014, and compared clinicopathological effects between RPN2-positive and RPN2-negative groups. We also examined sensitivity of RPN2-knockout gastric cancer cells by genome editing to docetaxel and cisplatin. RPN2 expression was observed in 19 of 40 gastric cancer cases. The RPN2-negative group had better clinicopathological responses to docetaxel and cisplatin combination chemotherapy than the RPN2-positive group, especially, in assessment of the histopathological criteria to preoperative chemotherapy. And RPN2-negative group had a significantly higher overall survival and progression-free survival compared to the RPN2-positive group. We also found RPN2-knockout to change docetaxel and cisplatin sensitivity in vitro. RPN2 expression in upper endoscopic biopsy tissues can be an effective predictive biomarker for the treatment outcome to docetaxel and cisplatin combination preoperative chemotherapy in advanced gastric cancer.
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Affiliation(s)
- Daisuke Fujimoto
- Department of Surgery 1, Faculty of Medicine, University of Fukui, Fukui, Japan
| | - Takanori Goi
- Department of Surgery 1, Faculty of Medicine, University of Fukui, Fukui, Japan
| | - Kenji Koneri
- Department of Surgery 1, Faculty of Medicine, University of Fukui, Fukui, Japan
| | - Yasuo Hirono
- Department of Surgery 1, Faculty of Medicine, University of Fukui, Fukui, Japan
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Ohnuma H, Sato Y, Hirakawa M, Kikuchi S, Miyanishi K, Sagawa T, Takahashi Y, Nobuoka T, Okamoto K, Miyamoto H, Takemasa I, Takayama T, Kato J. Docetaxel, cisplatin and S-1 (DCS) combination chemotherapy for gastric cancer patients with peritoneal metastasis: a retrospective study. Cancer Chemother Pharmacol 2018; 81:539-548. [PMID: 29383482 DOI: 10.1007/s00280-018-3523-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Accepted: 01/16/2018] [Indexed: 12/13/2022]
Abstract
PURPOSE Peritoneal metastasis (PM) in advanced or recurrent gastric cancer (AGC) is the most frequent cause of death from this disease. However, current treatments remain unsatisfactory. We previously conducted studies of docetaxel, cisplatin and S-1 (DCS) combination chemotherapy for AGC. The aim of this study was to investigate the benefits and tolerability of DCS in PM patients. METHODS Patients were divided into three groups: patients without PM (non-PM); PM patients without ascites, or mild to moderate ascites (None-Mod); and PM patients with massive ascites (Massive). Patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14, and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Drug exposure, adverse events, tumor response, progression-free and overall survival (OS) rates were evaluated. RESULTS Of the 111 AGC patients who received DCS as first-line therapy, 37 cases had complicated PM, 15 of whom displayed massive ascites. The response rate for PM patients was 81.5%. Drug exposure and toxicities were not meaningfully different among the groups. The MSTs were also similar: 22.6 months for the non-PM, 21.7 months for the None-Mod PM, and 16.8 months for the Massive, respectively. Ten (27.0%) patients with PM achieved downstaging and underwent curative surgery, subsequently demonstrating an excellent MST of 28.0 months. An independent prognostic factor for OS, as revealed by multivariate analyses. was a good performance status. CONCLUSION DCS is feasible and efficacious for AGC with PM, especially when patients present with a good PS.
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Affiliation(s)
- Hiroyuki Ohnuma
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Masahiro Hirakawa
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Shohei Kikuchi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Koji Miyanishi
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, 4-2-3-54, Kikusui, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan
| | - Yasuo Takahashi
- Department of Gastroenterology, Hokkaido Cancer Center, 4-2-3-54, Kikusui, Shiroishi-ku, Sapporo, Hokkaido, 003-0804, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Koichi Okamoto
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Tetsuji Takayama
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15, Kuramoto-cho, Tokushima, Tokushima, 770-8503, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
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A multi-institution phase II study of docetaxel and S-1 in combination with trastuzumab for HER2-positive advanced gastric cancer (DASH study). Cancer Chemother Pharmacol 2017; 81:387-392. [PMID: 29290024 DOI: 10.1007/s00280-017-3505-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Accepted: 12/25/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Trastuzumab when combined with fluoropyrimidine and cisplatin was proven to improve survival in patients with human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) in the ToGA study. The safety and efficacy of trastuzumab in combination with docetaxel and S-1 have not yet been evaluated. METHODS This study was a multicenter, phase II study. Patients with chemotherapy-naïve HER2-positive advanced or metastatic GC were eligible. Trastuzumab was administered intravenously on day 1 of the first cycle at 8 and 6 mg/kg in subsequent cycles. Docetaxel was administered intravenously at 40 mg/m2 on day 1 of each cycle. S-1 was administered at a dosage based on body surface area for 14 days in a 3-weekly cycle. The primary endpoint was progression-free survival (PFS). RESULTS A total of 23 patients were enrolled. Median PFS was 6.7 months (95% CI 4.1-10.1). The response rate (RR) was 39.1%. Median overall survival (OS) and time to treatment failure (TTF) were 17.5 and 4.4 months, respectively. Major grade 3-4 adverse events were neutropenia (39.1%), leukopenia (30.4%), and febrile neutropenia (8.7%). CONCLUSION Trastuzumab in combination with docetaxel and S-1 showed effective antitumor activity and manageable toxicities as first-line treatment for patients with HER2-positive GC.
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Phase I/II Study of S-1 Plus Cisplatin Alternating With S-1 Plus Docetaxel in Patients With Advanced Gastric Cancer. Am J Clin Oncol 2017; 41:977-981. [PMID: 28930775 DOI: 10.1097/coc.0000000000000405] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES To investigate the usefulness of S-1 plus cisplatin alternating with S-1 plus docetaxel as first-line treatment in patients with advanced gastric cancer, we conducted a phase I/II study to determine the maximum tolerated dose and recommended dose, and evaluate efficacy and toxicity. MATERIALS AND METHODS Patients with histologically confirmed unresectable and recurrent gastric cancer were enrolled in this study. Cisplatin was administered on day 1 and the dose escalated by 10 mg/m from a starting dose of 40 mg/m in the phase I part. S-1 was given orally at 80 mg/m on days 1 to 14 and docetaxel at 40 mg/m on day 22 in combination with S-1 80 mg/m on days 22 to 35. The treatment was repeated every 6 weeks. The primary endpoint of the phase II analysis was the response rate. RESULTS Nine patients entered the phase I and 24 the phase II part. Because 50% of patients (3/6) developed dose-limiting toxicities in the phase I part, the maximum tolerated dose of cisplatin was presumed to be 50 mg/m. Therefore, the estimated recommended dose of cisplatin was 40 mg/m; 27 patients received that dose. The response rate was 59.3% (95% confidence interval, 40.8-77.8) and the median follow-up 26.2 months. The median progression-free survival was 7.9 months and the median overall survival 18.6 months. The most common grade 3/4 toxicities were neutropenia (59.3%), leucopenia (37.0%), and anemia (29.6%). These toxicities were tolerable and manageable. CONCLUSION This alternating treatment seems to have promising activity with tolerable toxicities in the first-line treatment of patients with advanced gastric cancer.
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Uemura N, Kikuchi S, Sato Y, Ohnuma H, Okamoto K, Miyamoto H, Hirakawa M, Sagawa T, Fujikawa K, Takahashi Y, Okuda T, Minami S, Takahashi M, Okamoto T, Takada K, Miyanisi K, Takayama T, Kato J. A phase II study of modified docetaxel, cisplatin, and S-1 (mDCS) chemotherapy for unresectable advanced gastric cancer. Cancer Chemother Pharmacol 2017; 80:707-713. [PMID: 28849257 DOI: 10.1007/s00280-017-3404-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 07/24/2017] [Indexed: 02/06/2023]
Abstract
PURPOSE Triplet therapy using docetaxel, cisplatin, and S-1 (DCS) against unresectable gastric cancer as previously reported by us showed high clinical efficacy, with a 87.1% total response rate; however, it also showed a high incidence of grade 3/4 toxicity. With the aim of reducing toxicities, we conducted a phase II study of modified DCS (mDCS), using a reduced dose of docetaxel, and evaluated the clinical efficacy and adverse events of this regimen. METHODS Patients with unresectable gastric cancer received chemotherapy with S-1 (40 mg/m2 b.i.d) on days 1-14, and docetaxel (50 mg/m2) plus cisplatin (60 mg/m2) on day 8 every 3 weeks. The primary endpoint was the response rate (RR). Overall (OS) and progression-free survival (PFS), and toxicities were also evaluated. RESULTS Forty-nine patients were enrolled from November 2011 to April 2014, and 43 were eligible. The overall RR was 79.1%, including two cases of a complete response (4.7%), and 32 cases of a partial response (74.4%). Nine cases had stable disease (20.9%) but none showed progressive disease. Of the 43 cases, 15 cases (34.9%) underwent curative conversion surgery. The median PFS was 350 days (95% CI 240-416 days) and median OS was 722 days (95% CI 411 days-not reached). Grade 3/4 neutropenia developed in 79.1%, and febrile neutropenia in 34.9%, of patients. Non-hematological grade 3/4 adverse events were anorexia (25.6%), nausea (4.7%), and diarrhea (9.3%). CONCLUSION Modified DCS therapy showed high clinical efficacy sufficient enough to attempt conversion therapy against unresectable gastric cancer. Modified DCS showed fewer toxicities, but careful management of these is still essential.
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Affiliation(s)
- Naoki Uemura
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Shohei Kikuchi
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroyuki Ohnuma
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Koichi Okamoto
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Masahiro Hirakawa
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Tamotsu Sagawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Japan
| | - Koshi Fujikawa
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Japan
| | - Yasuo Takahashi
- Department of Gastroenterology, Hokkaido Cancer Center, Sapporo, Japan
| | - Toshinori Okuda
- Department of Gastroenterology, Oji General Hospital, Tomakomai, Japan
| | - Shinya Minami
- Department of Gastroenterology, Oji General Hospital, Tomakomai, Japan
| | - Minoru Takahashi
- Department of Gastroenterology, Sapporo Kyoritsu-Gorinbashi Hospital, Sapporo, Japan
| | - Tetsuro Okamoto
- Department of Gastroenterology, Kiyota Hospital, Sapporo, Japan
| | - Kohichi Takada
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Koji Miyanisi
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan
| | - Tetsuji Takayama
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Junji Kato
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, S-1, W-16, Chuo-Ku, Sapporo, 060-8543, Japan.
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Validity of neoadjuvant chemotherapy with docetaxel, cisplatin, and S-1 for resectable locally advanced gastric cancer. Med Oncol 2017; 34:139. [PMID: 28707042 DOI: 10.1007/s12032-017-0997-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 07/10/2017] [Indexed: 01/07/2023]
Abstract
Gastrectomy with D2 lymphadenectomy plus postoperative chemotherapy is the standard treatment for resectable locally advanced gastric cancer in Japan. However, the prognosis of patients with serosa-positive tumors remains unsatisfactory because of peritoneal recurrence. This study aimed to investigate the validity of neoadjuvant therapy with docetaxel, cisplatin, and S-1 (DCS) in patients with locally advanced gastric cancer. Thirty patients with locally advanced gastric cancer underwent neoadjuvant DCS therapy at Dokkyo Medical University Hospital between June 2013 and October 2015. Gastrectomy and D2 lymphadenectomy were performed after two cycles of preoperative DCS therapy. The clinical responses of the primary gastric tumors based on endoscopic findings were partial response in 17 patients (57%) and stable disease in 13 patients (43%). Analysis of pathological response in the primary gastric lesions showed grade 1a in five patients (17%), grade 1b in nine patients (30%), grade 2 in 11 patients (37%), and grade 3 in five patients (17%). Twenty-four patients (80%) remained alive after a median follow-up period of 31 months. The 2- and 3-year overall survival rates in all patients were 89 and 70%, respectively. The 2-year overall survival rate in pathological responders (grade 1b-3) was 96%, compared with 50% in pathological non-responders (grade 1a) (P = 0.00187). Pathological responders had a significantly higher survival rate than non-responders. These results indicate that neoadjuvant DCS therapy may improve the prognosis in patients with serosa-positive locally advanced gastric cancer.
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Conversion therapy for inoperable advanced gastric cancer patients by docetaxel, cisplatin, and S-1 (DCS) chemotherapy: a multi-institutional retrospective study. Gastric Cancer 2017; 20:517-526. [PMID: 27553665 DOI: 10.1007/s10120-016-0633-1] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 08/08/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Conversion therapy is an option for unresectable metastatic gastric cancer when distant metastases are controlled by chemotherapy; however, the feasibility and efficacy remain unclear. This study aimed to assess the feasibility and efficacy of conversion therapy in patients with initially unresectable gastric cancer treated with docetaxel, cisplatin, and S-1 (DCS) chemotherapy by evaluating clinical outcomes. METHODS One hundred unresectable metastatic gastric cancer patients, enrolled in three DCS chemotherapy clinical trials, were retrospectively evaluated. The patients received oral S-1 (40 mg/m2 b.i.d.) on days 1-14 and intravenous cisplatin (60 mg/m2) and docetaxel (50-60 mg/m2) on day 8 every 3 weeks. Conversion therapy was defined when the patients could undergo R0 resection post-DCS chemotherapy and were able to tolerate curative surgery. RESULTS Conversion therapy was achieved in 33/100 patients, with no perioperative mortality. Twenty-eight of the 33 patients (84.8 %) achieved R0 resection, and 78.8 % were defined as histological chemotherapeutic responders. The median overall survival (OS) of patients who underwent conversion therapy was 47.8 months (95 % CI 28.0-88.5 months). Patients who underwent R0 resection had significantly longer OS than those who underwent R1 and R2 resections (P = 0.0002). Of the patients with primarily unresectable metastases, 10 % lived >5 years. Among patients who underwent conversion therapy, multivariate analysis showed that the pathological response was a significant independent predictor for OS. CONCLUSIONS DCS safely induced a high conversion rate, with very high R0 and pathological response rates, and was associated with a good prognosis; these findings warrant further prospective investigations.
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Saito H, Fushida S, Miyashita T, Oyama K, Yamaguchi T, Tsukada T, Kinoshita J, Tajima H, Ninomiya I, Ohta T. Potential of extravasated platelet aggregation as a surrogate marker for overall survival in patients with advanced gastric cancer treated with preoperative docetaxel, cisplatin and S-1: a retrospective observational study. BMC Cancer 2017; 17:294. [PMID: 28449652 PMCID: PMC5408413 DOI: 10.1186/s12885-017-3279-4] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 04/12/2017] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The theory of extravasated platelet aggregation in cancer lesions was recently introduced. We investigated the association of platelet aggregation in gastric cancer stroma with clinicopathological features, chemotherapeutic response, pathological response, and survival. METHODS The study comprised 78 patients with advanced gastric cancer who had undergone gastrectomy with or without combination of docetaxel, cisplatin and S-1 (DCS) as preoperative chemotherapy between 2005 and 2014. The patients were divided into two groups: patients who had received preoperative DCS therapy forming the p-DCS group and patients who had not received preoperative DCS therapy forming the control group. The 39 patients in the control group had received gastrectomy and postoperative chemotherapy of S-1 alone. Platelet aggregation in biopsy specimens before preoperative DCS therapy in the p-DCS group and at the time of diagnosis in the control group were evaluated using CD42b immunohistochemical staining. RESULTS Twenty-four patients in the p-DCS group and 19 in the control group were found to have platelet aggregation in their cancer stroma. Patients with histologically confirmed platelet aggregation had significantly higher rates of chemoresistance (58.3%) than those without platelet aggregation (20.0%) (P = 0.019). According to multivariate analysis, CD42b expression (odds ratio: 5.102, 95% confidence interval: 1.039-25.00, P = 0.045) was correlated with chemoresistance. CD42b expression and histological non-responder status were both significantly correlated with poor overall survival (OS) (P = 0.012, P = 0.016); however, RECIST was not correlated with OS. In the control group, CD42b expression was also significantly correlated with poor overall survival (OS) (P = 0.033). In the p-DCS group, according to multivariate analysis, male sex (hazard ratio: 0.281, 95% confidence interval: 0.093-0.846, P = 0.024) was correlated with good prognosis and CD42b expression (hazard ratio: 4.406, 95% confidence interval: 1.325-14.65, P = 0.016) with poor prognosis. CONCLUSIONS This study suggests that platelets in gastric cancer stroma may create a favorable microenvironment for chemoresistance. CD42b immunohistochemical staining of biopsy specimens is a promising candidate for being a prognostic marker in patients with gastric cancer.
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Affiliation(s)
- Hiroto Saito
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan.
| | - Tomoharu Miyashita
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Katsunobu Oyama
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tomoya Tsukada
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Jun Kinoshita
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Itasu Ninomiya
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan
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Yuan M, Shi Z, Wang Z, Lv W, Yang Y, Lu F, Zhao Y, Zhong H. The significance of multi-line chemotherapy for advanced gastric cancer: A retrospective analysis. Mol Clin Oncol 2017; 6:606-612. [PMID: 28413678 DOI: 10.3892/mco.2017.1163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 12/22/2016] [Indexed: 11/05/2022] Open
Abstract
Palliative chemotherapy is known to benefit patients with advanced gastric cancer by palliating symptoms and improving survival. The aim of the present study was to evaluate the efficacy and toxicity of chemotherapy regimens that are commonly used in patients with advanced or recurrent gastric cancer. Patients with advanced or recurrent gastric cancer who were treated by at least two chemotherapy regimens between May 2006 and July 2014 at Zhejiang Cancer Hospital (Hangzhou, China) were retrospectively investigated. Survival was evaluated using the Kaplan-Meier method. A total of 248 patients were reviewed, and 158 were evaluated in the final analysis, with a median age of 57 years and a Karnofsky performance status score of ≥80. The median progression-free survival (PFS) time was 168 days for first-line chemotherapy, 96 days for second-line chemotherapy, and the median overall survival (OS) time was 356 days. Further analysis revealed that patients with the disease controlled [complete response (CR) + partial response (PR) + stable disease (SD)], no matter whether they received first-or second-line chemotherapy, may have had an improved OS compared with patients with disease progression (PD). Patients who were treated with >2 lines of chemotherapy had an improved OS compared those who ceased treatment following failure of the second-line chemotherapy. The cycle number of chemotherapy that patients received was associated with OS. The site of the primary and metastatic tumors was also associated with OS. Other factors, including gender, age, histological type, whether a radical operation was received, and chemotherapy regimens, had no evident association with survival. The toxicities were generally tolerated. Taken together, the results from the present study have demonstrated that an increased cycle number of effective chemotherapy may prolong the survival of patients with advanced gastric cancer. Differences among the chemotherapy regimens had no clear correlation with survival.
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Affiliation(s)
- Meiqin Yuan
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zhong Shi
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Zeng Wang
- Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Wangxia Lv
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yunshan Yang
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Fangxiao Lu
- Department of Radiology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Yazhen Zhao
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
| | - Haijun Zhong
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Ito S, Sano T, Mizusawa J, Takahari D, Katayama H, Katai H, Kawashima Y, Kinoshita T, Terashima M, Nashimoto A, Nakamori M, Onaya H, Sasako M. A phase II study of preoperative chemotherapy with docetaxel, cisplatin, and S-1 followed by gastrectomy with D2 plus para-aortic lymph node dissection for gastric cancer with extensive lymph node metastasis: JCOG1002. Gastric Cancer 2017; 20:322-331. [PMID: 27299887 DOI: 10.1007/s10120-016-0619-z] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2016] [Accepted: 05/23/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer with extensive lymph node metastasis is commonly considered unresectable, with a poor prognosis. We previously reported the results of the use of cisplatin and S-1 as preoperative chemotherapy for gastric cancer with extensive lymph node metastasis; docetaxel, cisplatin, and S-1 (DCS) have now been investigated for the same purpose. METHODS Patients received two or three 28-day cycles of DCS therapy (docetaxel at 40 mg/m2 and cisplatin at 60 mg/m2 on day 1, S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 plus para-aortic nodal dissection. After R0 resection, S-1 chemotherapy was given for 1 year. The primary end point was the response rate (RR) to preoperative chemotherapy determined by central peer review according to the Response Evaluation Criteria in Solid Tumors version 1.0. The planned sample size was 50, with one-sided alpha of 10 %, power of 80 %, expected RR of 80 %, and threshold of 65 %. RESULTS Between July 2011 and May 2013, 53 patients were enrolled, of whom 52 were eligible. The clinical RR was 57.7 % [30/52, 80 % confidence interval 47.9-67.1 %, p = 0.89], and R0 resection was achieved in 84.6 % of patients (44/52). Common grade 3 or grade 4 adverse events during DCS therapy were leukocytopenia (18.9 %), neutropenia (39.6 %), and hyponatremia (15.1 %). The common grade 3 or grade 4 surgical morbidity was abdominal infection (10.2 %). The pathological RR was 50.0 % (26/52). CONCLUSIONS Preoperative DCS therapy was feasible but did not show a sufficient RR. Preoperative cisplatin and S-1 therapy is still considered the tentative standard treatment for this population until survival results are known.
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Affiliation(s)
- Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan.
| | - Takeshi Sano
- Department of Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | | | - Hitoshi Katai
- Gastric Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshiyuki Kawashima
- Division of Gastroenterological Surgery, Saitama Cancer Center, Saitama, Japan
| | - Takahiro Kinoshita
- Gastric Surgery Division, National Cancer Center Hospital East, Kashiwa, Japan
| | | | - Atsushi Nashimoto
- Department of Surgery, Niigata Cancer Center Hospital, Niigata, Japan
| | - Mikihito Nakamori
- Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan
| | - Hiroaki Onaya
- Department of Diagnostic Radiology, Gunma Prefectural Cancer Center, Ota, Japan
| | - Mitsuru Sasako
- Division of Upper Gastrointestinal Surgery, Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan
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Maeda O, Matsuoka A, Miyahara R, Funasaka K, Hirooka Y, Fukaya M, Nagino M, Kodera Y, Goto H, Ando Y. Modified docetaxel, cisplatin and capecitabine for stage IV gastric cancer in Japanese patients: A feasibility study. World J Gastroenterol 2017; 23:1090-1097. [PMID: 28246483 PMCID: PMC5311098 DOI: 10.3748/wjg.v23.i6.1090] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 12/30/2016] [Accepted: 01/17/2017] [Indexed: 02/07/2023] Open
Abstract
AIM
To evaluate the feasibility of chemotherapy including fluoropyrimidine, platinum and taxane with modified dosages for unresectable gastric cancer in Japanese patients.
METHODS
We performed a feasibility study of a modified docetaxel, cisplatin and capecitabine (DCX) regimen for stage IV gastric cancer. In particular, 30 or 40 mg/m2 of docetaxel on day 1, 60 mg/m2 of cisplatin on day 1, and 2000 mg/m2 of capecitabine for 2 wk were administered every three weeks.
RESULTS
Three patients were treated with modified DCX (mDCX) with 30 mg/m2 docetaxel, and five patients were treated with this regimen with 40 mg/m2 docetaxel. Grade 3 or 4 neutropenia was observed in six of the eight patients; no patients exhibited febrile neutropenia. Partial response was achieved in four of the eight patients. Three patients underwent gastrectomy, which achieved R0 resection without residual tumors in dissected lymph nodes. In one of these three patients, resected specimens revealed pathological complete response in the primary lesion and in lymph nodes.
CONCLUSION
mDCX was well tolerated by Japanese patients with stage IV gastric cancer. This regimen might be useful for allowing gastric cancer patients with distant lymph node metastasis to undergo conversion surgery.
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Kubo T, Kawano Y, Himuro N, Sugita S, Sato Y, Ishikawa K, Takada K, Murase K, Miyanishi K, Sato T, Takimoto R, Kobune M, Nobuoka T, Hirata K, Takayama T, Mori M, Hasegawa T, Kato J. BAK is a predictive and prognostic biomarker for the therapeutic effect of docetaxel treatment in patients with advanced gastric cancer. Gastric Cancer 2016; 19:827-38. [PMID: 26486506 DOI: 10.1007/s10120-015-0557-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 10/06/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Preoperative chemotherapy is a promising strategy for downstaging advanced gastric cancer before radical resection, although severe adverse events can occur and clinical outcomes are often unsatisfactory. To identify predictive biomarkers of drug sensitivity, we used a well-designed functional apoptosis assay and assessed the correlations between chemosensitivity and clinical outcomes. METHODS Drug sensitivity to docetaxel, cisplatin, and 5-fluorouracil was examined in 11 gastric cancer cell lines. BCL2-homology domain 3 (BH3) profiling was performed and assessed for correlations with drug sensitivity. Immunohistochemical staining of clinical gastric cancer specimens was performed before preoperative chemotherapy, and correlations with histopathological responses and clinical outcomes were assessed. RESULTS BIM (BCL2L11)-BH3 profiling results correlated with docetaxel sensitivity and BAK protein expression, whose knockdown caused docetaxel resistance. The BAK expression indexes of 69 gastric cancer specimens before preoperative chemotherapy (including docetaxel treatment) were determined by multiplying numerical values describing the degrees of BAK positivity and staining intensity observed. Patients whose specimens showed good chemotherapeutic histopathological responses had higher BAK indexes than those with poor responses. Patients with BAK index values ≥3 showed improved progression-free survival (HR, 2.664; 95 % CI, 1.352-5.248; P = 0.005) and overall survival (HR, 3.390; 95 % CI, 1.549-7.422; P = 0.002). CONCLUSIONS BH3 profiling clearly showed that BIM expression, which depends on BAK expression, correlated with docetaxel sensitivity. BAK expression in gastric cancer is thus predictive of chemotherapeutic responses to docetaxel and clinical prognosis in patients treated with preoperative chemotherapy.
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Affiliation(s)
- Tomohiro Kubo
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yutaka Kawano
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Nobuaki Himuro
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Shintaro Sugita
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasushi Sato
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kazuma Ishikawa
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kohichi Takada
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kazuyuki Murase
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Koji Miyanishi
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Tsutomu Sato
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Rishu Takimoto
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Masayoshi Kobune
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Takayuki Nobuoka
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, 060-8543, Japan
| | - Koichi Hirata
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Hokkaido, 060-8543, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, The University of Tokushima Graduate School, Tokushima, Tokushima, 770-8503, Japan
| | - Mitsuru Mori
- Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, 060-8543, Japan
| | - Junji Kato
- Department of Medical Oncology and Hematology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
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Taxanes in the Treatment of Advanced Gastric Cancer. Molecules 2016; 21:molecules21050651. [PMID: 27196887 PMCID: PMC6274234 DOI: 10.3390/molecules21050651] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Revised: 05/12/2016] [Accepted: 05/13/2016] [Indexed: 01/11/2023] Open
Abstract
Although rapid advances in treatment options have improved the prognosis of advanced gastric cancer (AGC), it remains a major public health problem and the second leading cause of cancer-related deaths in the world. Taxanes (paclitaxel and docetaxel) are microtubule stabilizing agents that inhibit the process of cell division, and have shown antitumor activity in the treatment of AGC as a single or combination chemotherapy. Accordingly, this review focuses on the efficacy and tolerability of taxanes in the first- or second-line chemotherapy setting for AGC.
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Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification. Gastric Cancer 2016; 19:329-338. [PMID: 26643880 PMCID: PMC4824831 DOI: 10.1007/s10120-015-0575-z] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 11/06/2015] [Indexed: 02/07/2023]
Abstract
Conversion therapy for gastric cancer (GC) has been the subject of much recent attention. It is defined as a surgical treatment aiming at an R0 resection after chemotherapy for tumors that were originally unresectable or marginally resectable for technical and/or oncological reasons. However, the indications for resection remain to be clarified. In the present review, we focus on the biology and heterogeneous characteristics of stage IV GC and propose new categories of classification. Stage IV GC patients can be divided based on the absence (categories 1 and 2) or presence (categories 3 and 4) of macroscopically detectable peritoneal dissemination, which has a different biological outcome compared to hematological metastasis. Category 1 is defined oncologically as stage IV but the metastasis is technically resectable. Category 2 includes a marginally resectable metastasis or patients for whom the operation would not necessarily be the best choice. Category 3 includes a potentially unresectable metastasis of peritoneal dissemination that is only macroscopically detectable. Category 4 includes noncurable metastasis with peritoneal and other organ metastasis. The indications for conversion therapy might include the patients from category 2, some patients from category 3 and a very small number of patients from category 4. The longer survival can be expected for patients corresponding to categories 1, 2 and, to a lesser extent, 3, while the treatment of other patients focuses on "care." The provision of conversion therapy for stage IV GC patients might be one of the main roles of surgical oncologists in the near future.
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Ito S, Ito Y, Misawa K, Shimizu Y, Kinoshita T. Neoadjuvant chemotherapy followed by surgery in gastric cancer patients with extensive lymph node metastasis. World J Clin Oncol 2015; 6:291-294. [PMID: 26677442 PMCID: PMC4675914 DOI: 10.5306/wjco.v6.i6.291] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2015] [Revised: 08/26/2015] [Accepted: 09/28/2015] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer with extensive lymph node metastasis (ELM) is usually considered unresectable and is associated with poor outcomes. Cases with clinical enlargement of the para-aortic lymph nodes and/or bulky lymph node enlargement around the celiac artery and its branches are generally dealt with as ELM. A standard treatment for gastric cancer with ELM has yet to be determined. Two phase II studies of neoadjuvant chemotherapy followed by surgery showed that neoadjuvant chemotherapy with S-1 plus cisplatin followed by surgical resection with extended lymph node dissection could represent a treatment option for gastric cancer with ELM. However, many clinical questions remain unresolved, including the criteria for diagnosing ELM, optimal regime, number of courses and extent of lymph node dissection.
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35
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Miyoshi J, Miyamoto H, Goji T, Taniguchi T, Tomonari T, Sogabe M, Kimura T, Kitamura S, Okamoto K, Fujino Y, Muguruma N, Okahisa T, Takayama T. Serum diamine oxidase activity as a predictor of gastrointestinal toxicity and malnutrition due to anticancer drugs. J Gastroenterol Hepatol 2015; 30:1582-1590. [PMID: 25968084 DOI: 10.1111/jgh.13004] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/16/2015] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Objective evaluation of intestinal mucosal damage due to anticancer drugs is generally difficult. Serum diamine oxidase (DAO) activity is reported to reflect the integrity and maturity of the small intestinal mucosa. Therefore, we investigated whether serum DAO activity is an indicator of gastrointestinal toxicity or nutritional status in patients receiving chemotherapy. METHODS We prospectively enrolled 20 patients with unresectable metastatic gastric cancer who received oral S-1 (80 mg/m(2) ) on days 1-14, and intravenous cisplatin (60 mg/m(2) ) and docetaxel (50 mg/m(2) ) on day 8 every 3 weeks. Serum DAO activity was measured by colorimetry. Gastrointestinal toxicity was evaluated by Common Toxicity Criteria for Adverse Events version 4.0. Endoscopic examination and biopsy of duodenal mucosa assessed mucosal damage. Malnutrition was evaluated by measuring serum total protein and albumin levels. RESULTS Serum DAO activity decreased step-by-step significantly during anticancer drug treatment and recovered after drug holidays. In all 14 patients who experienced diarrhea, serum DAO activity significantly decreased prior to diarrhea onset. Percent decrease in DAO activity was significantly correlated with severity of diarrhea. Significant correlation was observed between percent decrease in DAO activity and percent decrease in duodenal villus height or surface area from baseline. There were also significant correlations between percent decrease in serum DAO activity at day 14 and percent decrease in serum total protein or albumin levels at day 21 from baseline. CONCLUSION Serum DAO activity sensitively indicates gastrointestinal damage prior to symptom onset and can be a useful predictor of intestinal mucosal damage and nutritional status in patients receiving chemotherapy.
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Affiliation(s)
- Jinsei Miyoshi
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Takahiro Goji
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Tatsuya Taniguchi
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Tetsu Tomonari
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Masahiro Sogabe
- Department of General Medicine and Community Health Science, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Tetsuo Kimura
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Shinji Kitamura
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Yasuteru Fujino
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Toshiya Okahisa
- Department of General Medicine and Community Health Science, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan
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Kinoshita J, Fushida S, Tsukada T, Oyama K, Okamoto K, Makino I, Nakamura K, Miyashita T, Tajima H, Takamura H, Ninomiya I, Ohta T. Efficacy of conversion gastrectomy following docetaxel, cisplatin, and S-1 therapy in potentially resectable stage IV gastric cancer. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2015; 41:1354-1360. [PMID: 26028256 DOI: 10.1016/j.ejso.2015.04.021] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Revised: 04/21/2015] [Accepted: 04/24/2015] [Indexed: 12/31/2022]
Abstract
BACKGROUND Recent advances in gastric cancer chemotherapy have made macroscopic complete resection possible in some patients with stage IV disease. METHODS We retrospectively investigated the efficacy of multimodal therapy with combined docetaxel, cisplatin, and S-1 (DCS) and conversion gastrectomy in 57 patients with stage IV gastric cancer. RESULTS Of the 57 patients, 15 patients were categorized into potentially resectable case, which is defined as patients with single incurable factor including the upper abdominal para-aortic lymph node metastasis (16a2b1 PAN metastasis) or fewer than three peripheral liver metastases. The other 42 were categorized as initially unresectable. All of patients underwent DCS therapy, and then 34 patients underwent conversion gastrectomy. The 3-year overall survival (OS) rate among the patients who underwent conversion gastrectomy was 50.1% with MST of 29.9 months. They had significantly longer OS than patients who underwent DCS therapy alone (p < 0.01). Univariate analysis among the patents with conversion gastrectomy identified 16a2b1PAN metastasis, peritoneal metastasis, potential resectable case, R0 resection as significant prognostic factors. A 3-year OS in potential resectable cases was 92.9%. Multivariate analysis identified potential resectability as the only independent prognostic factor contributing to OS (HR 0.133, 95%CI 0.024-0. 744, p = 0.021). In contrast, clinical response was selected as the only independent prognostic factor in the subgroup of initially unresectable cases (HR 0.354, 95%CI 0.151-0.783, p = 0.021). CONCLUSION Patients with potentially resectable disease had a remarkably good prognosis among stage IV gastric cancer patients, and might be ideal candidates for conversion gastrectomy following DCS therapy.
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Affiliation(s)
- J Kinoshita
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - S Fushida
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan.
| | - T Tsukada
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - K Oyama
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - K Okamoto
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - I Makino
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - K Nakamura
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - T Miyashita
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - H Tajima
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - H Takamura
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - I Ninomiya
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
| | - T Ohta
- Department of Gastroenterologic Surgery Division of Cancer Medicine, Graduate School of Medicine Science, Kanazawa University, 13-1 Takaramachi, Kanazawa, 920-8641, Japan
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Mitsui Y, Sato Y, Miyamoto H, Fujino Y, Takaoka T, Miyoshi J, Kagawa M, Ohnuma H, Hirakawa M, Kubo T, Osuga T, Sagawa T, Sato Y, Takahashi Y, Katsuki S, Okuda T, Takimoto R, Kobune M, Nobuoka T, Hirata K, Kato J, Takayama T. Trastuzumab in combination with docetaxel/cisplatin/S-1 (DCS) for patients with HER2-positive metastatic gastric cancer: feasibility and preliminary efficacy. Cancer Chemother Pharmacol 2015; 76:375-82. [PMID: 26099968 DOI: 10.1007/s00280-015-2807-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 06/12/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE We previously reported that a triplet combination of docetaxel, cisplatin, and S-1 (DCS) is active against metastatic gastric cancer with a very high response rate of 87.1 % in a phase II study. Recently, the efficacy of trastuzumab (T-mab) for the treatment of HER2-positive gastric cancer has been reported. Therefore, we investigated the feasibility and preliminary efficacy of DCS + T-mab (DCS-T) for unresectable HER2-positive metastatic gastric cancer. METHODS Patients received oral S-1 (40 mg/m(2) b.i.d.) on days 1-14, intravenous cisplatin (60 mg/m(2)), docetaxel (50 mg/m(2)), and T-mab (8 mg/kg in the first cycle and 6 mg/kg in the second cycle and thereafter) on day 8 every 3 weeks. RESULTS The study included 16 patients: median age, 60 (34-76) years; males/females, 11:5; intestinal-type/diffuse-type histology, 11:5; and HER2 3+/2+(FISH+), 13:3. The completion rate until the third cycle was 87.5 % (14/16) (95 %CI 71.3-103.7 %). Adverse events of grade 3/4 severity during the first 3 cycles were: leukopenia/neutropenia, 50.0:75.0 %; febrile neutropenia, 12.5 %; diarrhea, 12.5 %; and stomatitis, 12.5 %. All of these side effects were manageable and well controlled. There were no treatment-related deaths. The overall response rate was 93.8 % (15/16), and the response rate in patients with measurable lesions was 100 % (15/15). The median cycle to response was only 1 (1-3 cycles). Non-curative factors disappeared in 56.3 % (9/16) of patients, and conversion surgery (R0 resection) was performed in all these cases. Pathological response rates in primary and metastatic lesions were 88.9 % (8/9) and 100 % (9/9), respectively. The median PFS and OS were not reached during the median follow-up time of 18.3 months ranged from 11.0 to 34.3 months. CONCLUSIONS DCS-T was feasible in patients with unresectable HER2-positive metastatic gastric cancer. The observed response was very promising and warrants further investigation. CLINICAL TRIAL REGISTRATION NUMBER UMIN000005603.
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Affiliation(s)
- Yasuhiro Mitsui
- Department of Gastroenterology and Oncology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15, Kuramoto-cho, Tokushima City, 770-8503, Japan
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Efficacy of neoadjuvant chemotherapy with docetaxel, cisplatin and S-1 for resectable locally advanced gastric cancer. Int J Clin Oncol 2015; 21:102-9. [DOI: 10.1007/s10147-015-0851-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 05/18/2015] [Indexed: 12/17/2022]
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Yang J, Zhou Y, Min K, Yao Q, Xu CN. S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer: A meta-analysis. World J Gastroenterol 2014; 20:11886-11893. [PMID: 25206296 PMCID: PMC4155382 DOI: 10.3748/wjg.v20.i33.11886] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 04/24/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the efficacy and tolerability of S-1-based vs non-S-1-based chemotherapy in advanced gastric cancer (AGC).
METHODS: We extracted reported endpoints, including overall survival (OS), progression-free survival (PFS), time-to-treatment failure (TTF), objective response rate (ORR) and adverse effects, from randomized controlled trials identified in PubMed, the Cochrane library, Science Direct, EMBASE and American Society of Clinical Oncology meetings. Stata software was used to calculate the pooled values.
RESULTS: Seven randomized controlled trials involving 2176 patients were included in this meta-analysis. Compared to non-S-1-based regimens, the use of S-1-based regimens were associated with an increase in ORR (RR = 1.300; 95%CI: 1.028-1.645); OS (HR = 0.89; 95%CI: 0.81-0.99; P = 0.025), TTF (HR = 0.83; 95%CI: 0.75-0.92; P = 0.000), and a lower risk of febrile neutropenia (RR = 0.225; P = 0.000) and stomatitis (RR = 0.230; P = 0.032). OS, PFS and TTF were prolonged, especially in the Asian population. In subgroup analysis, statistically significant increases in ORR (RR = 1.454; P = 0.029), OS (HR = 0.895; P = 0.041) and TTF (HR = 0.832; P = 0.000) were found when S-1-based chemotherapy was compared to 5-fluorouracil (5-FU)-based chemotherapy. The incidence of leukopenia (RR = 0.584; P = 0.002) and stomatitis (RR = 0.230; P = 0.032) was higher in the 5-FU-based arm. S-1-based regimens had no advantage in ORR, OS, PFS, TTF and grade 3 or 4 adverse events over capecitabine-based regimens.
CONCLUSION: S-1-based chemotherapy may be a good choice for AGC because of longer survival times, better tolerance and more convenient use.
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Ina K, Kataoka T, Ando T. The use of lentinan for treating gastric cancer. Anticancer Agents Med Chem 2014; 13:681-8. [PMID: 23092289 PMCID: PMC3664515 DOI: 10.2174/1871520611313050002] [Citation(s) in RCA: 136] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 08/23/2012] [Accepted: 10/17/2012] [Indexed: 12/11/2022]
Abstract
Natural compounds containing fungal β-glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of β-(1, 3)-glucan with β-(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by β-glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review.
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Affiliation(s)
- Kenji Ina
- Department of Medical Oncology, Nagoya Memorial Hospital, Nagoya 468-8520, Japan.
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Xu AM, Huang L, Liu W, Gao S, Han WX, Wei ZJ. Neoadjuvant chemotherapy followed by surgery versus surgery alone for gastric carcinoma: systematic review and meta-analysis of randomized controlled trials. PLoS One 2014; 9:e86941. [PMID: 24497999 PMCID: PMC3907439 DOI: 10.1371/journal.pone.0086941] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2013] [Accepted: 12/16/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The effect of neoadjuvant chemotherapy (NAC) on Gastric carcinoma (GC) has been extensively studied, while its survival and surgical benefits remain controversial. This study aims to perform a meta-analysis of high-quality randomized controlled trials (RCTs), comparing efficacy, safety and other outcomes of NAC followed by surgery with surgery alone (SA) for GC. METHODS We systematically searched databases of MEDLINE, EMBASE, The Cochrane Library and Springer for RCTs comparing NAC with SA when treating GC. Reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases were also searched. Primary outcomes were 3-year and 5-year survival rates, survival time, and total and perioperative mortalities. Secondary outcomes included down-staging effects, R0 resection rate, and postoperative complications. Meta-analysis was conducted where possible comparing items using relative risks (RRs) and weighted mean differences (WMDs) according to type of data. NAC-related objective response, safety and toxicity were also specifically analyzed. RESULTS A total of 9 RCTs comparing NAC (n = 511) with SA (n = 545) published from 1995 to 2010 were identified. SA tended to be accompanied with higher overall mortality rate than NAC (46.03% vs 40.61%, RR: 0.83, 95% CI: 0.65-1.06, P = 0.14). Significantly, higher incidence of cases without regional lymph node metastasis observed upon resection were achieved among patients receiving NAC than those undergoing SA (25.68% vs 16.95%, RR: 1.92, 95% CI: 1.20-3.06, P = 0.006). All other parameters were comparable. Of the evaluable patients, 43.0% demonstrated either complete or partial response. The comprehensive NAC-related side-effect rate was 18.2% among patients available for safety assessment. CONCLUSIONS NAC contributes to lowering nodal stages, and potentially reduces overall mortality. Response rate may be an important influential factor impacting advantages, with chemotherapy-related adverse effects as a drawback. This level 1a evidence doesn't support NAC to outweigh SA in terms of survival and surgical benefits when dealing with GC.
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Affiliation(s)
- A-Man Xu
- Anhui Medical University, Hefei, China
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lei Huang
- Anhui Medical University, Hefei, China
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuang Gao
- Anhui Medical University, Hefei, China
- Department of Medical Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wen-Xiu Han
- Anhui Medical University, Hefei, China
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi-Jian Wei
- Anhui Medical University, Hefei, China
- Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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Xu AM, Huang L, Liu W, Gao S, Han WX, Wei ZJ. Neoadjuvant chemotherapy followed by surgery versus surgery alone for gastric carcinoma: systematic review and meta-analysis of randomized controlled trials. PLoS One 2014. [PMID: 24497999 DOI: 10.1371/journal.pone.0086941.ecollection] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The effect of neoadjuvant chemotherapy (NAC) on Gastric carcinoma (GC) has been extensively studied, while its survival and surgical benefits remain controversial. This study aims to perform a meta-analysis of high-quality randomized controlled trials (RCTs), comparing efficacy, safety and other outcomes of NAC followed by surgery with surgery alone (SA) for GC. METHODS We systematically searched databases of MEDLINE, EMBASE, The Cochrane Library and Springer for RCTs comparing NAC with SA when treating GC. Reference lists of relevant articles and reviews, conference proceedings and ongoing trial databases were also searched. Primary outcomes were 3-year and 5-year survival rates, survival time, and total and perioperative mortalities. Secondary outcomes included down-staging effects, R0 resection rate, and postoperative complications. Meta-analysis was conducted where possible comparing items using relative risks (RRs) and weighted mean differences (WMDs) according to type of data. NAC-related objective response, safety and toxicity were also specifically analyzed. RESULTS A total of 9 RCTs comparing NAC (n = 511) with SA (n = 545) published from 1995 to 2010 were identified. SA tended to be accompanied with higher overall mortality rate than NAC (46.03% vs 40.61%, RR: 0.83, 95% CI: 0.65-1.06, P = 0.14). Significantly, higher incidence of cases without regional lymph node metastasis observed upon resection were achieved among patients receiving NAC than those undergoing SA (25.68% vs 16.95%, RR: 1.92, 95% CI: 1.20-3.06, P = 0.006). All other parameters were comparable. Of the evaluable patients, 43.0% demonstrated either complete or partial response. The comprehensive NAC-related side-effect rate was 18.2% among patients available for safety assessment. CONCLUSIONS NAC contributes to lowering nodal stages, and potentially reduces overall mortality. Response rate may be an important influential factor impacting advantages, with chemotherapy-related adverse effects as a drawback. This level 1a evidence doesn't support NAC to outweigh SA in terms of survival and surgical benefits when dealing with GC.
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Affiliation(s)
- A-Man Xu
- Anhui Medical University, Hefei, China ; Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lei Huang
- Anhui Medical University, Hefei, China ; Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wei Liu
- Guangdong Provincial Key Laboratory of Liver Disease Research, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shuang Gao
- Anhui Medical University, Hefei, China ; Department of Medical Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Wen-Xiu Han
- Anhui Medical University, Hefei, China ; Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi-Jian Wei
- Anhui Medical University, Hefei, China ; Department of General Surgery, the First Affiliated Hospital of Anhui Medical University, Hefei, China
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Fushida S, Oyama K, Kinoshita J, Yagi Y, Okamoto K, Tajima H, Ninomiya I, Fujimura T, Ohta T. VEGF is a target molecule for peritoneal metastasis and malignant ascites in gastric cancer: prognostic significance of VEGF in ascites and efficacy of anti-VEGF monoclonal antibody. Onco Targets Ther 2013; 6:1445-51. [PMID: 24204159 PMCID: PMC3804591 DOI: 10.2147/ott.s51916] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background In gastric cancer, poor prognosis is associated with peritoneal dissemination, which often accompanies malignant ascites. We searched for a target molecule in peritoneal metastasis and investigated its clinical utility as a biomarker. Methods Biopsy specimens from both primary lesions and peritoneal metastasis, and if possible, malignant ascites, were obtained from 40 patients with gastric cancer. Vascular endothelial growth factor (VEGF) expression was analyzed by immunohistochemical staining and enzyme-linked immunosorbent assay. Results VEGF expression was seen in 70% of peritoneal samples. Of the 40 patients, 35 had malignant ascites. These 35 patients were divided into two groups: 15 with ascites found beyond the pelvic cavity (large group) and 20 whose ascites were within the pelvic cavity (small group). The two groups did not significantly differ by serum VEGF levels, but ascites VEGF levels in the large group were significantly higher than in the small group (P < 0.0001). Serum VEGF and ascites VEGF levels were highly correlated in the large group (r = 0.686). A high ascites VEGF level was found to be a risk factor for survival (P = 0.045). We include a report of a patient with chemoresistant refractory gastric cancer and symptomatic ascites who obtained 8 months of palliation from systemic bevacizumab. Conclusion Anti-VEGF therapies are promising, and the ascites VEGF level is an important marker in managing patients with gastric cancer and peritoneal metastasis.
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Affiliation(s)
- Sachio Fushida
- Department of Gastroenterological Surgery, Kanazawa University Hospital, Kanazawa, Japan
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Yang J, Zhou Y, Chen JF. Role of S-1 in treatment of advanced gastric cancer. Shijie Huaren Xiaohua Zazhi 2013; 21:2950-2956. [DOI: 10.11569/wcjd.v21.i28.2950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is the fourth most common malignancy worldwide. More than 50% of gastric cancer patients have unresectable disease at diagnosis, and there is a high rate of local or distant recurrence, even in patients with an operable tumor. Chemotherapy is regarded as a significant and basic treatment that can provide a longer symptom-free period and improve quality of life. S-1 is a novel oral derivative of 5-FU. Compared with 5-FU, S-1 is more tolerable and effective, and will be more convenient to use for patients with advanced gastric cancer. Recent phase II randomized trials of S-1 based chemotherapy have achieved encouraging results with regard to objective response rate and overall survival. This paper aims to review the efficacy of S-1 in treating advanced gastric cancer, molecular markers that can predict efficacy, and the prospect for therapy with S-1 in combination with new chemotherapeutic drugs or molecularly targeted drugs.
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Yamamoto M, Sakaguchi Y, Matsuyama A, Yoshinaga K, Tsutsui S, Ishida T. Surgery after preoperative chemotherapy for patients with unresectable advanced gastric cancer. Oncology 2013; 85:241-7. [PMID: 24107642 DOI: 10.1159/000354420] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 07/15/2013] [Indexed: 01/16/2023]
Abstract
OBJECTIVE The study aimed to evaluate the efficacy of surgery after preoperative chemotherapy for unresectable advanced gastric cancer. METHOD Twenty patients with disappeared peritoneal dissemination or decreased lymph node metastasis by systemic chemotherapy underwent surgery (group S), while 14 with peritoneal dissemination or lymph nodes >N2 (group C) received continuous systemic chemotherapy. Among group S patients, 15 underwent a curative resection (group R0), while the other 5 did not microscopically undergo a curative resection (group R1). RESULTS The median survival time for all patients was 535 days. Survival time was significantly dependent on the chemotherapy response (p < 0.002). The survival period in group S was significantly longer than that in group C (median survival time 747 vs. 476 days; p < 0.02). The relapse-free survival was 299 days in group S. In particular, the survival period of patients who underwent R0 surgery by preoperative chemotherapy was significantly longer than that of group R1 patients (median survival time 794 vs. 485 days; p < 0.02). Multivariate analysis revealed that R0 surgery was a significant and independent prognostic factor. CONCLUSION Surgery was effective for advanced gastric cancer patients when performed as R0 resection following the disappearance of non-curative factors by preoperative chemotherapy.
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Affiliation(s)
- Manabu Yamamoto
- Department of Surgery, Hiroshima Atomic Bomb Survivors Hospital, Hiroshima, Japan
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Shiraishi K, Mimura K, Izawa S, Inoue A, Shiba S, Maruyama T, Watanabe M, Kawaguchi Y, Inoue M, Fujii H, Kono K. Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity. Gastric Cancer 2013. [PMID: 23187882 DOI: 10.1007/s10120-012-0219-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). METHODS Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. RESULTS Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer. CONCLUSIONS Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.
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Affiliation(s)
- Kensuke Shiraishi
- First Department of Surgery, University of Yamanashi, Yamanashi, Japan
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Chen XL, Chen XZ, Yang C, Liao YB, Li H, Wang L, Yang K, Li K, Hu JK, Zhang B, Chen ZX, Chen JP, Zhou ZG. Docetaxel, cisplatin and fluorouracil (DCF) regimen compared with non-taxane-containing palliative chemotherapy for gastric carcinoma: a systematic review and meta-analysis. PLoS One 2013; 8:e60320. [PMID: 23593191 PMCID: PMC3617226 DOI: 10.1371/journal.pone.0060320] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Accepted: 02/25/2013] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric carcinoma (GC) is one of the highest cancer-mortality diseases with a high incidence rate in Asia. For surgically unfit but medically fit patients, palliative chemotherapy is the main treatment. The chemotherapy regimen of docetaxel, cisplatin and 5-fluorouracil (DCF) has been used to treat the advanced stage or metastatic GC. It is necessary to compare effectiveness and toxicities of DCF regimen with non-taxane-containing palliative chemotherapy for GC. METHODS PubMed, EmBase, Cochrane Central Register of Controlled Trials and China National Knowledge Infrastructure databases were searched to select relative randomized controlled trials (RCTs) comparing DCF to non-taxane-containing chemotherapy for patients with palliatively resected, unresectable, recurrent or metastatic GC. Primary outcome measures were 1-year and 2-year overall survival (OS) rates. Secondary outcome measures were median survival time (MST), median time to progression (TTP), response rate and toxicities. RESULTS Twelve RCTs were eligible and 1089 patients were analyzed totally (549 in DCF and 540 in control). DCF regimen increased partial response rate (38.8% vs 27.9%, p = 0.0003) and reduced progressive disease rate (18.9% vs 33.3%, p = 0.0005) compared to control regimen. Significant improvement of 2-year OS rate was found in DCF regimen (RR = 2.03, p = 0.006), but not of 1-year OS rate (RR = 1.22, p = 0.08). MST was significantly prolonged by DCF regimen (p = 0.039), but not median TTP (p = 0.054). Both 1-year OS rate and median TTP had a trend of prolongation by DCF regimen. Chemotherapy-related mortality was comparable (RR = 1.23, p = 0.49) in both regimens. In grade I-IV toxicities, DCF regimen showed a major raise of febrile neutropenia (RR = 2.33, p<0.0001) and minor raises of leucopenia (RR = 1.25, p<0.00001), neutropenia (RR = 1.19, p<0.00001), and diarrhea (RR = 1.59, p<0.00001), while in other toxicities there were no significant differences. CONCLUSION DCF regimen has better response than non-taxane containing regimen and could potentially improve the survival outcomes. The chemotherapy-related toxicity of DCF regimen is acceptable to some extent.
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Affiliation(s)
- Xiao-Long Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Faculty of Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Xin-Zu Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chen Yang
- Faculty of Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Yan-Biao Liao
- Faculty of Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - He Li
- Faculty of Medicine, West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Li Wang
- Chinese Cochrane Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Kun Yang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ka Li
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jian-Kun Hu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zhi-Xin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jia-Ping Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Zong-Guang Zhou
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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A phase II study of neoadjuvant combination chemotherapy with docetaxel, cisplatin, and S-1 for locally advanced resectable gastric cancer: nucleotide excision repair (NER) as potential chemoresistance marker. Cancer Chemother Pharmacol 2013; 71:789-97. [PMID: 23338051 DOI: 10.1007/s00280-013-2073-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Accepted: 12/31/2012] [Indexed: 01/27/2023]
Abstract
PURPOSE The combination of docetaxel, cisplatin, and S-1 (DCS) chemotherapy is expected to be a promising regimen for advanced gastric cancer. This study was performed to evaluate the efficacy and safety of neoadjuvant DCS chemotherapy for locally advanced resectable gastric cancer. METHODS Patients with locally advanced gastric cancer received 2 courses of preoperative chemotherapy with S-1 (40 mg/m(2) b.i.d.) on days 1-14 and docetaxel (60 mg/m(2)) plus cisplatin (60 mg/m(2)) on day 8 every 3 weeks, followed by standard curative surgery within 4-8 weeks. The primary endpoint was R0 resectability. Expression of damage DNA binding protein complex subunit 2 (DDB2)/excision repair cross-complementing 1 (ERCC1) in the pretreated tumor tissues was examined by immunohistochemistry. RESULTS A total of 43 patients received neoadjuvant chemotherapy. The response rate was 74.4%, and disease control ratio was 100%. Grade 4 neutropenia developed in 53.5% of patients and febrile neutropenia in 16.3%. Non-hematological grade 3/4 adverse events were anorexia (23.3%), nausea (14.0%), and diarrhea (23.3%), but these were generally transient and manageable. The proportion of R0 resections in the 43 eligible patients was 90.7%, and a pathological response was found in 65.9% of patients. There were no treatment-related deaths and no major surgical complications. The accuracy of the combination of DDB2 and ERCC1 expression for predicting chemoresistance was 82.5%. CONCLUSIONS Preoperative treatment with DCS combination for locally advanced gastric cancer demonstrated a sufficient R0 resection rate and a good pathological response with manageable toxicities. The DDB2/ERCC1-high phenotype, as determined by immunohistochemistry, may be useful predictor of resistance to DCS chemotherapy.
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Kimura Y, Yano H, Imamura H, Fujitani K, Imano M, Tokunaga Y, Matsuoka M, Kurokawa Y, Shimokawa T, Takiuchi H, Tsujinaka T, Furukawa H. A phase I study of triplet combination chemotherapy of paclitaxel, cisplatin and S-1 in patients with advanced gastric cancer. Jpn J Clin Oncol 2012; 43:125-31. [PMID: 23225911 DOI: 10.1093/jjco/hys204] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVE S-1 and cisplatin combination therapy is a standard regimen for patients with advanced gastric cancer in Japan. The primary objective of this study was to determine the maximum tolerated dose and dose-limiting toxicities of a triplet regimen adding paclitaxel to S-1 and cisplatin combination therapy. METHODS Patients with previously untreated metastatic or recurrent gastric cancer were enrolled. Patients received S-1 (40 mg/m(2) p.o., twice daily, on days 1-21 every 35 days), cisplatin (30 mg/m(2) divided, on days 1 and 15) and paclitaxel (divided on days 1 and 15). The starting dose of paclitaxel was 50 mg/m(2) (level 1); the dose was escalated to 60 (level 2), 70 (level 3) and 80 mg/m(2) (level 4) in a stepwise fashion. Dose-limiting toxicity was determined during the first treatment cycle. RESULTS Eighteen patients enrolled. During the first cycle, no dose-limiting toxicity was observed at dose levels 1 and 2. At dose level 3, one of the six patients had dose-limiting toxicity (one patient had grade 4 neutropenia) and at dose level 4, one of the six patients had dose-limiting toxicity (one patient had febrile neutropenia, hypoalbuminemia and fatigue of grade 3). The maximum tolerated dose was not reached at level 4; however, grade 3 hyponatremia and hypokalemia in two of the six patients occurred during the second treatment course at level 4. From the point of view of safety in the outpatient setting, the recommended dose of paclitaxel was determined at 70 mg/m(2). The overall response rate was 50%. CONCLUSIONS The recommended dose of paclitaxel added to S-1 (80 mg/m(2) days 1-21) plus cisplatin (30 mg/m(2) days 1 and 15) was 70 mg/m(2) on days 1 and 15 of a 5-week cycle.
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Affiliation(s)
- Yutaka Kimura
- Department of Surgery, NTT West Osaka Hospital, 2-6-40 Karasugatsuji, Tennojiku, Osaka 543-8922, Japan.
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Tada Y, Maruya SI, Saotome T, Miura K, Masubuchi T, Fushimi C, Okamoto I, Takeishi E, Yamada S, Asai H, Kamata SE. Phase I/II study of docetaxel, cisplatin and S-1 in locally advanced, recurrent and metastatic head and neck squamous cell carcinoma. Oncol Lett 2012; 4:898-904. [PMID: 23162619 DOI: 10.3892/ol.2012.846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2012] [Accepted: 07/13/2012] [Indexed: 11/06/2022] Open
Abstract
The purpose of this study was to evaluate the maximum tolerated dose, dose-limiting toxicities and preliminary efficacy of chemotherapy with cisplatin, docetaxel and S-1 (TPS) to treat advanced head and neck squamous cell cancer. S-1 was administered orally twice daily on days 1-14 and docetaxel and cisplatin were injected intravenously on day 8, with one course lasting 4 weeks. The recommended dose obtained from a phase I study was set at docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2)/day. The phase II study revealed that the overall response rate was 81%, comprising 95% in untreated patients with localized advanced cancer and no distant metastases, 50% in untreated patients with distant metastases and 33% in previously treated patients with recurrence. The overall survival rate of untreated patients with localized advanced cancer and no distant metastases was 95% at 1 year and 64.33% at 2 years. In terms of grade 3 or higher hematotoxicity, neutropenia occurred in 100%, thrombocytotopenia in 4% and anemia in 4%. Febrile neutropenia occurred in 46%, with the rate rising to 57% in elderly patients ≥66 years. Grade 3 or higher non-hematotoxicity consisted of loss of appetite in 8%, diarrhea in 8%, hyponatremia in 13% and hypokalemia in 13%. This TPS therapy may be recommended for use as induction chemotherapy. For patients ≤65 years, the appropriate dose was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 80 mg/m(2), whereas for those ≥66 years, it was docetaxel 60 mg/m(2), cisplatin 60 mg/m(2) and S-1 60 mg/m(2).
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Affiliation(s)
- Yuichiro Tada
- Department of Head and Neck Oncology and Surgery, International University of Health and Welfare, Mita Hospital, Tokyo 108-8329
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