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Chen W, Shi K, Liu J, Yang P, Han R, Pan M, Yuan L, Fang C, Yu Y, Qian Z. Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer. Bioact Mater 2023; 23:1-15. [PMID: 36406247 PMCID: PMC9650011 DOI: 10.1016/j.bioactmat.2022.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/02/2022] [Accepted: 10/03/2022] [Indexed: 11/09/2022] Open
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.
Intraoperative chemotherapy could reduce the recurrence and metastasis after surgical resection of gastroenteric tumors. 5-FU and DDP co-delivery system based on PLEL was developed for intraoperative combination chemotherapy of gastric cancer. This dual-drug loaded hydrogel helped to improve synergistic anti-tumor effects and reduce adverse side effects in vivo. 5-FU+DDP/PLEL could inhibit recurrence of orthotopic tumors and growth of abdominal metastatic tumors in gastric cancer.
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Choi M, Ishizawa S, Kraemer D, Sasson A, Feinberg E. Perioperative chemotherapy versus adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer: A Markov decision analysis. Eur J Surg Oncol 2021; 48:403-410. [PMID: 34446344 DOI: 10.1016/j.ejso.2021.08.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 07/22/2021] [Accepted: 08/09/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Perioperative chemotherapy has been shown to improve overall survival (OS) for operable gastric and gastroesophageal cancer. However, optimal sequence of surgery and chemotherapy has not been clearly identified. Markov models are useful for analyzing the outcomes of different treatment strategies in the absence of adequately powered randomized clinical trials. In this study, we use Markov decision analysis models to compare median OS (mOS), quality-adjusted mOS, life expectancy (LE), and quality-adjusted life expectancy (QALE) of perioperative chemotherapy with adjuvant chemotherapy strategies in resectable gastric and gastroesophageal cancer patients. METHODS Markov models are constructed to compare two strategies: adjuvant chemotherapy after surgery and preoperative chemotherapy followed by cancer resection and postoperative chemotherapy. LE and QALE are calculated analytically, and mOS are obtained by simulation. Parameters used in the models are computed from prospective clinical trial data published in PUBMED from January 2000 to July 2020. RESULTS Total of 8088 patients from 25 prospective studies were included in this analysis. Regardless of R0 resection ratio, the analyses of the models show a higher mOS for patients in the perioperative therapy arm compared to adjuvant chemotherapy. For R0 resected patients, the perioperative therapy arm provided an additional 11.0 mOS months (61.3 months vs. 50.3 months). For R1 resected patients, the perioperative therapy arm had mOS of 17.0 months vs. 10.7 months in adjuvant therapy. CONCLUSIONS The Markov models indicate that perioperative chemotherapy improves mOS, quality-adjusted mOS, LE, and QALE for resectable gastric and gastroesophageal cancer patients compared to adjuvant chemotherapy strategies.
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Affiliation(s)
- Minsig Choi
- Department of Medicine, Stony Brook University, USA.
| | - Sayaka Ishizawa
- Department of Applied Mathematics and Statistics, Stony Brook University, USA
| | - David Kraemer
- Department of Applied Mathematics and Statistics, Stony Brook University, USA
| | - Aaron Sasson
- Department of Surgery, Stony Brook University, Stony Brook, NY, 11794-3600, USA
| | - Eugene Feinberg
- Department of Applied Mathematics and Statistics, Stony Brook University, USA
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Sugawara K, Kawaguchi Y, Seto Y, Vauthey JN. Multidisciplinary treatment strategy for locally advanced gastric cancer: A systematic review. Surg Oncol 2021; 38:101599. [PMID: 33991939 DOI: 10.1016/j.suronc.2021.101599] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/26/2021] [Indexed: 01/17/2023]
Abstract
BACKGROUND Multidisciplinary management of patients with locally advanced gastric cancer (LAGC) remains unstandardized worldwide. We performed a systemic review to summarize the advancements, regional differences, and current recommended multidisciplinary treatment strategies for LAGC. METHODS Eligible studies were identified through a comprehensive search of PubMed, Web of Science, Cochrane Library databases and Embase. Phase 3 randomized controlled trials which investigated survival of patients with LAGC who underwent gastrectomy with pre-/perioperative, postoperative chemotherapy, or chemoradiotherapy were included. RESULTS In total, we identified 11 studies of pre-/perioperative chemotherapy, 38 of postoperative chemotherapy, and 14 of chemoradiotherapy. In Europe and the USA, the current standard of care is perioperative chemotherapy for patients with LAGC using the regimen of 5-FU, folinic acid, oxaliplatin and docetaxel (FLOT). In Eastern Asia, upfront gastrectomy and postoperative chemotherapy is commonly used. The S-1 monotherapy or a regimen of capecitabine and oxaliplatin (CapOx) are used for patients with stage II disease, and the CapOx regimen or the S-1 plus docetaxel regimen are recommended for those with stage III Gastric cancer (GC). The addition of postoperative radiotherapy to peri- or postoperative chemotherapy is currently not recommended. Additionally, clinical trials testing targeted therapy and immunotherapy are increasingly performed worldwide. CONCLUSIONS Recent clinical trials showed a survival benefit of peri-over postoperative chemotherapy and chemoradiotherapy. As such, this strategy may have a potential as a global standard for patients with LAGC. Outcome of the ongoing clinical trials is expected to establish the global standard of multidisciplinary treatment strategy in patients with LAGC.
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Affiliation(s)
- Kotaro Sugawara
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yoshikuni Kawaguchi
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jean-Nicolas Vauthey
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Ge J, Liu T, Lei T, Li X, Song K, Azizi S, Liu H, Tang M. Retrospective Cohort Study of Intraoperative Administration of Sustained-Release 5-Fluorouracil Implants in Advanced Gastric Cancer Patients. Front Pharmacol 2021; 12:659258. [PMID: 33927633 PMCID: PMC8076801 DOI: 10.3389/fphar.2021.659258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background: 5-fluorouracil (5-FU) is basically used in the field of postoperative chemotherapy of gastric cancer (GC), the goal of this study was to evaluate improvement of long-term survival rate among GC patients after the 5-FU implants treatment. Methods: The study included 145 patients with gastric cancer who received postoperative chemotherapy with 5-FU implants and had complete follow-up information. According to the sex, age and clinical stage of 5-FU implants group, 74 patients were matched as the control group at the same time. In the study, we compared the 5-year overall survival rate with progression-free survival rate in the two groups, and the drug safety for both groups during the treatment was also compared. Results: The median follow-up time was 85 months (range 60–116 months). 31 patients (21.38%) died of tumor recurrence in 5-FU implants group and 21 (28.38%) in control group. In the control group, metastatic lesions were found in the small intestine, left adrenal gland and peritoneum in three patients. The 5-year progression-free survival (PFS) rate was 79.71% in 5-FU group and 67.12% in control (p = 0.0045). The 5-year overall survival (OS) rate was 77.68% in 5-FU implants group and 64.87% in control (p = 0.0159). Both the 5-years OS and PFS rates in 5-FU group were better than control group without significant side effect. Conclusions: 5-FU implants may improve 5-years OS and PFS rates after surgery in gastric cancer patients, while good safety profile suggests it could be reliable.
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Affiliation(s)
- Jie Ge
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ting Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xuan Li
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kun Song
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Samim Azizi
- Department of Cardiothoracic and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mimi Tang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
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Peixoto RD, Rocha-Filho DR, Weschenfelder RF, Rego JFM, Riechelmann R, Coutinho AK, Fernandes GS, Jacome AA, Andrade AC, Murad AM, Mello CAL, Miguel DSCG, Gomes DBD, Racy DJ, Moraes ED, Akaishi EH, Carvalho ES, Mello ES, Filho FM, Coimbra FJF, Capareli FC, Arruda FF, Vieira FMAC, Takeda FR, Cotti GCC, Pereira GLS, Paulo GA, Ribeiro HSC, Lourenco LG, Crosara M, Toneto MG, Oliveira MB, de Lourdes Oliveira M, Begnami MD, Forones NM, Yagi O, Ashton-Prolla P, Aguillar PB, Amaral PCG, Hoff PM, Araujo RLC, Filho RPDP, Gansl RC, Gil RA, Pfiffer TEF, Souza T, Jr. UR, Jesus VHF, Jr WLC, Prolla G. Brazilian Group of Gastrointestinal Tumours' consensus guidelines for the management of gastric cancer. Ecancermedicalscience 2020; 14:1126. [PMID: 33209117 PMCID: PMC7652540 DOI: 10.3332/ecancer.2020.1126] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2020] [Indexed: 12/23/2022] Open
Abstract
Gastric cancer is among the ten most common types of cancer worldwide. Most cases and deaths related to the disease occur in developing countries. Local socio-economic, epidemiologic and healthcare particularities led us to create a Brazilian guideline for the management of gastric carcinomas. The Brazilian Group of Gastrointestinal Tumors (GTG) invited 50 physicians with different backgrounds, including radiology, pathology, endoscopy, nuclear medicine, genetics, oncological surgery, radiotherapy and clinical oncology, to collaborate. This document was prepared based on an extensive review of topics related to heredity, diagnosis, staging, pathology, endoscopy, surgery, radiation, systemic therapy and follow-up, which was followed by presentation, discussion, and voting by the panel members. It provides updated evidence-based recommendations to guide clinical management of gastric carcinomas in several scenarios and clinical settings.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Diogo B D Gomes
- Hospital Israelita Albert Einstein, São Paulo. Brazil, 05652- 900
| | - Douglas J Racy
- Hospital Beneficência Portuguesa de São Paulo, São Paulo, Brazil, 01323-001
| | | | - Eduardo H Akaishi
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
| | | | - Evandro S Mello
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
| | - Fauze Maluf Filho
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
| | | | | | | | | | - Flavio R Takeda
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
| | | | | | - Gustavo A Paulo
- Universidade Federal de São Paulo, São Paulo, Brazil, 04040-003
| | | | | | | | | | - Marcos B Oliveira
- Faculdade de Ciências Médicas da Santa Casa de São Paulo, Sâo Paulo, Brazil, 01238-010
| | | | | | - Nora M Forones
- Universidade Federal de São Paulo, São Paulo, Brazil, 04040-003
| | - Osmar Yagi
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
| | | | | | | | | | | | | | | | | | | | - Tulio Souza
- Hospital Aliança de Salvador, Salvador, Brazil, 41920-900
| | - Ulysses Ribeiro Jr.
- Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil, 01246903
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S1 versus Doublet Regimens as Adjuvant Chemotherapy in Patients with Advanced Gastric Cancer after Radical Surgery with D2 Dissection-A Propensity Score Matching Analysis. Cancers (Basel) 2020; 12:cancers12092384. [PMID: 32842507 PMCID: PMC7565691 DOI: 10.3390/cancers12092384] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Fluoropyrimidine- and platinum-based doublet regimen is the standard treatment of adjuvant chemotherapy (AC) for gastric cancer (GC). Our study aims to compare S1 with doublet regimens as AC in patients with advanced GC after radical surgery with D2 dissection. METHODS Patients who were diagnosed with GC and underwent a curative surgery with D2 dissection followed by AC were enrolled into our study. A propensity score matching analysis was performed to reduce the selection bias. Kaplan-Meier curves were estimated for recurrence-free survival (RFS) and overall survival (OS). Cox regression models were conducted for survival. RESULTS After propensity sore matching, 64 patients with S1 and 64 patients with doublet regimens were identified. The median RFS (p = 0.355) and OS (p = 0.309) were both insignificant between S1 and ST. Cox regression analysis demonstrated that pathologic stage and lymph node ratio (LNR) were independently correlated with survival. Patients were then stratified into low risk and high risk groups. The median RFS (p < 0.001) and OS (p < 0.001) had significant differences between low risk and high risk. In the high-risk group, doublet regimens were strongly associated with survival (p = 0.020) as compared with S1. While in the low-risk group, doublet regimen and S1 did not have statistically different survival benefits. CONCLUSIONS Our study demonstrated that doublet regimens are superior to S1 in high-risk groups, and that survival outcomes are similar between doublet regimens and S1 in low-risk groups. Our prognostic model might have clinical implications for AC.
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van den Ende T, Abe Nijenhuis FA, van den Boorn HG, Ter Veer E, Hulshof MCCM, Gisbertz SS, van Oijen MGH, van Laarhoven HWM. COMplot, A Graphical Presentation of Complication Profiles and Adverse Effects for the Curative Treatment of Gastric Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2019; 9:684. [PMID: 31403035 PMCID: PMC6677173 DOI: 10.3389/fonc.2019.00684] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/11/2019] [Indexed: 12/24/2022] Open
Abstract
Background: For the curative treatment of gastric cancer, several neoadjuvant, and adjuvant treatment-regimens are available which have shown to improve overall survival. No overview is available regarding toxicity and surgery related outcomes. Our aim was to construct a novel graphical method concerning adverse events (AEs) associated with multimodality treatment and perform a meta-analysis to compare different clinically relevant cytotoxic regimens with each other. Methods: The PubMed, EMBASE, CENTRAL, and ASCO/ESMO databases were searched up to May 2019 for randomized controlled trials investigating curative treatment regimens for gastric cancer. To construct single and bidirectional bar-charts (COMplots), grade 1–2 and grade 3–5 AEs were extracted per cytotoxic regimen. For surgery-related outcomes a pre-specified set of complications was used. Thereafter, treatment-arms comparing the same regimens were combined in a single-arm random-effects meta-analysis and pooled-proportions were calculated with 95% confidence-intervals. Comparative meta-analyses were performed based on clinical relevance and compound similarity. Results: In total 16 RCTs (n = 4,526 patients) were included investigating pre-operative-therapy and 39 RCTs investigating adjuvant-therapy (n = 13,732 patients). Pre-operative COMplots were created for among others; 5-fluorouracil/leucovorin-oxaliplatin-docetaxel (FLOT), epirubicin-cisplatin-fluoropyrimidine (ECF), cisplatin-fluoropyrimidine (CF), and oxaliplatin-fluoropyrimidine (FOx). Pre-operative FLOT showed a minor increase in grade 1–2 and grade 3–4 AEs compared to pre-operative ECF, CF, and FOx. A pooled analysis of patients who had received pre-operative therapy compared to patients who underwent direct surgery did not reveal any significant difference in surgery related morbidity/mortality. When we compared three commonly used adjuvant regimens; S-1 had the lowest amount of grade 3–4 AEs compared to capecitabine with oxaliplatin (CAPOX) and 5-FU with radiotherapy (5-FU+RT). Conclusion: COMplot provides a novel tool to visualize and compare treatment related AEs for gastric cancer. Based on our comparisons, pre-operative FLOT had a manageable toxicity profile compared to other pre-operative doublet or triplet regimens. We found no evidence indicating surgical outcomes might be hampered by pre-operative therapy. Adjuvant S-1 had a more favorable toxicity profile compared to CAPOX and 5-FU+RT.
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Affiliation(s)
- Tom van den Ende
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Frank A Abe Nijenhuis
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Héctor G van den Boorn
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Emil Ter Veer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Maarten C C M Hulshof
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Suzanne S Gisbertz
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), University of Amsterdam, Amsterdam, Netherlands
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van den Ende T, Ter Veer E, Mali RMA, van Berge Henegouwen MI, Hulshof MCCM, van Oijen MGH, van Laarhoven HWM. Prognostic and Predictive Factors for the Curative Treatment of Esophageal and Gastric Cancer in Randomized Controlled Trials: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:E530. [PMID: 31013858 PMCID: PMC6521055 DOI: 10.3390/cancers11040530] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND An overview of promising prognostic variables and predictive subgroups concerning the curative treatment of esophageal and gastric cancer from randomized controlled trials (RCTs) is lacking. Therefore, we conducted a systematic review and meta-analysis. METHODS PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to March 2019 for RCTs on the curative treatment of esophageal or gastric cancer with data on prognostic and/or predictive factors for overall survival. Prognostic factors were deemed potentially clinically relevant according to the following criteria; (1) statistically significant (p < 0.05) in a multivariate analysis, (2) reported in at least 250 patients, and (3) p < 0.05, in ≥ 33% of the total number of patients in RCTs reporting this factor. Predictive factors were potentially clinically-relevant if (1) the p-value for interaction between subgroups was <0.20 and (2) the hazard ratio in one of the subgroups was significant (p < 0.05). RESULTS For gastric cancer, 39 RCTs were identified (n = 13,530 patients) and, for esophageal cancer, 33 RCTs were identified (n = 8618 patients). In total, we identified 23 potentially clinically relevant prognostic factors for gastric cancer and 16 for esophageal cancer. There were 15 potentially clinically relevant predictive factors for gastric cancer and 10 for esophageal cancer. CONCLUSION The identified prognostic and predictive factors can be included and analyzed in future RCTs and be of guidance for nomograms. Further validation should be performed in large patient cohorts.
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Affiliation(s)
- Tom van den Ende
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Emil Ter Veer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Rosa M A Mali
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Mark I van Berge Henegouwen
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Maarten C C M Hulshof
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC), location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, (UMC) location AMC, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
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Arai H, Sunakawa Y, Nakajima TE. Co-operative groups in the development of chemotherapy for gastric cancer. Jpn J Clin Oncol 2019; 49:210-227. [PMID: 30508188 DOI: 10.1093/jjco/hyy176] [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: 05/29/2018] [Revised: 09/14/2018] [Accepted: 11/01/2018] [Indexed: 01/05/2023] Open
Abstract
In the multimodality treatment strategy for gastric cancer, chemotherapy has an important role in conferring survival benefit. For the last three decades, great progress has been achieved in adjuvant and palliative chemotherapy. Powerful combination regimens using doublet or triplet cytotoxic agents have been developed and new molecular targeted drugs, including trastuzumab and ramucirumab, have been introduced in clinical practice. These advances have resulted from the accumulation of many clinical trials. A well-designed phase III trial can change standard treatment; however, such a trial is hard to complete due to its huge cost and need to recruit many patients. Some co-operative groups have actively made efforts at fundraising and patient recruitment, which can make implementation of high-quality and large-scale phase III trials possible. This review summarizes the development of chemotherapy for gastric cancer with focus on co-operative groups around the world, considering effective treatment developments in gastric cancer. We studied 11 active co-operative groups, including six in Europe, two in the United States, and three in Japan, that have completed one or more phase III trials cited in the major guidelines. Each co-operative group had its own characteristics and contributed to the establishment of standard treatment in each region. International collaboration in the development of gastric cancer treatment may be difficult due to regional differences in standards of care, particularly for resectable gastric cancer. Whereas, intergroup collaboration within each region is a reasonable method to effectively develop treatments for resectable and advanced gastric cancer.
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Affiliation(s)
- Hiroyuki Arai
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan
| | - Takako Eguchi Nakajima
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki-shi, Kanagawa, Japan
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van den Ende T, Ter Veer E, Machiels M, Mali RMA, Abe Nijenhuis FA, de Waal L, Laarman M, Gisbertz SS, Hulshof MCCM, van Oijen MGH, van Laarhoven HWM. The Efficacy and Safety of (Neo)Adjuvant Therapy for Gastric Cancer: A Network Meta-analysis. Cancers (Basel) 2019; 11:E80. [PMID: 30641964 PMCID: PMC6356558 DOI: 10.3390/cancers11010080] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 01/05/2019] [Accepted: 01/05/2019] [Indexed: 12/21/2022] Open
Abstract
Background: Alternatives in treatment-strategies exist for resectable gastric cancer. Our aims were: (1) to assess the benefit of perioperative, neoadjuvant and adjuvant treatment-strategies and (2) to determine the optimal adjuvant regimen for gastric cancer treated with curative intent. Methods: PubMed, EMBASE, CENTRAL, and ASCO/ESMO conferences were searched up to August 2017 for randomized-controlled-trials on the curative treatment of resectable gastric cancer. We performed two network-meta-analyses (NMA). NMA-1 compared perioperative, neoadjuvant and adjuvant strategies only if there was a direct comparison. NMA-2 compared different adjuvant chemo(radio)therapy regimens, after curative resection. Overall-survival (OS) and disease-free-survival (DFS) were analyzed using random-effects NMA on the hazard ratio (HR)-scale and calculated as combined HRs and 95% credible intervals (95% CrIs). Results: NMA-1 consisted of 9 direct comparisons between strategies for OS (14 studies, n = 4187 patients). NMA-2 consisted of 16 direct comparisons between adjuvant chemotherapy/chemoradiotherapy regimens for OS (37 studies, n = 10,761) and 14 for DFS (30 studies, n = 9714 patients). Compared to taxane-based-perioperative-chemotherapy, surgery-alone (HR = 0.58, 95% CrI = 0.38⁻0.91) and perioperative-chemotherapy regimens without a taxane (HR = 0.79, 95% CrI = 0.58⁻1.15) were inferior in OS. After curative-resection, the doublet oxaliplatin-fluoropyrimidine (for one-year) was the most efficacious adjuvant regimen in OS (HR = 0.47, 95% CrI = 0.28⁻0.80). Conclusions: For resectable gastric cancer, (1) taxane-based perioperative-chemotherapy was the most promising treatment strategy; and (2) adjuvant oxaliplatin-fluoropyrimidine was the most promising regimen after curative resection. More research is warranted to confirm or reproach these findings.
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Affiliation(s)
- Tom van den Ende
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Emil Ter Veer
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Mélanie Machiels
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Rosa M A Mali
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Frank A Abe Nijenhuis
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Laura de Waal
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Marety Laarman
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Suzanne S Gisbertz
- Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Maarten C C M Hulshof
- Department of Radiotherapy, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers (UMC) location AMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
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11
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Slagter AE, Jansen EPM, van Laarhoven HWM, van Sandick JW, van Grieken NCT, Sikorska K, Cats A, Muller-Timmermans P, Hulshof MCCM, Boot H, Los M, Beerepoot LV, Peters FPJ, Hospers GAP, van Etten B, Hartgrink HH, van Berge Henegouwen MI, Nieuwenhuijzen GAP, van Hillegersberg R, van der Peet DL, Grabsch HI, Verheij M. CRITICS-II: a multicentre randomised phase II trial of neo-adjuvant chemotherapy followed by surgery versus neo-adjuvant chemotherapy and subsequent chemoradiotherapy followed by surgery versus neo-adjuvant chemoradiotherapy followed by surgery in resectable gastric cancer. BMC Cancer 2018; 18:877. [PMID: 30200910 PMCID: PMC6131797 DOI: 10.1186/s12885-018-4770-2] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 08/22/2018] [Indexed: 12/21/2022] Open
Abstract
Background Although radical surgery remains the cornerstone of cure in resectable gastric cancer, survival remains poor. Current evidence-based (neo)adjuvant strategies have shown to improve outcome, including perioperative chemotherapy, postoperative chemoradiotherapy and postoperative chemotherapy. However, these regimens suffer from poor patient compliance, particularly in the postoperative phase of treatment. The CRITICS-II trial aims to optimize preoperative treatment by comparing three treatment regimens: (1) chemotherapy, (2) chemotherapy followed by chemoradiotherapy and (3) chemoradiotherapy. Methods In this multicentre phase II non-comparative study, patients with clinical stage IB-IIIC (TNM 8th edition) resectable gastric adenocarcinoma are randomised between: (1) 4 cycles of docetaxel+oxaliplatin+capecitabine (DOC), (2) 2 cycles of DOC followed by chemoradiotherapy (45Gy in combination with weekly paclitaxel and carboplatin) or (3) chemoradiotherapy. Primary endpoint is event-free survival, 1 year after randomisation (events are local and/or regional recurrence or progression, distant recurrence, or death from any cause). Secondary endpoints include: toxicity, surgical outcomes, percentage radical (R0) resections, pathological tumour response, disease recurrence, overall survival, and health related quality of life. Exploratory endpoints include translational studies on predictive and prognostic biomarkers. Discussion The aim of this study is to select the most promising among three preoperative treatment arms in patients with resectable gastric adenocarcinoma. This treatment regimen will subsequently be compared with the standard therapy in a phase III trial. Trial registration clinicaltrials.gov NCT02931890; registered 13 October 2016. Date of first enrolment: 21 December 2017.
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Affiliation(s)
- Astrid E Slagter
- Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Edwin P M Jansen
- Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Hanneke W M van Laarhoven
- Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1106 AZ, Amsterdam, The Netherlands
| | - Johanna W van Sandick
- Department of Surgery, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Nicole C T van Grieken
- Department of Pathology, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Karolina Sikorska
- Statistical Department, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Annemieke Cats
- Department of Gastroenterology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Pietje Muller-Timmermans
- Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Maarten C C M Hulshof
- Department of Radiation Oncology, Academic Medical Center Amsterdam, Meibergdreef 9, 1106 AZ, Amsterdam, The Netherlands
| | - Henk Boot
- Department of Gastroenterology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Maartje Los
- Department of Medical Oncology, St. Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, The Netherlands
| | - Laurens V Beerepoot
- Department of Medical Oncology, St. Elisabeth Hospital, Hilvarenbeekse Weg 60, 5022 GC, Tilburg, The Netherlands
| | - Frank P J Peters
- Department of Medical Oncology, Zuyderland Sittard-Geleen, Dr. H. van der Hoffplein 1, 6162 BG, Sittard-Geleen, The Netherlands
| | - Geke A P Hospers
- Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Boudewijn van Etten
- Department of Surgery, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
| | - Henk H Hartgrink
- Department of Surgery, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Mark I van Berge Henegouwen
- Department of Surgery, Academic Medical Center Amsterdam, Meibergdreef 9, 1106 AZ, Amsterdam, The Netherlands
| | - Grard A P Nieuwenhuijzen
- Department of Surgery, Catharina Hospital Eindhoven, Michelangelolaan 2, 5623 EJ, Eindhoven, The Netherlands
| | - Richard van Hillegersberg
- Department of Surgery, University Medical Center Utrecht, Heidelberglaan 100, 3484 CX, Utrecht, The Netherlands
| | - Donald L van der Peet
- Department of Surgery, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Heike I Grabsch
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P Debyelaan 25, 6229 HX, Maastricht, The Netherlands.,Department of Pathology & Tumour Biology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Marcel Verheij
- Department of Radiation Oncology, Netherlands Cancer Institute - Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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12
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Cai Z, Yin Y, Shen C, Wang J, Yin X, Chen Z, Zhou Y, Zhang B. Comparative effectiveness of preoperative, postoperative and perioperative treatments for resectable gastric cancer: A network meta-analysis of the literature from the past 20 years. Surg Oncol 2018; 27:563-574. [PMID: 30217320 DOI: 10.1016/j.suronc.2018.07.011] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/14/2018] [Accepted: 07/15/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND Different preoperative, postoperative or perioperative treatment strategies, including chemotherapy or chemoradiotherapy, are available for patients with gastric cancer, but conventional meta-analyses that assess two alternative treatments are unable to compare differences in overall survival. Thus, we performed a network meta-analysis to identify the best treatment strategy. METHODS We systematically searched and assessed studies for eligibility and extracted data. We then pooled the data and conducted a Bayesian network meta-analysis to combine direct comparisons with indirect evidence. The node-splitting method was used to assess the inconsistency. Rank probabilities were assessed by the probability of treatment rankings. RESULTS Thirty-three eligible randomized controlled trials were included in the network meta-analysis. Four treatments that had significantly improved prognoses when compared with surgery only were postoperative chemotherapy [HR = 0.80 with 95% CrI: (0.73, 0.88)], postoperative chemoradiotherapy [HR = 0.73 with 95% CrI: (0.61, 0.87)], preoperative chemoradiotherapy [HR = 0.77 with 95% CrI: (0.62, 0.98)] and perioperative chemotherapy [HR = 0.69 with 95% CrI: (0.55, 0.84)]. Preoperative chemotherapy, however, did not significantly improve survival when compared with surgery alone [HR = 0.94 with 95% CrI: (0.71, 1.2)]. There was no statistically significant difference between postoperative chemotherapy, postoperative chemoradiotherapy, preoperative chemoradiotherapy and perioperative chemotherapy in terms of overall survival. Chemoradiotherapy after D2 lymphadenectomy did not significantly improve OS when compared with postoperative chemotherapy [HR = 0.95 with 95% CrI: (0.73, 1.3)]. CONCLUSION Among patients with operable gastric cancer, perioperative chemotherapy had the highest probability of being the best treatment. Further clinical resources may be required to assess the efficacy and safety of perioperative chemotherapy for patients with gastric cancer.
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Affiliation(s)
- Zhaolun Cai
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Yuan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Chaoyong Shen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Jian Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Xiaonan Yin
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Zhixin Chen
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Ye Zhou
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
| | - Bo Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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13
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Wu DM, Wang S, Wen X, Han XR, Wang YJ, Shen M, Fan SH, Zhang ZF, Zhuang J, Shan Q, Li MQ, Hu B, Sun CH, Lu J, Zheng YL. Survival Benefit of Three Different Therapies in Postoperative Patients With Advanced Gastric Cancer: A Network Meta-Analysis. Front Pharmacol 2018; 9:929. [PMID: 30210338 PMCID: PMC6119769 DOI: 10.3389/fphar.2018.00929] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023] Open
Abstract
Purpose: Gastric cancer is mainly treated by gastrectomy, the results of which were unsatisfactory without any adjuvant treatments. This study aimed to examine the performance of radiotherapy, chemotherapy, and chemoradiotherapy after surgery in order to acquire the optimal adjuvant treatment. Method: Embase and PubMed were retrieved to conduct a systematic research. Hazard ratios (HR) of overall survival (OS) and progression-free survival (PFS) as outcomes were calculated by synthesizing direct and indirect evidence to evaluate the efficacy of three treatments against surgery alone. The P-score ranking was utilized to rank the therapies. Consistency was assessed by heat plot. Begg's test was performed to evaluate publication bias. Results: A total of 35 randomized controlled studies (RCTs) with 8973 patients were included in our network meta-analysis (NMA). As for efficacy outcomes, OS and PFS of 1, 2, 3, and 5 years, all revealed chemoradiotherapy (CRT) as the best of three adjuvant therapies. Meanwhile, P-score ranking results also displayed that CRT was the optimal regimen. Additionally, radiotherapy (RT) and chemotherapy (CT) were two alternative options following CRT since RT performed well in short-term survival while CT could improve the long-term survival. Conclusion: CRT was the most recommended therapy to accompany surgery according to our results. However, no analysis about the safety of these three treatments was mentioned in our study. Further studies including safety outcomes were required to draw a more comprehensive conclusion.
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Affiliation(s)
- Dong-Mei Wu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Shan Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Xin Wen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Xin-Rui Han
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Yong-Jian Wang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Min Shen
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Shao-Hua Fan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Zi-Feng Zhang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Juan Zhuang
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Qun Shan
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Meng-Qiu Li
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Bin Hu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Chun-Hui Sun
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Jun Lu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
| | - Yuan-Lin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, China.,College of Health Sciences, Jiangsu Normal University, Xuzhou, China
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14
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Mizrak Kaya D, Harada K, Amlashi FG, Vasilakopoulou M, Ajani JA. Customization of therapy for gastroesophageal adenocarcinoma patients. Chronic Dis Transl Med 2018; 4:8-17. [PMID: 29756119 PMCID: PMC5938285 DOI: 10.1016/j.cdtm.2018.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Indexed: 12/18/2022] Open
Abstract
Gastroesophageal adenocarcinomas (GEACs) remain a global health problem. These are most often diagnosed at advanced stage and the estimated 5-year relative survival rate is about 5%. Although cure is not possible for patients with advanced GEAC, systemic therapy (chemotherapy or biochemotherapy) can palliate symptoms, improve survival and provide a better quality of life. One of the most promising options for some patients with advanced stage GEAC is immunotherapy, which can result in durable responses. Numerous phase III trials evaluating targeted therapies in different lines are ongoing and it is hoped that better biomarkers will emerge to identify patients who can benefit from targeted agents and immunotherapy in the future. Surgery remains as the corner stone for localized GEAC and adjunctive therapies can increase the survival rates by about 10%. The high toxicity and low completion rates of adjuvant therapy led to the strategies of preoperative treatment. With the results of ongoing pre-operative therapy trials we will be able to determine the optimal adjunctive approach for resectable GEAC.
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Affiliation(s)
| | | | | | | | - Jaffer A. Ajani
- Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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15
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Cordero-García E, Ramos-Esquivel A, Alpízar-Alpízar W. Predictors of overall survival after surgery in gastric cancer patients from a Latin-American country. J Gastrointest Oncol 2018; 9:64-72. [PMID: 29564172 DOI: 10.21037/jgo.2017.10.07] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background Gastric cancer is one of the major causes of cancer-related deaths in several Latin-American countries, including Costa Rica. However, determinants of poor outcomes are fairly unknown for patients from this region. The aim of this study was to determine prognostic variables of overall survival (OS) in a cohort of Hispanic patients after curative-intent surgery for gastric cancer. Methods We retrospectively evaluated the clinical records of 236 consecutive patients who underwent surgery for advanced gastric cancer at four major hospitals in Costa Rica. Univariate and multivariate Cox proportional models were used to assess the influence of age, sex, clinical stage, adjuvant therapy, type of dissection (D1 vs. D2), extent of gastrectomy (partial vs. total), margin status (R0 vs. R1/2), tumour differentiation, and tumour location on OS. Results After a median follow-up of 46.5 months, median OS was 47.6 months [95% confidence interval (CI): 34.7-60.4]. There was no survival benefit of adjuvant chemotherapy [hazard ratio (HR): 1.18; 95% CI: 0.70-2.00; P=0.53] or postoperative chemoradiotherapy (CRT) (HR: 1.04; 95% CI: 0.71-1.52; P=0.85) compared to surgery alone. After adjustment for potential confounders, the R0 status was associated with better OS (HR: 0.51; 95% CI: 0.28-0.92; P=0.03). Similarly, clinical stage (III vs. I) (HR: 2.26; 95% CI: 1.39-4.29; P=0.001), poor differentiated (HR: 1.72; 95% CI: 1.22-2.76; P=0.03) and undifferentiated tumours (HR: 2.37; 95% CI: 1.39-4.23; P=0.001) were associated with worse outcomes. Conclusions The surgical margin status, clinical stage, and tumour differentiation were predictor variables for OS in this cohort of gastric cancer patients.
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Affiliation(s)
- Eugenia Cordero-García
- Department of Pharmacology, Toxicology and Drug Dependence, Faculty of Pharmacy, University of Costa Rica, San José, Costa Rica.,Institute of Pharmaceutical Research, University of Costa Rica, San José, Costa Rica
| | - Allan Ramos-Esquivel
- Department of Medical Oncology, Hospital San Juan de Dios, Caja Costarricense de Seguro Social, San José, Costa Rica.,Department of Pharmacology, School of Medicine, University of Costa Rica, San José, Costa Rica
| | - Warner Alpízar-Alpízar
- Center for Research in Microscopic Structures (CIEMIC for its acronym in Spanish), University of Costa Rica, San José, Costa Rica.,Department of Biochemistry, School of Medicine, University of Costa Rica, San José, Costa Rica
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16
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Predictors and Prognostic Implications of Perioperative Chemotherapy Completion in Gastric Cancer. J Gastrointest Surg 2017; 21:1984-1992. [PMID: 28963709 DOI: 10.1007/s11605-017-3594-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Accepted: 09/18/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND Perioperative chemotherapy in gastric cancer is increasingly used since the "MAGIC" trial, while clinical practice data outside of trials remain limited. We sought to evaluate the predictors and prognostic implications of perioperative chemotherapy completion in patients undergoing curative-intent gastrectomy across multiple US institutions. METHODS Patients who underwent curative-intent resection of gastric adenocarcinoma between 2000 and 2012 in eight institutions of the US Gastric Cancer Collaborative were identified. Patients who received preoperative chemotherapy were included, while those who died within 90 days or with unknown adjuvant chemotherapy status were excluded. Predictors of chemotherapy completion and survival were identified using multivariable logistic regression and Cox proportional hazards. RESULTS One hundred sixty three patients were included (median age 63.3, 36.8% female). The postoperative component of perioperative chemotherapy was administered in 112 (68.7%) patients. Factors independently associated with receipt of adjuvant chemotherapy were younger age (odds ratio (OR) 2.73, P = 0.03), T3 tumors (OR 14.3, P = 0.04), lymph node metastasis (OR 5.82, P = 0.03), and D2 lymphadenectomy (OR 4.12, P = 0.007), and, inversely, postoperative complications (OR 0.25, P = 0.008). Median overall survival (OS) was 25.1 months and 5-year OS was 36.5%. Predictors of OS were preexisting cardiac disease (hazard ratio (HR) 2.7, 95% CI 1.13-6.46), concurrent splenectomy (HR 4.11, 95% CI 1.68-10.0), tumor stage (reference stage I; stage II HR 2.62; 95% CI 0.99-6.94; stage III HR 4.86, 95% CI 1.81-13.02), and D2 lymphadenectomy (HR 0.43, 95% CI 0.19-0.95). After accounting for these factors, adjuvant chemotherapy administration was associated with improved OS (HR 0.33, 95% CI 0.14-0.82). CONCLUSION Completion of perioperative chemotherapy was successful in two thirds of patients with gastric cancer and was independently associated with improved survival.
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17
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Petrelli F, Ghidini M, Barni S, Steccanella F, Sgroi G, Passalacqua R, Tomasello G. Prognostic Role of Primary Tumor Location in Non-Metastatic Gastric Cancer: A Systematic Review and Meta-Analysis of 50 Studies. Ann Surg Oncol 2017; 24:2655-2668. [DOI: 10.1245/s10434-017-5832-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
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18
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He B, Wei W, Liu J, Xu Y, Zhao G. Synergistic anticancer effect of curcumin and chemotherapy regimen FP in human gastric cancer MGC-803 cells. Oncol Lett 2017; 14:3387-3394. [PMID: 28927092 PMCID: PMC5587997 DOI: 10.3892/ol.2017.6627] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2015] [Accepted: 03/14/2017] [Indexed: 01/07/2023] Open
Abstract
Curcumin is an anticancer compound that exerts anti-proliferative and apoptotic effects via multiple molecular targets. The purpose of the present study was to investigate the anticancer effects of curcumin in combination with 5-fluorouracil plus cisplatin (FP) on the MGC-803 human gastric cancer cell line. Following treatment with curcumin and/or FP for 24, 48 and 72 h, cell viability, cell cycle progression and the apoptosis rate were evaluated using an MTT assay, flow cytometry and dual acridine orange/ethidium bromide staining, respectively. In addition, colony formation, Transwell migration and caspase-3/caspase-8 activity assays were performed. The expression of the apoptosis regulator B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blotting analysis. Following treatment with curcumin and/or FP, cell viability, colony formation and cell migration were significantly reduced compared with the untreated control group. The rate of apoptosis, caspase-3/caspase-8 activity and the expression of Bax were significantly increased, whereas Bcl-2 expression was significantly reduced following treatment with curcumin and/or FP, compared with the untreated control group. The efficacy of curcumin combined with low-dose FP was significantly increased, compared with that of curcumin combined with high-dose FP (P<0.05). Therefore, curcumin may enhance the anticancer effects of FP chemotherapy in MGC-803 cells through the promotion of apoptosis via the caspase-3/caspase-8, Bcl-2 and Bax signaling pathways. These results suggest that curcumin may serve as a synergistic drug with chemotherapy regimen FP for the treatment of gastric cancer.
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Affiliation(s)
- Bin He
- Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China.,Department of Traditional Chinese Medicine, The Third People's Hospital of Hubei (Zhongshan Hospital of Hubei), Wuhan, Hubei 430033, P.R. China
| | - Wen Wei
- Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Ji Liu
- Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Yundan Xu
- Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
| | - Gang Zhao
- Department of Medical Biology, School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, Hubei 430065, P.R. China
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19
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Chen W, Zou P, Zhao Z, Chen X, Fan X, Vinothkumar R, Cui R, Wu F, Zhang Q, Liang G, Ji J. Synergistic antitumor activity of rapamycin and EF24 via increasing ROS for the treatment of gastric cancer. Redox Biol 2016; 10:78-89. [PMID: 27697670 PMCID: PMC5048112 DOI: 10.1016/j.redox.2016.09.006] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2016] [Revised: 09/10/2016] [Accepted: 09/14/2016] [Indexed: 01/27/2023] Open
Abstract
Mechanistic/mammalian target of rapamycin (mTOR) has emerged as a new potential therapeutic target for gastric cancer. Rapamycin and rapamycin analogs are undergoing clinical trials and have produced clinical responses in a subgroup of cancer patients. However, monotherapy with rapamycin at safe dosage fails to induce cell apoptosis and tumor regression which has hampered its clinical application. This has led to the exploration of more effective combinatorial regimens to enhance the effectiveness of rapamycin. In our present study, we have investigated the combination of rapamycin and a reactive oxygen species (ROS) inducer EF24 in gastric cancer. We show that rapamycin increases intracellular ROS levels and displays selective synergistic antitumor activity with EF24 in gastric cancer cells. This activity was mediated through the activation of c-Jun N terminal kinase and endoplasmic reticulum stress (ER) pathways in cancer cells. We also show that inhibiting ROS accumulation reverses ER stress and prevents apoptosis induced by the combination of rapamycin and EF24. These mechanisms were confirmed using human gastric cancer xenografts in immunodeficient mice. Taken together, our work provides a novel therapeutic strategy for the treatment of gastric cancer. The work reveals that ROS generation could be an important target for the development of new combination therapies for cancer treatment.
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Affiliation(s)
- Weiqian Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
| | - Zhongwei Zhao
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Xi Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaoxi Fan
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Rajamanickam Vinothkumar
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ri Cui
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Fazong Wu
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Qianqian Zhang
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China.
| | - Jiansong Ji
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China.
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Wang D, Li Y, Cui P, Zhao Q, Tan BB, Zhang ZD, Liu Y, Jia N. Zerumbone induces gastric cancer cells apoptosis: Involving cyclophilin A. Biomed Pharmacother 2016; 83:740-745. [PMID: 27479192 DOI: 10.1016/j.biopha.2016.07.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 07/07/2016] [Accepted: 07/18/2016] [Indexed: 11/25/2022] Open
Abstract
Gastric cancer is one of the leading causes for cancer death. There is an urgent need to develop new therapeutic approaches targeting metastatic gastric cancer. It has been reported that zerumbone has the anti-cancer effects in various malignant cells. However, the effect and the mechanism of zerumbone on melanoma cells is still largely unknown. In the study, we determined the actions of zerumbone on the human gastric cancer cell line SGC-7901.We also observed the mechanism by which zerumbone induced gastric cancer cell apoptosis. Our data indicated that zerumbone significantly inhibited the growth of human gastric cancer cells in a dose-dependent manner and apoptosis was the main cause of decreased cell viability in zerumbone -treated cells. The treatment with zerumbone downregulated Cyp A and Bcl-2 levels, upregulated Bax levels, and caused Cytochrome c (Cyt-C) to release, activating Caspase-3. In summary, our study suggests that zerumbone mightinduced human gastric cancer cells apoptosis through down-regulating Cyp A and mitochondria-mediated pathways.
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Affiliation(s)
- Dong Wang
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
| | - Yong Li
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China.
| | - Ping Cui
- Divison of Medical Affairs, Hebei General Hospital, Shijiazhuang 050051, China
| | - Qun Zhao
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
| | - Bi-Bo Tan
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
| | - Zhi-Dong Zhang
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
| | - Yv Liu
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
| | - Nan Jia
- Department of General Surgery, The Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuan 050011, China
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21
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Chang SH, Kim SN, Choi HJ, Park M, Kim RB, Go SI, Lee WS. Adjuvant Chemotherapy for Advanced Gastric Cancer in Elderly and Non-elderly Patients: Meta-Analysis of Randomized Controlled Trials. Cancer Res Treat 2016; 49:263-273. [PMID: 27384158 PMCID: PMC5266393 DOI: 10.4143/crt.2016.054] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Accepted: 05/27/2016] [Indexed: 02/07/2023] Open
Abstract
PURPOSE This study evaluated the benefits of adjuvant chemotherapy on elderly patients with advanced gastric cancer (AGC) using meta-analysis of well-designed randomized controlled clinical studies. MATERIALS AND METHODS PubMed, Embase, and Cochrane were searched to retrieve clinical studies evaluating the benefits of adjuvant chemotherapy in the elderly with AGC. Hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled across studies using a fixed-effects model. RESULTS Two studies were included in this meta-analysis to estimate HR for the overall survival (OS), and relapse-free survival (RFS) between adjuvant chemotherapy and surgery in elderly and non-elderly patients. HR for OS in the elderly and non-elderly was 0.745 (95% CI, 0.552 to 1.006, p=0.055) and 0.636 (95% CI, 0.522 to 0.776; p < 0.001), respectively, which showed no heterogeneity regarding HR between the two groups (pinteraction=0.389). HR for RFS in the elderly and non-elderly was 0.613 (95% CI, 0.466 to 0.806; p < 0.001) and 0.633 (95% CI, 0.533 to 0.753; p < 0.001), respectively (pinteraction=0.846). CONCLUSION Meta-analysis suggests that the benefit of adjuvant chemotherapy to the elderly is not big enough to reach statistical significance while the HR for OS is less than 1 (0.745) and no heterogeneity are observed regarding the HR between the elderly and non-elderly patients.
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Affiliation(s)
- Seong-Hwan Chang
- Department of Surgery, Konkuk University School of Medicine, Seoul, Korea
| | - Soo-Nyung Kim
- Department of Obstetrics and Gynecology, Konkuk University School of Medicine, Seoul, Korea
| | - Hye Jung Choi
- Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Misuk Park
- Medical Library, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Rock Bum Kim
- Department of Preventive Medicine and Environmental Health, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Se-Il Go
- Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
| | - Won Sup Lee
- Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju, Korea
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22
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Samalin E, Ychou M. Neoadjuvant therapy for gastroesophageal adenocarcinoma. World J Clin Oncol 2016; 7:284-292. [PMID: 27298768 PMCID: PMC4896896 DOI: 10.5306/wjco.v7.i3.284] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 04/11/2016] [Indexed: 02/06/2023] Open
Abstract
Gastric and esophageal adenocarcinomas are one of the main causes of cancer-related death worldwide. While the incidence of gastric adenocarcinoma is decreasing, the incidence of gastroesophageal junction adenocarcinoma is rising rapidly in Western countries. Considering that surgical resection is currently the major curative treatment, and that the 5-year survival rate highly depends on the pTNM stage at diagnosis, gastroesophageal adenocarcinoma management is very challenging for oncologists. Several treatment strategies are being evaluated, and among them systemic chemotherapy, to decrease recurrences and improve overall survival. The MAGIC and FNCLCC-FFCD trials showed a survival benefit of perioperative chemotherapy in patients with operable gastric and lower esophageal cancer, and these results had an impact on the European clinical practice. New strategies, including induction chemotherapy followed by preoperative chemoradiotherapy, targeted therapies in combination with perioperative chemotherapy and the new cytotoxic regimens, are currently assessed to improve current standards and help developing patient-tailored therapeutic interventions.
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Kilic L, Ordu C, Yildiz I, Sen F, Keskin S, Ciftci R, Pilanci KN. Current adjuvant treatment modalities for gastric cancer: From history to the future. World J Gastrointest Oncol 2016; 8:439-449. [PMID: 27190583 PMCID: PMC4865711 DOI: 10.4251/wjgo.v8.i5.439] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 01/24/2016] [Accepted: 02/24/2016] [Indexed: 02/05/2023] Open
Abstract
The discrepancy between the surgical technique and the type of adjuvant chemotherapy used in clinical trials and patient outcomes in terms of overall survival rates has led to the generation of different adjuvant treatment protocols in distinct parts of the world. The adjuvant treatment recommendation is generally chemoradiotherapy in the United States, perioperative chemotherapy in the United Kingdom and parts of Europe, and chemotherapy in Asia. These options mainly rely on the United States Intergroup-0116, United Kingdom British Medical Research Council Adjuvant Gastric Infusional Chemotherapy, and the Asian Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer and Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer trials. However, the benefits were evident for only certain patients, which were not very homogeneous regarding the type of surgery, chemotherapy regimens, and stage of disease. Whether the dissimilarities in survival are attributable to surgical technique or intrinsic biological differences is a subject of debate. Regardless of the extent of surgery, multimodal therapy may offer modest survival advantage at least for diseases with lymph node involvement. Moreover, in the era of individualized treatment for most of the other cancer types, identification of special subgroups comprising those who will derive more or no benefit from adjuvant therapy merits further investigation. The aim of this review is to reveal the historical evolution and future reflections of adjuvant treatment modalities for resected gastric cancer patients.
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24
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Wang X, Guo Q, Tao L, Zhao L, Chen Y, An T, Chen Z, Fu R. E platinum, a newly synthesized platinum compound, induces apoptosis through ROS-triggered ER stress in gastric carcinoma cells. Mol Carcinog 2016; 56:218-231. [DOI: 10.1002/mc.22486] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2015] [Revised: 03/09/2016] [Accepted: 03/20/2016] [Indexed: 12/17/2022]
Affiliation(s)
- Xiaoping Wang
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
| | - Qinglong Guo
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
| | - Lei Tao
- State Key Laboratory of Natural Medicines; Department of Physiology; China Pharmaceutical University; Nanjing People's Republic of China
| | - Li Zhao
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
| | - Yan Chen
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
| | - Teng An
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
| | - Zhen Chen
- Experimental and Teaching Center of Medical Basis for Pharmacy; China Pharmaceutical University; Nanjing People's Republic of China
| | - Rong Fu
- Jiangsu Key Laboratory of Carcinogenesis and Intervention; State Key Laboratory of Natural Medicines; JiangSu Key Laboratory of Drug Design and Optimization; Key Laboratory of Drug Quality Control and Pharmacovigilance; Ministry of Education; China Pharmaceutical University; Nanjing People's Republic of China
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25
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Wang ZX, Yang XL, He MM, Wang F, Zhang DS, Li YH, Zhou ZW, Zhan YQ, Xu RH. The Efficacy of Adjuvant FOLFOX6 for Patients With Gastric Cancer after D2 Lymphadenectomy: A Propensity Score-matched Analysis. Medicine (Baltimore) 2016; 95:e3214. [PMID: 27100411 PMCID: PMC4845815 DOI: 10.1097/md.0000000000003214] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Adjuvant 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX6) are widely used for treating resected gastric cancer in clinics in China, but only few clinical trials have investigated its efficacy. Using propensity score matching, we evaluated the efficacy of adjuvant FOLFOX6 following D2 lymphadenectomy. Patients who received adjuvant FOLFOX6 following D2 lymphadenectomy (FOLFOX6, n = 113) or D2 lymphadenectomy only (surgery-only, n = 512) between 1998 and 2007 at our center were propensity score-matched; we identified a balanced 1:2 cohort, with 96 patients in the FOLFOX6 group and 192 patients in the surgery-only group. The overall survival (OS) was estimated using the Kaplan-Meier method; factors affecting survival were identified by Cox regression models. A nomogram incorporating independent prognosticators was constructed for predicting the 3-, 5-, and 7-year OS, and bootstrap validation was performed. The median follow-up was 9.3 years, and the 7-year OS was 52.1% in the FOLFOX6 group and 43.8% in the surgery-only group (P = 0.04), with an adjusted hazard ratio of 0.69 (95% confidence interval = 0.49-0.98). A prognostic nomogram was generated with the identified significant prognosticators (adjuvant FOLFOX6, number of total harvested nodes, the interaction effect between these two variables, tumor size, T and N stage). Internal validation of the nomogram revealed good predictive abilities, with a bootstrap-corrected concordance index of 0.70. Adjuvant FOLFOX6 following D2 lymphadenectomy is associated with survival benefit in resected gastric cancer. Receiving adjuvant FOLFOX6 can be developed into a nomogram with other independent prognosticators to refine OS prediction and estimation of benefit from adjuvant FOLFOX6 for resected gastric cancer.
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Affiliation(s)
- Zi-Xian Wang
- From the Department of Medical Oncology (Z-XW, M-MH, FW, D-SZ, Y-HL, R-HX); Faculty of Medical Sciences, (Z-XW, X-LY); and Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (Z-WZ, Y-QZ)
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Fazio N, Biffi R, Maibach R, Hayoz S, Thierstein S, Brauchli P, Bernhard J, Stupp R, Andreoni B, Renne G, Crosta C, Morant R, Chiappa A, Luca F, Zampino M, Huber O, Goldhirsch A, de Braud F, Roth A, Pace U, Cenciarelli S, Pozzi S, Bertani E, Mura S, Lorizzo K, Di Meglio G, Ravizza D, Boselli S, Matter M, Richter M, Monfardini S, Dittrich C, Häfner M, Clemens M. Preoperative versus postoperative docetaxel–cisplatin–fluorouracil (TCF) chemotherapy in locally advanced resectable gastric carcinoma: 10-year follow-up of the SAKK 43/99 phase III trial. Ann Oncol 2016; 27:668-673. [DOI: 10.1093/annonc/mdv620] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
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A retrospective study of paclitaxel combining nedaplatin chemotherapy for esophageal cancer. Anticancer Drugs 2016; 26:101-5. [PMID: 25222530 DOI: 10.1097/cad.0000000000000170] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
The aim of this study was to evaluate the efficacy and tolerability of the combination of paclitaxel and nedaplatin in patients with advanced esophageal cancer. Patients (n = 310) with recurrent or metastatic esophageal squamous cell carcinoma, who had a maximum of one previous chemotherapy regimen, were enrolled in this study. All patients had bidimensionally measurable disease. Patients received 175 mg/m of paclitaxel over a 3 h infusion, followed by nedaplatin 80 mg/m in a 1 h infusion on day 1 every 3 weeks for up to 6 treatment cycles. The overall response rate was 47.7%, with complete and partial response rates of 6.1 and 41.7%, respectively. The median time to progression for all patients was 6.8 months (95% confidence interval, 6.2-7.4 months) and the 3-year disease-free survival probability was 3 (15.8%). The major toxicity observed was cumulative neutropenia, with 29% patients developing grade 4 toxicity. There was no treatment-related death. The most common nonhematologic toxicity encountered with this regimen was pain and cumulative peripheral neuropathy, with 26% patients experiencing grade 2 or 3 toxicity. The combination of paclitaxel and nedaplatin shows significant antitumor activity and a favorable toxicity profile in patients with metastatic carcinoma of esophageal cancer.
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28
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Zou P, Zhang J, Xia Y, Kanchana K, Guo G, Chen W, Huang Y, Wang Z, Yang S, Liang G. ROS generation mediates the anti-cancer effects of WZ35 via activating JNK and ER stress apoptotic pathways in gastric cancer. Oncotarget 2016; 6:5860-76. [PMID: 25714022 PMCID: PMC4467407 DOI: 10.18632/oncotarget.3333] [Citation(s) in RCA: 120] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Accepted: 01/03/2015] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer is one of the leading causes of cancer mortality in the world, and finding novel agents and strategies for the treatment of advanced gastric cancer is of urgent need. Curcumin is a well-known natural product with anti-cancer ability, but is limited by its poor chemical stability. In this study, an analog of curcumin with high chemical stability, WZ35, was designed and evaluated for its anti-cancer effects and underlying mechanisms against human gastric cancer. WZ35 showed much stronger anti-proliferative effects than curcumin, accompanied by dose-dependent induction of cell cycle arrest and apoptosis in gastric cancer cells. Mechanistically, our data showed that WZ35 induced reactive oxygen species (ROS) production, resulting in the activation of both JNK-mitochondrial and ER stress apoptotic pathways and eventually cell apoptosis in SGC-7901 cells. Blockage of ROS production totally reversed WZ35-induced JNK and ER stress activation as well as cancer cell apoptosis. In vivo, WZ35 showed a significant reduction in SGC-7901 xenograft tumor size in a dose-dependent manner. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer, and importantly, reveals that increased ROS generation might be an effective strategy in human gastric cancer treatment.
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Affiliation(s)
- Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China.,School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China
| | - Junru Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
| | - Yiqun Xia
- Department of Digestive Diseases, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Karvannan Kanchana
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
| | - Guilong Guo
- Department of Oncological Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wenbo Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
| | - Yi Huang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
| | - Zhe Wang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
| | - Shulin Yang
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou Zhejiang, China
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29
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Kim HS, Kim JH, Kim JW, Kim BC. Chemotherapy in Elderly Patients with Gastric Cancer. J Cancer 2016; 7:88-94. [PMID: 26722364 PMCID: PMC4679385 DOI: 10.7150/jca.13248] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 11/01/2015] [Indexed: 12/23/2022] Open
Abstract
Gastric cancer (GC) is one of the most frequent malignant diseases in the elderly. Systemic chemotherapy showed an improvement of quality of life and survival benefit compared to supportive care alone in patients with advanced GC. Because comorbidities or age-related changes in pharmacokinetics and pharmacodynamics may lead to higher toxicity, however, many oncologists hesitate to recommend elderly patients to receive chemotherapy. Available data suggest that elderly patients with GC are able to tolerate and benefit from systemic chemotherapy to the same extent as younger patients. The age alone should not be the only criteria to preclude effective chemotherapy. However, proper patient selection is extremely important to deliver effective treatment safely. A comprehensive geriatric assessment (CGA) is a useful method to assess life expectancy and risk of morbidity in older patients and to guide providing optimal treatment. Treatment should be personalized based on the nature of the disease, the life expectancy, the risk of complication, and the patient's preference. Combination chemotherapy can be considered for older patients with metastatic GC who are classified as non-frail patients by CGA. For frail or vulnerable patients, however, monotherapy or only symptomatic treatment may be desirable. Targeted agents seem to be promising treatment options for elderly patients with GC considering their better efficacy and less toxicity.
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Affiliation(s)
- Hyeong Su Kim
- 1. Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, South Korea
| | - Jung Han Kim
- 1. Department of Internal Medicine, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, South Korea
| | - Ji Won Kim
- 2. Department of Surgery, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, South Korea
| | - Byung Chun Kim
- 2. Department of Surgery, Kangnam Sacred-Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Seoul, South Korea
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30
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Pan H, Wang BH, Lv W, Jiang Y, He L. Esculetin induces apoptosis in human gastric cancer cells through a cyclophilin D-mediated mitochondrial permeability transition pore associated with ROS. Chem Biol Interact 2015; 242:51-60. [PMID: 26388407 DOI: 10.1016/j.cbi.2015.09.015] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Revised: 08/20/2015] [Accepted: 09/16/2015] [Indexed: 01/20/2023]
Abstract
Esculetin is a coumarin derivative from natural plants that has been commonly used as a folk medicine and has been reported to have beneficial pharmacological and biochemical activities; however, the mechanism by which esculetin prevents human gastric cancer cell growth is still largely unknown. In this study, we investigated the effect of esculetin on human gastric cancer cells and explored the cell death mechanism. Our data indicated that esculetin inhibited the growth of human gastric cancer cells in a dose- and time-dependent manner and apoptosis was the main cause of decreased cell viability in esculetin-treated cells. Additionally, esculetin treatment increased the activity of caspase-9 and caspase-3, and resulted in the appearance of the PARP cleavage product; and esculetin-induced cell death and apoptosis was decreased by pretreatment with CsA and NAC, but not BA; these results demonstrate that esculetin induced apoptosis via the caspase-dependent mitochondrial pathway in human gastric cancer cells in which cyclophilin D mediated the cytotoxic action by triggering the opening of the mitochondrial permeability transition pore; and the generation of ROS not only was a consequence of mitochondrial dysfunction, but also triggered esculetin-induced apoptosis. These results reveal a novel mechanism of esculetin on gastric cancer cells and suggest that esculetin could be a novel agent in the treatment of gastric cancer.
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Affiliation(s)
- Hui Pan
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, China.
| | - Bao-Hui Wang
- Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Wang Lv
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, China
| | - Yan Jiang
- Zhejiang Hospital of Traditional Chinese Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Lei He
- The First Affiliated Hospital, College of Medicine, Zhejiang University, Qingchun Road 79, Hangzhou, China
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31
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Zou P, Chen M, Ji J, Chen W, Chen X, Ying S, Zhang J, Zhang Z, Liu Z, Yang S, Liang G. Auranofin induces apoptosis by ROS-mediated ER stress and mitochondrial dysfunction and displayed synergistic lethality with piperlongumine in gastric cancer. Oncotarget 2015; 6:36505-21. [PMID: 26431378 PMCID: PMC4742192 DOI: 10.18632/oncotarget.5364] [Citation(s) in RCA: 113] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Accepted: 09/15/2015] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. In addressing the need of treatments for relapsed disease, we report the identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for GC treatment. Auranofin (AF), clinically used to treat rheumatic arthritis, but it exhibited preclinical efficacy in GC cells. By increasing intracellular reactive oxygen species (ROS) levels, AF induces a lethal endoplasmic reticulum stress response and mitochondrial dysfunction in cultured GC cells. Blockage of ROS production reversed AF-induced ER stress and mitochondrial pathways activation as well as apoptosis. In addition, AF displays synergistic lethality with an ROS-generating agent piperlongumine, which is a natural product isolated from the long pepper Piper longum L. Taken together, this work provides a novel anticancer candidate for the treatment of gastric cancer. More importantly, it reveals that increased ROS generation might be an effective strategy in treating human gastric cancer.
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Affiliation(s)
- Peng Zou
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
| | - Minxiao Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Jiansong Ji
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Weiqian Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
- Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, China
| | - Xi Chen
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shilong Ying
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Junru Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Ziheng Zhang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Zhiguo Liu
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Shulin Yang
- School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China
| | - Guang Liang
- Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
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Newton AD, Datta J, Loaiza-Bonilla A, Karakousis GC, Roses RE. Neoadjuvant therapy for gastric cancer: current evidence and future directions. J Gastrointest Oncol 2015; 6:534-43. [PMID: 26487948 DOI: 10.3978/j.issn.2078-6891.2015.047] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.
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Affiliation(s)
- Andrew D Newton
- 1 Department of Surgery, 2 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jashodeep Datta
- 1 Department of Surgery, 2 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Arturo Loaiza-Bonilla
- 1 Department of Surgery, 2 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Giorgos C Karakousis
- 1 Department of Surgery, 2 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Robert E Roses
- 1 Department of Surgery, 2 Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
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Adjuvant Chemoradiation Therapy in Gastric Cancer: Critically Reviewing the Past and Visualizing the Next Step Forward. Gastroenterol Res Pract 2015; 2015:650846. [PMID: 26101524 PMCID: PMC4460248 DOI: 10.1155/2015/650846] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Revised: 05/10/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023] Open
Abstract
Gastric cancer remains one of the most common malignancies worldwide. Despite the significant advances in surgical treatment and multimodality strategies, prognosis has modestly improved over the last two decades. Locoregional relapse remains one of the main issues and the combined chemoradiation treatment seems to be one of the preferred approaches. However, more than ten years after the hallmark INT-0116 trial, minimal progress has been made both in terms of effectiveness and toxicity. Moreover, new regimens added to combined therapy failed to prove favourable results. Herein, we attempt a thorough literature review comparing pros and cons of all relative studies and potential bias, targeting well-designed future approaches.
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He AB, Peng XL, Song J, Zhang JX, Dong WG, Luo RF, Tang Y. Efficacy of S-1 vs capecitabine for the treatment of gastric cancer: A meta-analysis. World J Gastroenterol 2015; 21:4358-4364. [PMID: 25892887 PMCID: PMC4394098 DOI: 10.3748/wjg.v21.i14.4358] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/12/2014] [Accepted: 10/21/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To rationally evaluate the effect of S-1 vs capecitabine for the treatment of gastric cancer.
METHODS: MEDLINE, EMBASE, Cochrane Controlled Trials Register, Google Scholar, and China Journal Full Text Database were accessed to collect clinical randomized controlled trials regarding the effect of S-1 vs capecitabine for the treatment of gastric cancer patients. Statistical analysis was performed by meta-analysis. Four randomized controlled trials met the inclusion criteria.
RESULTS: Compared with capecitabine regimens, the 1-year survival rate in gastric cancer patients was 0.80 (95%CI: 0.52-1.21, P = 0.29). The overall response rate of S-1 vs capecitabine was 0.94 (95%CI: 0.59-1.51, P = 0.93). Compared with capecitabine regimens, the most frequent hematologic toxicities were neutropenia (OR = 0.99, 95%CI: 0.65-1.49, P = 0.94) and thrombocytopenia (OR = 0.72, 95%CI: 0.31-1.67, P = 0.44). The most frequent non-hematologic toxicities included nausea (OR = 0.85, 95%CI: 0.56-1.28, P = 0.43) and hand-foot syndrome (OR = 0.16, 95%CI: 0.10-0.27, P < 0.00001).
CONCLUSION: The existing studies suggest that S-1 is not more effective than capecitabine in the treatment of gastric cancer patients, but does exhibit less toxicity with regard to hand-foot syndrome.
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Kelly KJ, Selby L, Chou JF, Dukleska K, Capanu M, Coit DG, Brennan MF, Strong VE. Laparoscopic Versus Open Gastrectomy for Gastric Adenocarcinoma in the West: A Case-Control Study. Ann Surg Oncol 2015; 22:3590-6. [PMID: 25631063 DOI: 10.1245/s10434-015-4381-y] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Indexed: 01/04/2023]
Abstract
INTRODUCTION Data on laparoscopic gastrectomy in patients with gastric cancer in the Western hemisphere are lacking. This study aimed to compare outcomes following laparoscopic versus open gastrectomy for gastric adenocarcinoma at a Western center. METHODS Eighty-seven consecutive patients who underwent laparoscopic gastrectomy from November 2005 to April 2013 were compared with 87 patients undergoing open resection during the same time period. Patients were matched for age, stage, body mass index, and procedure (distal subtotal vs. total gastrectomy). Endpoints were short- and long-term perioperative outcomes. RESULTS Overall, 65 patients (37 %) had locally advanced disease, and 40 (23 %) had proximal tumors. The laparoscopic approach was associated with longer operative time (median 240 vs.165 min; p < 0.01), less blood loss (100 vs.150 mL; p < 0.01), higher rate of microscopic margin positivity (9 vs.1 %; p = 0.04), decreased duration of narcotic and epidural use (2 vs. 4 days, p = 0.04, and 3 vs. 4 days, p = 0.02, respectively), decreased minor complications in the early (27 vs. 16 %) and late (17 vs. 7 %) postoperative periods (p < 0.01), decreased length of stay (5 vs. 7 days; p = 0.01), and increased likelihood of receiving adjuvant therapy (82 vs. 51 %; p < 0.01). There was no difference in the number of lymph nodes retrieved (median 20 in both groups), major morbidity, or 30-day mortality. CONCLUSIONS Laparoscopic gastrectomy for gastric adenocarcinoma is safe and effective for select patients in the West.
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Affiliation(s)
- Kaitlyn J Kelly
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Luke Selby
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Katerina Dukleska
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Daniel G Coit
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Murray F Brennan
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Vivian E Strong
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
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Markar SR, Wiggins T, Ni M, Steyerberg EW, Van Lanschot JJB, Sasako M, Hanna GB. Assessment of the quality of surgery within randomised controlled trials for the treatment of gastro-oesophageal cancer: a systematic review. Lancet Oncol 2015; 16:e23-31. [DOI: 10.1016/s1470-2045(14)70419-x] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Soon YY, Leong CN, Tey JCS, Tham IWK, Lu JJ. Postoperative chemo-radiotherapy versus chemotherapy for resected gastric cancer: a systematic review and meta-analysis. J Med Imaging Radiat Oncol 2014; 58:483-96. [PMID: 24995607 DOI: 10.1111/1754-9485.12190] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Accepted: 04/17/2014] [Indexed: 12/16/2022]
Abstract
INTRODUCTION This study conducted a systematic review and meta-analysis (direct and indirect) of published randomised controlled trials (RCTs) to compare the effects of postoperative chemo-radiotherapy (ChRT) with chemotherapy (Ch) on overall and disease-free survival (DFS) for patients with resectable gastric cancer. METHODS We searched MEDLINE and CENTRAL from the date of inception and annual meeting proceedings of American Society of Clinical Oncology and American Society for Radiation Oncology from 1999 to November 2012 for RCTs comparing postoperative ChRT with Ch, postoperative ChRT with surgery alone and postoperative Ch with surgery alone. The primary outcome was overall survival (OS); secondary outcomes included DFS and toxicity. Hazard ratios (HRs), confidence intervals (CIs) and P values (P) were estimated with fixed effects models using Revman 5.1. RESULTS We found six trials comparing postoperative ChRT with Ch (n = 1171). Meta-analysis of direct comparison trials showed that postoperative ChRT significantly improved both OS (HR 0.80, 95% CI 0.65-0.98, P = 0.03) and DFS (HR 0.76, 95% CI 0.63-0.91, P = 0.003) when compared with Ch. There were no significant differences in toxicity between the two groups. CONCLUSIONS This study suggests a survival benefit of postoperative ChRT over Ch in patients with resected gastric cancer.
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Affiliation(s)
- Yu Yang Soon
- Department of Radiation Oncology, National University Cancer Institute, Singapore, National University Health System, National University of Singapore, Singapore
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Shi H, Ji M, Wu J, Zhou Q, Li X, Li Z, Zheng X, Xu B, Zhao W, Wu C, Jiang J. Serum B7-H4 expression is a significant prognostic indicator for patients with gastric cancer. World J Surg Oncol 2014; 12:188. [PMID: 24947047 PMCID: PMC4076248 DOI: 10.1186/1477-7819-12-188] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 06/08/2014] [Indexed: 12/24/2022] Open
Abstract
Background B7-H4 is a novel B7 ligand that plays an important role in the T cell-mediated immune response as a negative regulator. Previous studies have suggested the aberrant expression of membrane B7-H4 in tumor cells. The aim of this study is to determine the expression levels of preoperative soluble B7-H4 (sB7-H4) in circulation and to investigate the correlations between sB7-H4 levels and clinicopathological parameters as well as the survival rate of patients with gastric cancer. Methods Blood specimens from 132 patients with gastric cancer and 63 healthy volunteers were analyzed by sandwich enzyme-linked immunosorbent assay. Results Median concentrations of sB7-H4 in patients with gastric cancer were significantly higher than those in healthy volunteers (16.85 versus 10.46 ng/mL; P = 0.008). Median levels of sB7-H4 were significantly correlated with tumor size, lymph node metastasis, the depth of tumor invasion and tumor-node-metastasis classification (P = 0.002, P = 0.001, P = 0.041 and P <0.001, respectively), but not with sex, age, tumor location or histological subtype (all P >0.05). Additionally, the overall survival rate was significantly lower in patients with high sB7-H4 levels when compared with low sB7-H4 levels (50.0% versus 77.3%, χ2 = 10.78, P = 0.001). Moreover, multivariate analysis demonstrated that the risk of death was significantly higher in patients with high sB7-H4 levels than in those with low sB7-H4 levels (P = 0.039). Conclusions sB7-H4 is a valuable blood marker for predicting the progression and prognosis of patients with gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, Jiangsu Province, People's Republic of China.
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Cao J, Qi F, Liu T. Adjuvant chemotherapy after curative resection for gastric cancer: a meta-analysis. Scand J Gastroenterol 2014; 49:690-704. [PMID: 24731211 DOI: 10.3109/00365521.2014.907337] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aim of this article is to review up-to-date clinical data published in the literature in regard to adjuvant chemotherapy in patients with gastric cancer after radical surgical resection. MATERIALS AND METHODS Medline, Embase, PubMed, the Cochrane Library and CBMDisc were searched to identify data published regarding this issue from 1966 to 2013. All the calculations and statistical tests were done using RevMan5.2 software. RESULTS A total of 29 trials with 8580 patients met all inclusion criteria. Among them, 27 studies reported survival rates at the end of follow-ups, 64.2% alive among 3981 patients in the adjuvant chemotherapy arm and 57.3% alive among 4027 patients in the observation arm. Statistical results showed that the observation arm had a shorter disease-free survival (RR: 1.11, 95% CI: 1.07-1.15), and the treatment arm had a lower recurrence rate (RR: 0.79, 95% CI: 0.74-0.84). Leucopenia, anemia, nausea and vomiting, diarrhea, alopecia and infection occurred more frequently in the treatment arm. Adjuvant chemotherapy decreased the occurrence of peritoneum relapse [RR = 0.77, 95% CI (0.66-0.90)], lymphoid nodes relapse [RR = 0.58, 95% CI (0.45-0.75)] and local relapse [RR = 0.57, 95% CI (0.41-0.80)]. CONCLUSIONS Adjuvant chemotherapy can improve the survival rate and disease-free survival rate and reduce the relapse rate after curative resection. Adjuvant chemotherapy cannot induce thrombocytopenia and mucositis or affect liver function. The tumor in situ recurrence and peritoneum, lymph nodes relapse decrease after chemotherapy, and patients benefit from adjuvant chemotherapy regardless of the numbers of positive lymph node, depth of local invasion, Asian or non-Asian, the length of follow-up, and numbers of cycles.
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Affiliation(s)
- Jisen Cao
- Department of General Surgery, Tianjin Medical University General Hospital , Tianjin , China
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Peixoto RD, Cheung WY, Lim HJ. Perioperative chemotherapy for gastroesophageal cancer in British Columbia: a multicentre experience. ACTA ACUST UNITED AC 2014; 21:77-83. [PMID: 24764696 DOI: 10.3747/co.21.1788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND In 2006, perioperative epirubicin, cisplatin, and 5-fluorouracil (ecf), compared with surgery alone, demonstrated a significant survival benefit in resectable gastroesophageal cancers. We report the results of our experience with that protocol. METHODS The BC Cancer Agency (bcca) is a multicentre institution that treats most oncology patients for the province. Characteristics of the 83 bcca patients with localized gastric, gastroesophageal junction, or lower esophageal cancer who initiated perioperative chemotherapy either ecf or epirubicin, cisplatin, and capecitabine (ecx) from 2008 to 2011 were abstracted to an anonymous database and analyzed. RESULTS Of the 83 patients in the cohort [66 men; median age: 62 years (range: 37-79 years)], 87.9% completed 3 cycles of perioperative chemotherapy, and 93.9% (n = 78) underwent an attempt at surgery (2 patients died of chemotherapy toxicities, 1 refused surgery, and 2 developed disease progression before surgery). In 11 of the surgeries (14.1%), tumours could not be resected because of unresectability (n = 1), liver metastasis (n = 1), and peritoneal carcinomatosis (n = 9). One patient died of surgical complications. The 6 patients (7.2%) who achieved a pathologic complete response are all alive and recurrence-free. Of 46 patients (55.4%) who subsequently began postoperative chemotherapy, 44.5% completed 3 cycles. Estimated median survival was 40.3 months. Weight loss was the only significant prognostic factor for worse overall survival. CONCLUSIONS Our multicentre experience confirmed the feasibility of the magic protocol in a real-world scenario and showed that ecx is also an adequate regimen in the perioperative setting. Weight loss was the only significant prognostic factor for worse overall survival. All patients who achieved a pathologic complete response are recurrence-free after a median follow-up of 40.3 months.
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Affiliation(s)
| | | | - H J Lim
- BC Cancer Agency, Vancouver, BC
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Batista TP, Santos CADAL, Almeida GFG. Perioperative chemotherapy in locally advanced gastric cancer. ARQUIVOS DE GASTROENTEROLOGIA 2014; 50:236-42. [PMID: 24322198 DOI: 10.1590/s0004-28032013000200042] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2013] [Accepted: 04/29/2013] [Indexed: 03/03/2023]
Abstract
Gastric cancer is one of the most common cancers and a main cause of cancer-related death worldwide, since the majority of patients suffering of this malignancy are usually faced with a poor prognosis due to diagnosis at later stages. In order to improve treatment outcomes, the association of surgery with chemo and/or radiotherapy (multimodal therapy) has become the standard treatment for locally advanced stages. However, despite several treatment options currently available for management of these tumors, perioperative chemotherapy has been mainly accepted for the comprehensive therapeutic strategy including an appropriated D2-gastrectomy. This manuscript presents a (nonsystematic) critical review about the use of perioperative chemotherapy, with a special focus on the drugs delivery.
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Affiliation(s)
- Thales Paulo Batista
- Instituto de Medicina Integral Professor Fernando Figueira, Faculdade Pernambucana de Saúde
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Papenfuss WA, Kukar M, Oxenberg J, Attwood K, Nurkin S, Malhotra U, Wilkinson NW. Morbidity and mortality associated with gastrectomy for gastric cancer. Ann Surg Oncol 2014; 21:3008-14. [PMID: 24700300 DOI: 10.1245/s10434-014-3664-z] [Citation(s) in RCA: 179] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2013] [Indexed: 01/05/2023]
Abstract
BACKGROUND Surgery alone is often inadequate for advanced-stage gastric cancer. Surgical complications may delay adjuvant therapy. Understanding these complications is needed for multidisciplinary planning. MATERIAL AND METHODS The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried for patients who underwent gastrectomy for malignancy (ICD-9 code 151.x) from 2005 to 2010. Thirty-day mortality and morbidity were evaluated. RESULTS Overall, 2,580 patients underwent gastrectomy for malignancy, divided as total gastrectomy 999 (38.7 %) and partial gastrectomy 1,581 (61.3 %). Overall, serious morbidity occurred in 23.6 %, and the 30-day mortality was 4.1 %. Patients receiving a total gastrectomy were younger and healthier than those receiving a partial gastrectomy for the following measured criteria: age, diabetes, chronic obstructive pulmonary disease and hypertension. Serious morbidity and mortality were significantly higher in the total gastrectomy group than the partial gastrectomy group (29.3 vs. 19.9 %, p < 0.001; and 5.4 vs. 3.4 %, p < 0.015, respectively). The inclusion of additional procedures increased the risk of mortality for the following: splenectomy (odds ratio [OR] 2.8; p < 0.001), pancreatectomy (OR 3.5; p = 0.001), colectomy (OR 3.6; p < 0.001), enterectomy (OR 2.7; p = 0.030), esophagectomy (OR 3.5; p = 0.035). Abdominal lymphadenectomy was not associated with increased morbidity (OR 1.1; p = 0.41); rather, it was associated with decreased mortality (OR 0.468; p = 0.028). CONCLUSIONS Gastrectomy for cancer as currently practiced carries significant morbidity and mortality. Inclusion of additional major procedures increases these risks. The addition of lymphadenectomy was not associated with increased morbidity or mortality. Strategies are needed to optimize surgical outcomes to ensure delivery of multimodality therapy for advanced-stage disease.
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Affiliation(s)
- Wesley A Papenfuss
- Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
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Oba K, Paoletti X, Alberts S, Bang YJ, Benedetti J, Bleiberg H, Catalano P, Lordick F, Michiels S, Morita S, Ohashi Y, Pignon JP, Rougier P, Sasako M, Sakamoto J, Sargent D, Shitara K, Cutsem EV, Buyse M, Burzykowski T. Disease-free survival as a surrogate for overall survival in adjuvant trials of gastric cancer: a meta-analysis. J Natl Cancer Inst 2013; 105:1600-1607. [PMID: 24108812 PMCID: PMC4202244 DOI: 10.1093/jnci/djt270] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Revised: 07/25/2013] [Accepted: 07/25/2013] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND In investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, overall survival (OS) is considered the gold standard endpoint. However, the disadvantage of using OS as the endpoint is that it requires an extended follow-up period. We sought to investigate whether disease-free survival (DFS) is a valid surrogate for OS in trials of adjuvant chemotherapy for gastric cancer. METHODS The GASTRIC group initiated a meta-analysis of individual patient data collected in randomized clinical trials comparing adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer. Surrogacy of DFS was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints. External validation of the prediction based on DFS was also evaluated. RESULTS Individual patient data from 14 randomized clinical trials that included a total of 3288 patients were analyzed. The rank correlation coefficient between DFS and OS was 0.974 (95% confidence interval [CI] = 0.971 to 0.976). The coefficient of determination between the treatment effects on DFS and on OS was as high as 0.964 (95% CI = 0.926 to 1.000), and the surrogate threshold effect based on adjusted regression analysis was 0.92. In external validation, the six hazard ratios for OS predicted according to DFS were in very good agreement with those actually observed for OS. CONCLUSIONS DFS is an acceptable surrogate for OS in trials of cytotoxic agents for gastric cancer in the adjuvant setting.
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Affiliation(s)
- Koji Oba
- Affiliations of authors: Translational Research and Clinical Trial Center, Hokkaido University Hospital, Sapporo, Japan (KO); Biostatistics dpt, INSEM U900, Institut Curie, Paris, France (XP); Mayo Clinic, Rochester, MN (SA, DS); Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea (Y-JB); SWOG Statistical Center, Seattle, WA (JB); Brussels, Belgium (HB); Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Department of Biostatistics, Harvard School of Public Health, Boston, MA (PC); University Clinic Leipzig, University Cancer Center, Leipzig, Germany (FL); Biostatistics and Epidemiology department, Institut Gustave-Roussy, Universite Paris XI, Villejuif, France (SMi, J-PP); Department of Biostatistics, Yokohama City University, Yokohama, Japan (SMo); Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan (YO); Gastro-enterology department, University Hospital Europeen Georges Pompidou, Paris, France (PR); Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan (MS); Tokai Central Hospital, Kakumuhara, Japan (JS); Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan (KS); Digestive Oncology Unit, University Hospital Gasthuisberg, Leuven, Belgium (EVC); International Drug Development Institute, Louvain-la-Neuve, Belgium (MB, TB); I-BioStat, Hasselt University, Diepenbeek, Belgium (MB, TB)
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Paoletti X, Oba K, Bang YJ, Bleiberg H, Boku N, Bouché O, Catalano P, Fuse N, Michiels S, Moehler M, Morita S, Ohashi Y, Ohtsu A, Roth A, Rougier P, Sakamoto J, Sargent D, Sasako M, Shitara K, Thuss-Patience P, Van Cutsem E, Burzykowski T, Buyse M. Progression-free survival as a surrogate for overall survival in advanced/recurrent gastric cancer trials: a meta-analysis. J Natl Cancer Inst 2013; 105:1667-1670. [PMID: 24108811 PMCID: PMC4994928 DOI: 10.1093/jnci/djt269] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Revised: 07/25/2013] [Accepted: 07/25/2013] [Indexed: 12/23/2022] Open
Abstract
The traditional endpoint for assessing efficacy of chemotherapies for advanced/recurrent gastric cancer is overall survival (OS), but OS requires prolonged follow-up. We investigated whether progression-free survival (PFS) is a valid surrogate for OS. Using individual patient data from the GASTRIC meta-analysis, surrogacy of PFS was assessed through the correlation between the endpoints and through the correlation between the treatment effects on the endpoints. External validation of the prediction based on PFS was also evaluated. Individual data from 4069 patients in 20 randomized trials were analyzed. The rank correlation coefficient between PFS and OS was 0.853 (95% confidence interval [CI] = 0.852 to 0.854). The R (2) between treatment effects on PFS and on OS was 0.61 (95% CI = 0.04 to 1.00). Treatment effects on PFS and on OS were only moderately correlated, and we could not confirm the validity of PFS as a surrogate endpoint for OS in advanced/recurrent gastric cancer.
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Affiliation(s)
- Xavier Paoletti
- Affiliations of authors: Biostatistics Department, INSEM U900 Institut Curie, Paris, France (XP); Translational Research and Clinical Trial Center, Hokkaido University Hospital, Hokkaido, Japan (KO); Seoul National University College of Medicine, Oncology Division, Seoul, Korea (Y-JB); Jules Bordet Hospital, Brussels, Belgium (HB); St. Marianna University School of Medicine, Kawasaki, Japan (NB); Hôpital Robert Debré, Reims, Department of Clinical Oncology, France (OB); Dana-Farber Cancer Institute and Harvard School of Public Health, Department of Biostatistics, Boston, MA (PC); National Cancer Center Hospital East, Department of Gastrointestinal Oncology, Kashiwa, Japan (NF, AO); Institut Gustave Roussy, Université Paris XI, Biostatistics and Epidemiology Department, Villejuif, France (SMi); Johannes Gutenberg University, Medical Department, Mainz, Germany (MM); Yokohama City University, Department of Biostatistics and Epidemiology, Kanagawa, Japan (SMo); University of Tokyo, Tokyo, Japan (YO); University Hospital, Department of Surgery, Geneva, Switzerland (AR); University Hospital Europeen Georges Pompidou, Gastro-enterology Department, Paris, France (PR); Tokai Central Hospital, Sohara, Japan (JS); Mayo Clinic, Division of Biomedical Statistics and Informatics, Rochester, MN (DS); National Cancer Center Hospital East, Kashiwa, Japan (MS); Aichi Cancer Center Hospital, Department of Gastrointestinal Oncology, Aichi, Japan (KS); Charité-Universitätsmedizin Berlin, Department of Haematology, Oncology, and Tumorimmunology, Berlin, Germany (PT-P); University Hospital Gasthuisberg, Digestive Oncology Unit, Leuven, Belgium (EVC); Hasselt University, Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Diepenbeek, Belgium (TB, MB); International Drug Development Institute, Louvain-la-Neuve, Belgium (MB)
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Kang YK, Yook JH, Chang HM, Ryu MH, Yoo C, Zang DY, Lee JL, Kim TW, Yang DH, Jang SJ, Park YS, Lee YJ, Jung HY, Kim JH, Kim BS. Enhanced efficacy of postoperative adjuvant chemotherapy in advanced gastric cancer: results from a phase 3 randomized trial (AMC0101). Cancer Chemother Pharmacol 2013; 73:139-49. [PMID: 24162381 DOI: 10.1007/s00280-013-2332-5] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2013] [Accepted: 10/17/2013] [Indexed: 12/21/2022]
Abstract
PURPOSE To improve the efficacy of adjuvant chemotherapy with mitomycin-C and fluoropyrimidine (Mf) in gastric cancer, we designed a new regimen (iceMFP) and investigated in a phase III study. METHODS We randomly assigned 640 patients with resectable and macroscopically recognizable serosa-invading gastric cancer to Mf or iceMFP group during operation. The Mf consisted of intravenous mitomycin-C (20 mg/m(2)) at 3-6 weeks after surgery and oral doxifluridine (460-600 mg/m(2)/day) starting 4 weeks after the administration of mitomycin-C and continuing for 3 months. The iceMFP consisted of intraoperative intraperitoneal cisplatin (100 mg), intravenous mitomycin-C (15 mg/m(2)) on postoperative day 1, followed by oral doxifluridine for 12 months, and six monthly intravenous cisplatin (60 mg/m(2)). The primary endpoint was 3-year recurrence-free survival (RFS). RESULTS A total of 521 patients (258 in Mf, 263 in iceMFP) were eligible for analysis after excluding patients with stage I disease, distant metastasis, or R1 resection. With a median follow-up of 3.5 years, the iceMFP group had a higher RFS (hazard ratio [HR] 0.70; 95 % confidence interval [CI] 0.54-0.90; p = 0.006; 3-year RFS 60 % vs. 50 %) and overall survival (HR 0.71; 95 % CI 0.53-0.95; p = 0.02; 3-year overall survival, 71 vs. 60 %) compared with the Mf group. This was confirmed at extension analysis after a median 6.6 years of follow-up. Both regimens were well tolerated with no differences in surgical complications. CONCLUSION The efficacy of adjuvant Mf was significantly improved by the additional therapeutic strategies of iceMFP. Considering negative results of AMC0201, these suggest that early initiation of chemotherapy and/or intraperitoneal cisplatin played a distinct role in the improved efficacy.
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Affiliation(s)
- Yoon-Koo Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Korea,
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Indirect comparison showed survival benefit from adjuvant chemoradiotherapy in completely resected gastric cancer with d2 lymphadenectomy. Gastroenterol Res Pract 2013; 2013:634929. [PMID: 24194750 PMCID: PMC3806404 DOI: 10.1155/2013/634929] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 08/29/2013] [Indexed: 01/09/2023] Open
Abstract
Background. Little data on directly comparing chemoradiotherapy with observation has yet been published in the setting of adjuvant therapy for resected gastric cancer who underwent D2 lymphadenectomy. The present indirect comparison aims to provide more evidence on comparing the two approaches. Methods. We conducted a systematic review of randomized controlled trials, extracted time-to-event data using Tierney methods (when not reported), and performed indirect comparison to obtain the relative hazards of adjuvant chemoradiotherapy to observation on overall and disease-free survival. Results. seven randomized controlled trials were identified. Three trials compared adjuvant chemoradiotherapy with adjuvant chemotherapy, and 4 trials compared adjuvant chemotherapy with observation. Using indirect comparison, the relative hazards of adjuvant chemoradiotherapy to observation were 0.43 (95% CI: 0.33-0.55) in disease-free survival and 0.52 (95% CI: 0.38-0.71) in overall survival for completely resected gastric cancer with D2 lymphadenectomy. Conclusions. Postoperative chemoradiotherapy can prolong survival and decrease recurrence in patients with resected gastric cancer who underwent D2 gastrectomy. Molecular biomarker might be a promising direction in the prediction of clinical outcome to postoperative chemoradiotherapy, which warranted further study.
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Taketa T, Sudo K, Wadhawa R, Blum MM, Ajani JA. Adjuvant therapy in gastric cancer: what is the optimal approach? Curr Oncol Rep 2013; 15:146-51. [PMID: 23355076 DOI: 10.1007/s11912-013-0298-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Gastric cancer confers a poor prognosis even when diagnosed as localized disease. Multimodality therapy improves the cure rate of patients with localized cancer. However, adjunctive therapeutic approaches differ in different regions of the world. This review focuses on the current standards and unresolved issues based on updated literature on therapy for localized gastric cancer. In the USA, the Intergroup 0116 trial established the use of postoperative chemoradiotherapy as a standard for patients who have surgery first for treatment of gastric cancer. In Europe, the MAGIC trial investigating perioperative chemotherapy demonstrated a survival benefit for gastric cancer patients. Finally, in Asia, the ACTS-GC and CLASSIC trials investigating postoperative chemotherapy established this as the standard of care after primary surgery that included D2 dissection. It is clear, however, that surgery alone is insufficient to achieve the highest possible cure rates.
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Affiliation(s)
- Takashi Taketa
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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Kruse M, Parthan A, Coombs J, Sasane M, Taylor D. Comparison of different adjuvant therapies for 9 resectable cancer types. Postgrad Med 2013; 125:83-91. [PMID: 23816774 DOI: 10.3810/pgm.2013.03.2643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE The objective of this study was to compare the clinical benefit across adjuvant therapies for cancer treatment, including adjuvant imatinib, and to quantify the results using the number-needed-to-treat (NNT) approach. METHOD We reviewed studies meeting the following criteria: 1) US and European randomized clinical trial populations consisting of patients with cancer who underwent surgical resection of the primary tumor and were considered cancer free; 2) comparators were either placebo or no treatment; and 3) recurrence-free survival (RFS) and overall survival (OS) rates were reported and showed benefit with the experimental treatment. The NNT was calculated as the inverse of the difference in event rate between the study groups in each trial. RESULTS We identified 26 adjuvant treatment trials in 9 cancer types. With longer follow-up (3 years vs 1 year), 62.5% of treatments compared with placebo showed a decreased RFS NNT, including imatinib (7 vs 4). The largest relative decrease in RFS NNT over time was 91% (with trastuzumab or cyclophosphamide therapy). Approximately 25% of the treatments resulted in an increase in RFS NNT over time. The RFS NNT for imatinib was lower than that for all other treatments at 3 years of follow-up and lower than that for all but 2 treatments at 1 year. At both year 1 and year 3, the NNT for OS ranged from 6 to 100. Imatinib had an OS NNT of 31 at 3 years. CONCLUSION With longer follow-up duration, most adjuvant cancer treatments showed a decreased NNT. Imatinib had one of the lowest NNTs among the adjuvant treatments at 1 and 3 years of follow-up using the RFS data.
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Diaz‐Nieto R, Orti‐Rodríguez R, Winslet M, Cochrane Upper GI and Pancreatic Diseases Group. Post-surgical chemotherapy versus surgery alone for resectable gastric cancer. Cochrane Database Syst Rev 2013; 2013:CD008415. [PMID: 23999923 PMCID: PMC11896092 DOI: 10.1002/14651858.cd008415.pub2] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND For gastric cancer surgery is the mainstay treatment. Chemotherapy seems to improve the survival results. But chemotherapy is not a complication-free therapy and its role has been questioned by some trials. OBJECTIVES To determine whether post-surgical chemotherapy should be used routinely in resectable gastric cancer. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded (July 2013). SELECTION CRITERIA Randomised controlled trials (RCT) comparing post-surgical chemotherapy versus surgery alone for resectable gastric cancer. DATA COLLECTION AND ANALYSIS Two authors independently assessed trials for inclusion and independently extracted the data. We analysed the data with both the fixed-effect and the random-effects models using the RevMan analysis software. We calculated the hazard ratio (HR) with 95% confidence interval (CI) based on intention-to-treat or available case analysis. MAIN RESULTS The authors identified 34 studies (7824 patients) reporting overall survival (OS) and only 15 reporting disease free survival (DFS) as well. Post-surgical chemotherapy showed an improvement in OS (HR 0.85; 95% CI 0.80 to 0.90) and an improvement in DFS (HR 0.79; 95% CI 0.72 to 0.87), although all the trials had a high risk of bias.The planned analysis of quality of life, return to work, and number of hospital admissions was impossible to complete as the outcome data for the analysis were not available from any trials. AUTHORS' CONCLUSIONS Post-surgical chemotherapy should be used routinely for resectable gastric cancer where possible. Further RCTs are needed to determine the role at each stage of disease.
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Affiliation(s)
- Rafael Diaz‐Nieto
- Royal Free HospitalHPB Surgery and Liver Transplant UnitPond StreetLondonUKNW3
| | | | - Marc Winslet
- Royal Free Hospital and Medical SchoolAcademic Department of SurgeryPond StreetLondonUKNW3 2QG
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Shi WT, Wei L, Xiang J, Su K, Ding Q, Tang MJ, Li JQ, Guo Y, Wang P, Zhang JW. Chinese patients with gastric cancer need targeted adjuvant chemotherapy schemes. Asian Pac J Cancer Prev 2013; 13:5263-72. [PMID: 23244147 DOI: 10.7314/apjcp.2012.13.10.5263] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common cancers in China. Adjuvant chemotherapy (AC) is a routine auxiliary treatment for GC recommended by the guidelines issued in 2011 by the Ministry of Health of the People's Republic of China, but the relevant credible consequences in China have been insufficient because of China's late start and ethical concerns. METHODS A series of databases, including Cochrane Library, MEDLINE, EMBASE, the Chinese database of the National Knowledge Infrastructure and the VIP database, were searched by 2 reviewers independently for studies investigating AC for GC through March 2012. The retrieved literature was screened according to the eligibility criteria. RESULTS A total of 35 randomized control trials (RCTs) were subjected to the final analysis, including 4,043 patients in treatment group and 3,884 in the control group, as well as 4 clinical-control trials (CCTs), which accessed the final analysis with 238 and 252 patients, respectively. AC reduced the risk of death as a protective treatment with statistical significance (HR=0.91, 95%CI: [0.85, 0.97], P=0.002), and it seemed more effective for Asian than non-Asian patients. The effects of AC were not influenced by the starting time (P>0.05). D2 lymphadenectomy-based chemotherapy was effective (HR=0.89, 95%CI: [0.80, 0.99], P=0.04). Oral S-1 40 mg/m2 after D2 lymphadenectomy might be a better choice for Asians with advanced GC and might result in a greater reduction of adverse events than in non-Asian patients. GRADE quality assessment determined that the strength of the evidence from foreign studies from Europe, the United States and Asian countries other than China was high, while it was moderate for Chinese studies. CONCLUSION AC was effective or even curative in Chinese patients in general, although it is still necessary to optimize a targeted AC scheme for Chinese patients with GC.
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Affiliation(s)
- Wen-Tao Shi
- Department of Oncology, Zhongnan Hospital, Hubei Key Laboratory of Tumor Biological Behavior, Hubei Cancer Clinical Study Center, China
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