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Tosca EM, Ronchi D, Rocchetti M, Magni P. Predicting Tumor Volume Doubling Time and Progression-Free Survival in Untreated Patients from Patient-Derived-Xenograft (PDX) Models: A Translational Model-Based Approach. AAPS J 2024; 26:92. [PMID: 39117850 DOI: 10.1208/s12248-024-00960-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Accepted: 07/24/2024] [Indexed: 08/10/2024] Open
Abstract
Tumor volume doubling time (TVDT) has been shown to be a potential surrogate marker of biological tumor activity. However, its availability in clinics is strongly limited due to ethical and practical reasons, as its assessment requires at least two subsequent tumor volume measurements in untreated patients. Here, a translational modeling framework to predict TVDT distributions in untreated cancer patient populations from tumor growth data in patient-derived xenograft (PDX) mice is proposed. Eleven solid cancer types were considered. For each of them, a set of tumor growth studies in PDX mice was selected and analyzed through a mathematical model to characterize the distribution of the exponential tumor growth rate in mice. Then, assuming an exponential growth of the tumor mass in humans, the growth rates were scaled from PDX mice to humans through an allometric scaling approach and used to predict TVDTs in untreated patients. A very good agreement was found between model predicted and clinically observed TVDTs, with 91% of the predicted TVDT medians fell within 1.5-fold of observations. Further, exploiting the intrinsic relationship between tumor growth dynamics and progression free survival (PFS), the exponential growth rates in humans were used to generate the expected PFS curves in absence of anticancer treatment. Predicted curves were extremely close to published PFS data from studies involving patient cohorts treated with supportive care or low effective therapies. The proposed approach shows promise as a potential tool to increase knowledge about TVDT in humans without the need of directly measuring tumor dimensions in untreated patients, and to predict PFS curves in untreated patients, that could fill the absence of placebo-controlled arms against which to compare treaded arms during clinical trials. However, further validation and refinement are needed to fully assess its effectiveness in this regard.
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Affiliation(s)
- E M Tosca
- Dipartimento Di Ingegneria Industriale E Dell'Informazione, Università Degli Studi Di Pavia, 27100, Pavia, Italy
| | - D Ronchi
- Dipartimento Di Ingegneria Industriale E Dell'Informazione, Università Degli Studi Di Pavia, 27100, Pavia, Italy
| | | | - P Magni
- Dipartimento Di Ingegneria Industriale E Dell'Informazione, Università Degli Studi Di Pavia, 27100, Pavia, Italy.
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Arias-Martinez A, Martínez de Castro E, Gallego J, Arrazubi V, Custodio A, Fernández Montes A, Diez M, Hernandez R, Limón ML, Cano JM, Vidal-Tocino R, Macias I, Visa L, Martin Richard M, Sauri T, Hierro C, Gil M, Cerda P, Martínez Moreno E, Martínez Lago N, Mérida-García AJ, Gómez González L, García Navalón FJ, Ruiz Martín M, Marín G, López-López F, Ruperez Blanco AB, Fernández AF, Jimenez-Fonseca P, Carmona-Bayonas A, Alvarez-Manceñido F. Is there a preferred platinum and fluoropyrimidine regimen for advanced HER2-negative esophagogastric adenocarcinoma? Insights from 1293 patients in AGAMENON-SEOM registry. Clin Transl Oncol 2024; 26:1674-1686. [PMID: 38361134 PMCID: PMC11178610 DOI: 10.1007/s12094-024-03388-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 01/06/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND The optimal chemotherapy backbone for HER2-negative advanced esophagogastric cancer, either in combination with targeted therapies or as a comparator in clinical trials, is uncertain. The subtle yet crucial differences in platinum-based regimens' safety and synergy with combination treatments need consideration. METHODS We analyzed cases from the AGAMENON-SEOM Spanish registry of HER2-negative advanced esophagogastric adenocarcinoma treated with platinum and fluoropyrimidine from 2008 to 2021. This study focused exclusively on patients receiving one of the four regimens: FOLFOX (5-FU and oxaliplatin), CAPOX (capecitabine and oxaliplatin), CP (capecitabine and cisplatin) and FP (5-FU and cisplatin). The aim was to determine the most effective and tolerable platinum and fluoropyrimidine-based chemotherapy regimen and to identify any prognostic factors. RESULTS Among 1293 patients, 36% received either FOLFOX (n = 468) or CAPOX (n = 466), 20% CP (n = 252), and 8% FP (n = 107). FOLFOX significantly increased PFS (progression free survival) compared to CP, with a hazard ratio of 0.73 (95% CI 0.58-0.92, p = 0.009). The duration of treatment was similar across all groups. Survival outcomes among regimens were similar, but analysis revealed worse ECOG-PS (Eastern Cooperative Oncology Group-Performance Status), > 2 metastatic sites, bone metastases, hypoalbuminemia, higher NLR (neutrophil-to-lymphocyte ratio), and CP regimen as predictors of poor PFS. Fatigue was common in all treatments, with the highest incidence in FOLFOX (77%), followed by FP (72%), CAPOX (68%), and CP (60%). Other notable toxicities included neuropathy (FOLFOX 69%, CAPOX 62%), neutropenia (FOLFOX 52%, FP 55%), hand-foot syndrome in CP (46%), and thromboembolic events (FP 12%, CP 11%). CONCLUSIONS FOLFOX shown better PFS than CP. Adverse effects varied: neuropathy was more common with oxaliplatin, while thromboembolism was more frequent with cisplatin.
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Affiliation(s)
- Aranzazu Arias-Martinez
- Doctoral Program in Pharmacy, Universidad de Granada, Barrio Verxeles n°13 2°, CP 27850, Granada, Viveiro, Spain.
| | - Eva Martínez de Castro
- Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - Javier Gallego
- Medical Oncology Department, Hospital General Universitario de Elche, Elche, Spain
| | - Virginia Arrazubi
- Medical Oncology Department, Hospital Universitario de Navarra, IdiSNA, Pamplona, Spain
| | - Ana Custodio
- Medical Oncology Department, Hospital Universitario La Paz, CIBERONC, CB16/12/00398, Madrid, Spain
| | - Ana Fernández Montes
- Medical Oncology Department, Complejo Hospitalario Universitario de Orense, Orense, Spain
| | - Marc Diez
- Medical Oncology Department, Hospital Universitario Vall d'Hebron, VHIO, Barcelona, Spain
| | - Raquel Hernandez
- Medical Oncology Department, Hospital Universitario de Canarias, Tenerife, Spain
| | - María Luisa Limón
- Medical Oncology Department, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Juana María Cano
- Medical Oncology Department, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain
| | - Rosario Vidal-Tocino
- Medical Oncology Department, Complejo Asistencial Universitario de Salamanca - IBSAL, Salamanca, Spain
| | - Ismael Macias
- Medical Oncology Department, Hospital Universitario Parc Tauli, Sabadell, Spain
| | - Laura Visa
- Medical Oncology Department, Hospital Universitario El Mar, Barcelona, Spain
| | - Marta Martin Richard
- Medical Oncology Department, Instituto Catalán de Oncología (ICO), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Tamara Sauri
- Medical Oncology Department, Hospital Clinic, Barcelona, Spain
| | - Cinta Hierro
- Medical Oncology Department, Instituto Catalán de Oncología (ICO)-Badalona, Barcelona; Badalona-Applied Research Group in Oncology (B-ARGO), Badalona, Spain
| | - Mireia Gil
- Medical Oncology Department, Hospital General Universitario de Valencia-Ciberonc CB16/12/0035, Valencia, Spain
| | - Paula Cerda
- Medical Oncology Department, Hospital Universitario Santa Creu y Sant Pau, Barcelona, Spain
| | - Elia Martínez Moreno
- Medical Oncology Department, Hospital Universitario de Fuenlabrada, Madrid, Spain
| | - Nieves Martínez Lago
- Medical Oncology Department, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain
| | | | - Lucía Gómez González
- Medical Oncology Department, Hospital General Universitario de Alicante, Alicante, Spain
| | | | - Maribel Ruiz Martín
- Medical Oncology Department, Complejo Asistencial Universitario de Palencia, Palencia, Spain
| | - Gema Marín
- Medical Oncology Department, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain
| | - Flora López-López
- Medical Oncology Department, Hospital Universitario del Sureste, Madrid, Spain
| | | | | | - Paula Jimenez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain
| | - Alberto Carmona-Bayonas
- Hematology and Medical Oncology Department, Hospital Universitario Morales Meseguer, University of Murcia, IMIB, Murcia, Spain
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Wu Y, Li CS, Meng RY, Jin H, Chai OH, Kim SM. Regulation of Hippo-YAP/CTGF signaling by combining an HDAC inhibitor and 5-fluorouracil in gastric cancer cells. Toxicol Appl Pharmacol 2024; 482:116786. [PMID: 38086440 DOI: 10.1016/j.taap.2023.116786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/02/2023] [Accepted: 12/06/2023] [Indexed: 12/18/2023]
Abstract
Histone deacetylase (HDAC) inhibitors diminish carcinogenesis, metastasis, and cancer cell proliferation by inducing death in cancer cells. Tissue regeneration and organ development are highly dependent on the Hippo signaling pathway. Targeting the dysregulated hippo pathway is an excellent approach for cancer treatment. According to the results of this study, the combination of panobinostat, a histone deacetylase inhibitor, and 5-fluorouracil (5-FU), a chemotherapy drug, can act synergistically to induce apoptosis in gastric cancer cells. The combination of panobinostat and 5-FU was more effective in inhibiting cell viability than either treatment alone by elevating the protein levels of cleaved PARP and cleaved caspase-9. By specifically targeting E-cadherin, vimentin, and MMP-9, the combination of panobinostat and 5-FU significantly inhibited cell migration. Additionally, panobinostat significantly increased the anticancer effects of 5-FU by activating Hippo signaling (Mst 1 and 2, Sav1, and Mob1) and inhibiting the Akt signaling pathway. As a consequence, there was a decrease in the amount of Yap protein. The combination therapy of panobinostat with 5-FU dramatically slowed the spread of gastric cancer in a xenograft animal model by deactivating the Akt pathway and supporting the Hippo pathway. Since combination treatment exhibits much higher anti-tumor potential than 5-FU alone, panobinostat effectively potentiates the anti-tumor efficacy of 5-FU. As a result, it is believed that panobinostat and 5-FU combination therapy will be useful as supplemental chemotherapy in the future.
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Affiliation(s)
- Yanling Wu
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea
| | - Cong Shan Li
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea
| | - Ruo Yu Meng
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea; Department of Oncology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong 250021, China
| | - Hua Jin
- School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China
| | - Ok Hee Chai
- Department of Anatomy, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea
| | - Soo Mi Kim
- Department of Physiology, Institute for Medical Sciences, Jeonbuk National University Medical School, Jeonju, 54907, Republic of Korea.
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Riccò B, Martinelli G, Bardasi C, Dominici M, Spallanzani A, Salati M. Optimizing the Continuum of Care in Gastric Cancer. Onco Targets Ther 2023; 16:995-1012. [PMID: 38021446 PMCID: PMC10680466 DOI: 10.2147/ott.s365505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023] Open
Abstract
Gastric cancer (GC) still ranks as the fifth most common malignancy and the fourth leading cause of cancer-related death worldwide. Despite the recent progress in the therapeutic algorithm of the advanced disease with the advent of immune checkpoint inhibitors (ICIs) and next-generation HER2-directed therapies, survival rates remain poor, with a median survival hardly exceeding 12 months. Furthermore, only 40% of patients remain eligible for second- and later-line treatments due to the aggressiveness of the disease and the rapid deterioration of performance status (PS). Thus, current research is focusing either on the identification of novel treatment options or the development of personalized strategies to optimize the continuum of care and ultimately improve patients' outcome. In this article, we provide an overview of the current treatment landscape for advanced GC with a particular emphasis on later-line treatments and outline novel perspectives on the horizon.
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Affiliation(s)
- Beatrice Riccò
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Giulio Martinelli
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Camilla Bardasi
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimo Dominici
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Andrea Spallanzani
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
| | - Massimiliano Salati
- Department of Oncology and Hematology, University Hospital of Modena, Modena, Italy
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Xu W, Jiang T, Shen K, Zhao D, Zhang M, Zhu W, Liu Y, Xu C. GADD45B regulates the carcinogenesis process of chronic atrophic gastritis and the metabolic pathways of gastric cancer. Front Endocrinol (Lausanne) 2023; 14:1224832. [PMID: 37608794 PMCID: PMC10441793 DOI: 10.3389/fendo.2023.1224832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 07/18/2023] [Indexed: 08/24/2023] Open
Abstract
Background Gastric cancer continues to be a significant global healthcare challenge, and its burden remains substantial. The development of gastric cancer (GC) is closely linked to chronic atrophic gastritis (CAG), yet there is a scarcity of research exploring the underlying mechanisms of CAG-induced carcinogenesis. Methods In this study, we conducted a comprehensive investigation into the oncogenes involved in CAG using both bulk transcriptome and single-cell transcriptome data. Our approach employed hdWGCNA to identify pathogenic genes specific to CAG, with non-atrophic gastritis (NAG) serving as the control group. Additionally, we compared CAG with GC, using normal gastric tissue as the control group in the single-cell transcriptome analysis. By intersecting the identified pathogenic genes, we pinpointed key network molecules through protein interaction network analysis. To further refine the gene selection, we applied LASSO, SVM-RFE, and RF techniques, which resulted in a set of cancer-related genes (CRGs) associated with CAG. To identify CRGs potentially linked to gastric cancer progression, we performed a univariate COX regression analysis on the gene set. Subsequently, we explored the relationship between CRGs and immune infiltration, drug sensitivity, and clinical characteristics in gastric cancer patients. We employed GSVA to investigate how CRGs regulated signaling pathways in gastric cancer cells, while an analysis of cell communication shed light on the impact of CRGs on signal transmission within the gastric cancer tumor microenvironment. Lastly, we analyzed changes in metabolic pathways throughout the progression of gastric cancer. Results Using hdWGCNA, we have identified a total of 143 pathogenic genes that were shared by CAG and GC. To further investigate the underlying mechanisms, we conducted protein interaction network analysis and employed machine learning screening techniques. As a result, we have identified 15 oncogenes that are specifically associated with chronic atrophic gastritis. By performing ROC reanalysis and prognostic analysis, we have determined that GADD45B is the most significant gene involved in the carcinogenesis of CAG. Immunohistochemical staining and differential analysis have revealed that GADD45B expression was low in GC tissues while high in normal gastric tissues. Moreover, based on prognostic analysis, high expression of GADD45B has been correlated with poor prognosis in GC patients. Additionally, an analysis of immune infiltration has shown a relationship between GADD45B and the infiltration of various immune cells. By correlating GADD45B with clinical characteristics, we have found that it primarily affects the depth of invasion in GC. Through cell communication analysis, we have discovered that the CD99 signaling pathway network and the CDH signaling pathway network are the main communication pathways that significantly alter the microenvironment of gastric tissue during the development of chronic atrophic gastritis. Specifically, GADD45B-low GC cells were predominantly involved in the network communication of the CDH signaling pathway, while GADD45B-high GC cells played a crucial role in both signaling pathways. Furthermore, we have identified several metabolic pathways, including D-Glutamine and D-glutamate metabolism and N-Glycan biosynthesis, among others, that played important roles in the occurrence and progression of GC, in addition to the six other metabolic pathways. In summary, our study highlighted the discovery of 143 pathogenic genes shared by CAG and GC, with a specific focus on 15 oncogenes associated with CAG. We have identified GADD45B as the most important gene in the carcinogenesis of CAG, which exhibited differential expression in GC tissues compared to normal gastric tissues. Moreover, GADD45B expression was correlated with patient prognosis and is associated with immune cell infiltration. Our findings also emphasized the impact of the CD99 and CDH signaling pathway networks on the microenvironment of gastric tissue during the development of CAG. Additionally, we have identified key metabolic pathways involved in GC progression. Conclusion GADD45B, an oncogene implicated in chronic atrophic gastritis, played a critical role in GC development. Decreased expression of GADD45B was associated with the onset of GC. Moreover, GADD45B expression levels were closely tied to poor prognosis in GC patients, influencing the infiltration patterns of various cells within the tumor microenvironment, as well as impacting the metabolic pathways involved in GC progression.
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Affiliation(s)
- Wei Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Tianxiao Jiang
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Kanger Shen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dongxu Zhao
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Man Zhang
- Department of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenxin Zhu
- Department of Gastroenterology, Kunshan Third People’s Hospital, Suzhou, Jiangsu, China
| | - Yunfei Liu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Synergistic Effects of the Combinational Use of Escitalopram Oxalate and 5-Fluorouracil on the Inhibition of Gastric Cancer SNU-1 Cells. Int J Mol Sci 2022; 23:ijms232416179. [PMID: 36555820 PMCID: PMC9781210 DOI: 10.3390/ijms232416179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 12/23/2022] Open
Abstract
Owing to its high recurrence rate, gastric cancer (GC) is the leading cause of tumor-related deaths worldwide. Besides surgical treatment, chemotherapy is the most commonly used treatment against GC. However, the adverse events associated with chemotherapy use limit its effectiveness in GC treatment. In this study, we investigated the effects of using combinations of low-dose 5-fluorouracil (5-FU; 0.001 and 0.01 mM) with different concentrations of escitalopram oxalate (0.01, 0.02, 0.06, and 0.2 mM) to evaluate whether the assessed combination would have synergistic effects on SNU-1 cell survival. 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.06 mM) administered over 24 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Moreover, 5-FU (0.001 mM) + escitalopram oxalate (0.02 or 0.06 mM) and 5-FU (0.01 mM) + escitalopram oxalate (0.02, 0.06, or 0.2 mM) administered over 48 h showed synergistic effects on the inhibition of SNU-1 cell proliferation. Compared with controls, SNU-1 cells treated with 5-FU (0.01 mM) + escitalopram oxalate (0.02 mM) exhibited significantly increased levels of annexin V staining, reactive oxygen species, cleaved poly (ADP-ribose) polymerase, and caspase-3 proteins. Furthermore, 5-FU (12 mg/kg) + escitalopram oxalate (12.5 mg/kg) significantly attenuated xenograft SNU-1 cell proliferation in nude mice. Our study is the first to report the synergistic effects of the combinational use of low-dose 5-FU and escitalopram oxalate on inhibiting SNU-1 cell proliferation. These findings may be indicative of an alternative option for GC treatment.
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Xu W, Zhao D, Huang X, Zhang M, Zhu W, Xu C. Significance of monocyte infiltration in patients with gastric cancer: A combined study based on single cell sequencing and TCGA. Front Oncol 2022; 12:1001307. [PMID: 36479092 PMCID: PMC9720400 DOI: 10.3389/fonc.2022.1001307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 10/28/2022] [Indexed: 08/04/2023] Open
Abstract
BACKGROUND Gastric cancer is still one of the most lethal tumor diseases in the world. Despite some improvements, the prognosis of patients with gastric cancer is still not accurately predicted. METHODS Based on single cell sequencing data, we conducted a detailed analysis of gastric cancer patients and normal tissues to determine the role of monocytes in the progression of gastric cancer. WCGA facilitated our search for Grade-related genes in TCGA. Then, according to the marker genes and cell differentiation genes of monocytes, we determined the cancer-promoting genes of monocytes. Based on LASSO regression, we established a prognostic model using TCGA database. The accuracy of the model was verified by PCA, ROC curve, survival analysis and prognostic analysis. Finally, we evaluated the significance of the model in clinical diagnosis and treatment by observing drug sensitivity, immune microenvironment and immune checkpoint expression in patients with different risk groups. RESULTS Monocytes were poorly differentiated in tumor microenvironment. It mainly played a role in promoting cancer in two ways. One was to promote tumor progression indirectly by interacting with other tumor stromal cells. The other was to directly connect with tumor cells through the MIF and TNF pathway to play a tumor-promoting role. The former was more important in these two ways. A total of 292 monocyte tumor-promoting genes were obtained, and 12 genes were finally included in the construction of the prognosis model. A variety of validation methods showed that our model had an accurate prediction ability. Drug sensitivity analysis could provide guidance for clinical medication of patients. The results of immune microenvironment and immune checkpoint also indicated the reasons for poor prognosis of high-risk patients. CONCLUSION In conclusion, we provided a 12-gene risk score formula and nomogram for gastric cancer patients to assist clinical drug therapy and prognosis prediction. This model had good accuracy and clinical significance.
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Affiliation(s)
- Wei Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dongxu Zhao
- Department of Interventional Radiology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaowei Huang
- Department of General Surgery, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Man Zhang
- Department of Emergency Medicine, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Wenxin Zhu
- Department of Gastroenterology, Kunshan Third People’s Hospital, Suzhou, Jiangsu, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China
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Rosati G, Cella CA, Cavanna L, Codecà C, Prisciandaro M, Mosconi S, Luchena G, Silvestris N, Bernardini I, Casaretti R, Zoratto F, Amoroso D, Ciarlo A, Barni S, Cascinu S, Davite C, Di Sanzo A, Casolaro A, Bilancia D, Labianca R. A randomized phase III study of fractionated docetaxel, oxaliplatin, capecitabine (low-tox) vs epirubicin, oxaliplatin and capecitabine (eox) in patients with locally advanced unresectable or metastatic gastric cancer: the lega trial. Gastric Cancer 2022; 25:783-793. [PMID: 35352176 DOI: 10.1007/s10120-022-01292-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/16/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND EOX (epirubicin, oxaliplatin, and capecitabine) is one of the standard regimens for metastatic or locally advanced gastric cancer (GC). A new combination based on fractional docetaxel (low-TOX) has been developed in an attempt to increase the efficacy of EOX and reduce the heavy toxicity of classical docetaxel regimens. METHODS Overall, 169 previously untreated GC patients were randomized between EOX (arm A) and low-TOX (arm B). The primary endpoint was progression-free survival (PFS), while secondary ones were overall survival (OS), overall response rate (ORR), disease control rate (DCR), and tolerability. The study was designed to detect a 35% (80% power at a two-sided 5% significance level) PFS increase with low-TOX and an interim analysis for futility was planned after the first 127 events. RESULTS At the cut-off date of interim analysis, median PFS was 6.3 months [95% confidence interval (CI) 5.0-8.1] in arm A vs 6.3 months (95% CI 5.0-7.8) in arm B, without statistical difference. OS was comparable in the two arms: 12.4 in arm A (95% CI 9.1-19.2) vs 11.5 months in arm B (95% CI 8.6-15.0). ORR was 33% and 24%, while DCR was 68% and 67%, respectively. Treatment modification (91% vs 78%, P = 0.017) and number of patients with CTC grade ≥ 3 adverse events (42 vs 35) were higher in arm B. CONCLUSIONS A triplet regimen based on the fractional dose of docetaxel achieves no improvement over EOX which remains a potential standard treatment in many patients with inoperable, locally advanced or metastatic GC.
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Affiliation(s)
- Gerardo Rosati
- UOC di Oncologia Medica, Azienda Ospedaliera San Carlo, Via P. Petrone 1, 85100, Potenza, Italy.
| | - Chiara Alessandra Cella
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Luigi Cavanna
- Dipartimento di Oncologia-Ematologia, Azienda USL, Ospedale di Piacenza, Piacenza, Italy
| | - Carla Codecà
- U.O. Oncologia Medica, ASST Santi Paolo e Carlo, Presidio Ospedaliero San Paolo, Milan, Italy
| | - Michele Prisciandaro
- Divisione di Oncologia Medica, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Stefania Mosconi
- Dipartimento di Oncologia ed Ematologia, ASST Papa Giovanni XXIII, Bergamo, Italy
| | | | - Nicola Silvestris
- U.O.C. Oncologia Medica, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy
| | | | - Rossana Casaretti
- Department of Abdominal Oncology, Istituto Nazionale Tumori-IRCCS Fondazione "G. Pascale", Napoli, Italy
| | - Federica Zoratto
- U.O.C. Oncologia Medica, Ospedale Santa Maria Goretti, Latina, Italy
| | - Domenico Amoroso
- Ospedale Versilia, Azienda USL Toscana Nordovest (ATNO), Lido di Camaiore, Italy
| | - Andrea Ciarlo
- U.O. Oncologia Medica, AUSL Toscana Centro, Ospedale di Prato, Prato, Italy
| | - Sandro Barni
- U.O. Oncologia Medica, ASST Bergamo Ovest, Ospedale di Treviglio-Caravaggio, Treviglio, BG, Italy
| | - Stefano Cascinu
- Unità di Medicina Oncologica, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Cristina Davite
- Global Clinical Development, Nerviano Medical Sciences, Nerviano, MI, Italy
| | | | - Alessia Casolaro
- Global Clinical Development, Nerviano Medical Sciences, Nerviano, MI, Italy
| | - Domenico Bilancia
- UOC di Oncologia Medica, Azienda Ospedaliera San Carlo, Via P. Petrone 1, 85100, Potenza, Italy
| | - Roberto Labianca
- Dipartimento di Oncologia ed Ematologia, ASST Papa Giovanni XXIII, Bergamo, Italy
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Gürler F, İlhan A, Güven DC, Turhan O, Kurt İnci B, Sütçüoğlu O, Yildiz F, Arik Z, Öksüzoğlu B, Yalçin Ş, Özdemir N, Yazici O, Özet A. Does docetaxel matter in metastatic gastric cancer? FOLFOX versus FLOT regimens as first-line treatment. Anticancer Drugs 2022; 33:e477-e485. [PMID: 34261917 DOI: 10.1097/cad.0000000000001143] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
We aimed to compare the efficacy and the safety of the FOLFOX and the FLOT regimens in metastatic gastric cancer (mGC) as first-line treatment. It was a retrospective multicenter observational study. The comparisons between groups were conducted in terms of progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and hematologic adverse events. Seventy-nine patients, diagnosed with mGC between March 2012 and December 2019, treated with FOLFOX (n = 43) or FLOT (n = 36) regimens as first-line treatment were included in the study. The mPFS was 10.9 months [95% confidence interval (CI), 5.8-16.1] in the FLOT arm and 7.1 months (95% CI, 5.1-9.1) in the FOLFOX arm (P < 0.001). The ORR was 63.9% in the FLOT arm and 30.2% in the FOLFOX arm (P = 0.003). The mOS was 13.3 months (95% CI, 11.3-15.4) in the FLOT arm and 10.9 months (95% CI, 8.2-13.5) in the FOLFOX arm (P = 0.103). The hematologic adverse events in all grades were 88.4% (n = 38) in the FOLFOX arm compared with 80.6% (n = 29) in the FLOT arm (P = 0.335). The FLOT regimen might be a preferred option in mGC with an improved PFS and ORR compared with the FOLFOX regimen.
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Affiliation(s)
| | - Ayşegül İlhan
- Department of Medical Oncology, HSU Dr Abdurrahman Yurtaslan Oncology Training & Research Hospital
| | - Deniz Can Güven
- Department of Medical Oncology, Hacettepe University Cancer Institute
| | - Okan Turhan
- Department of Internal Medicine, Gazi University, Ankara, Turkey
| | | | | | - Fatih Yildiz
- Department of Medical Oncology, HSU Dr Abdurrahman Yurtaslan Oncology Training & Research Hospital
| | - Zafer Arik
- Department of Medical Oncology, Hacettepe University Cancer Institute
| | - Berna Öksüzoğlu
- Department of Medical Oncology, HSU Dr Abdurrahman Yurtaslan Oncology Training & Research Hospital
| | - Şuayib Yalçin
- Department of Medical Oncology, Hacettepe University Cancer Institute
| | | | - Ozan Yazici
- Department of Medical Oncology, Gazi University
| | - Ahmet Özet
- Department of Medical Oncology, Gazi University
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10
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O'Donovan C, Davern M, Donlon NE, Lysaght J, Conroy MJ. Chemokine-targeted therapies: An opportunity to remodel immune profiles in gastro-oesophageal tumours. Cancer Lett 2021; 521:224-236. [PMID: 34506844 DOI: 10.1016/j.canlet.2021.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 08/18/2021] [Accepted: 09/05/2021] [Indexed: 02/07/2023]
Abstract
Immunotherapies are transforming outcomes for many cancer patients and are quickly becoming the fourth pillar of cancer therapy. However, their efficacy of only ∼25% in gastro-oesophageal cancer has been disappointing. This is attributed to factors such as insufficient patient stratification and the pro-tumourigenic immune landscape of gastro-oesophageal tumours. The chemokine profiles of solid tumours and the availability of effector immune cells greatly influence the immune infiltrate, producing 'cold' or 'immune-excluded' tumours in which immunotherapies are unable to reinvigorate the immune response. Other biological functions for chemokines have emerged, such as promoting cell survival, polarising T cell responses, and supporting several hallmarks of cancer. Therefore, chemokine networks may be exploited with therapeutic intent to mobilise and polarise anti-tumour immune cells, with further utility as combination treatments to augment the efficacy of current cancer immunotherapies. Few studies have demonstrated the clinical benefit of chemokine-targeted therapies as monotherapies, and this review proposes their consideration as combination treatments. Herein, we explore the anti-tumour and pro-tumour implications of chemokine signalling in gastro-oesophageal cancer and discuss their value as prognostic and predictive biomarkers in response to treatment.
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Affiliation(s)
- Cillian O'Donovan
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Maria Davern
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Noel E Donlon
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Joanne Lysaght
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland
| | - Melissa J Conroy
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute, St. James's Hospital Campus, Dublin 8, Ireland; Department of Physiology, School of Medicine, Trinity College, Dublin, Ireland.
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11
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Hu Y, Liu D, Cui P, Zhang W, Chen H, Piao C, Lu Y, Liu X, Wang Y, Liu J, Lu X. IL-15-induced lymphocytes as adjuvant cellular immunotherapy for gastric cancer. Invest New Drugs 2021; 39:1538-1548. [PMID: 34387808 DOI: 10.1007/s10637-021-01160-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Accepted: 08/03/2021] [Indexed: 10/20/2022]
Abstract
Objectives To test the antitumor potential of lymphocytes transferred via adoptive cell therapy (ACT) in a mouse model of human gastric cancer (GC), and to evaluate the clinical efficacy and safety of combining lymphocytes as adjuvant therapy with first-line chemotherapy in patients with GC. Methods We constructed a human GC xenograft model in sublethally irradiated 6-8-week-old male NCG mice. MKN-45 cells (1 × 106 cells/mouse) were subcutaneously injected into mice's flanks. After tumors had become palpable, we randomized the mice into control, ACTIL-2, and ACTIL-15 groups. Human lymphocytes were then injected into mouse tail veins. In addition, 63 human patients with histologically or cytologically confirmed stage III-IV GC randomly received S-1 + oxaliplatin + ACTIL-15 (combination therapy group) or S-1 + oxaliplatin (chemotherapy group). Results In the mouse study, treatment with ACTIL-15 cells inhibited tumor growth on adoptive transfer, and mice that received ACTIL-15 cells had significantly longer survival rates (p < 0.05, ACTIL-15 vs. ACTIL-2). In the human study, the median survival rate of patients in the combination therapy group was 472 days (95% confidence interval [CI], 276-668 days), whereas that of patients in the chemotherapy group was 266 days (95% CI, 200-332 days; p < 0.05). Eleven percent (7/63) of patients had adverse reactions, but these reactions did not interfere with treatment. Conclusion Adoptive transfer of ACTIL-15 cells in a mouse model of GC and in patients with advanced GC treated with S1 + oxaliplatin improved survival rates in both, with an acceptable safety profile.
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Affiliation(s)
- Yuefeng Hu
- Department of Interventional Radiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Dong Liu
- Department of Radiology, The First Hospital of Tsinghua University, Beijing, China
| | - Peilin Cui
- Department of Internal Medicine, Beijing Tiantan Hospital, Capital Medical University, Bejing, China
| | - Wen Zhang
- Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hao Chen
- Department of Surgical Oncology, Lanzhou University Second Hospital, Lanzhou, China
| | - Chunmei Piao
- Department of Oncology, Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital Affiliated to the Capital Medical University, Beijing, China
| | - Yongcheng Lu
- Department of Physiology, Michigan State University, East Lansing, MI, USA
| | - Xuesong Liu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co, Ltd, Beijing, China
| | - Yue Wang
- Department of Oncology, Beijing Biohealthcare Biotechnology Co, Ltd, Beijing, China
| | - Jingwei Liu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co, Ltd, Beijing, China.
| | - Xu Lu
- Department of Oncology, Beijing Biohealthcare Biotechnology Co, Ltd, Beijing, China
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12
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Yamashita K, Hosoda K, Niihara M, Hiki N. History and emerging trends in chemotherapy for gastric cancer. Ann Gastroenterol Surg 2021; 5:446-456. [PMID: 34337293 PMCID: PMC8316740 DOI: 10.1002/ags3.12439] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/29/2020] [Accepted: 01/15/2021] [Indexed: 12/24/2022] Open
Abstract
Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first-line chemotherapy consists of multidrug regimens including oral 5-FU agents such as S1/Xeloda and platinum preparations, as well as Trastuzumab, which is effective in HER2-positive cases. Second- and third-line chemotherapy regimens include taxanes, Ramucirumab (R-mab), and Nivolumab (N-mab), which have different mechanisms of action from first-line chemotherapy. R-mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5-FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.
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Affiliation(s)
- Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical FrontiersKitasato University School of MedicineSagamiharaJapan
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Kei Hosoda
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Masahiro Niihara
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
| | - Naoki Hiki
- Department of Upper Gastrointestinal SurgeryKitasato University School of MedicineSagamiharaJapan
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13
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Deleporte A, Van den Eynde M, Forget F, Holbrechts S, Delaunoit T, Houbiers G, Kalantari HR, Laurent S, Vanderstraeten E, De Man M, Vergauwe P, Clausse M, Van Der Auwera J, D'Hondt L, Pierre P, Ghillemijn B, Covas A, Paesmans M, Ameye L, Awada A, Sclafani F, Hendlisz A. Fortnightly or fractionated weekly docetaxel-cisplatin-5-FU as first-line treatment in advanced gastric and gastroesophageal junction adenocarcinoma: The randomized phase II DoGE study. Cancer Med 2021; 10:4366-4374. [PMID: 34057299 PMCID: PMC8267119 DOI: 10.1002/cam4.3976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 03/20/2021] [Accepted: 04/01/2021] [Indexed: 11/24/2022] Open
Abstract
Background While docetaxel/cisplatin/5‐fluorouracil (DCF) outperforms CF in first‐line gastric adenocarcinoma, toxicity remains an issue. Methods This multicenter phase II trial randomized chemonaïve metastatic gastric adenocarcinoma patients to fractionated weekly DCF (D 40 mg/m2, C 35 mg/m², F 1800 mg/m² over 24 h, on days 1 and 8 every 3 weeks, arm (1) or fortnightly DCF (D 50 mg/m2, C 50 mg/m², F 2000 mg/m² over 48 h every 2 weeks, arm (2). Prophylactic granulocyte colony‐stimulating factor (G‐CSF) was not allowed. The primary endpoint was the rate of febrile neutropenia within the first six treatment weeks (early FN). Results A total of 106 eligible patients were recruited. The early and overall FN rates were 9.5% and 17% in arm 1, respectively, and 5.9% and 8% in arm 2, respectively. Grade ≥3 toxicities occurred in 81% of patients in arm 1 and 90% of patients in arm 2, the most common being neutropenia (33% vs. 61%), fatigue (27% vs. 25%), vomiting (21% vs. 12%), anorexia (19% vs. 18%), and diarrhea (17% vs. 10%). Median progression‐free survival and overall survival were 5.1 (95% CI, 3.2–6.5) and 8.2 months (95% CI, 6.0–14.5), respectively, in arm 1 and 5.2 (95% CI, 3.0–6.9) and 11.9 months (95% CI, 7.4–15.9), respectively, in arm 2. Conclusions Fractionated weekly and fortnightly DCF regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF. The DoGE multicenter study randomised prospectively patients with chemonaïve gastric cancer between fractionated weekly and fortnightly DCF regimens. Both regimens are associated with a low risk of early FN, and a better hematological toxicity profile as compared to historical DCF without compromising efficacy. Both regimens offer greater convenience removing the need for systematic use of prophylactic G‐CSF.
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Affiliation(s)
- Amélie Deleporte
- Department of Medicine, Gastrointestinal Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Marc Van den Eynde
- Department of Medical Oncology, Cliniques Universitaires Saint-Luc, Woluwe-St-Lambert, Belgium
| | - Frédéric Forget
- Centre Hospitalier de l'Ardenne (CHA), Department of Medical Oncology, Hôpital de Libramont, Libramont-Chevigny, Belgium
| | | | - Thierry Delaunoit
- Department of Medical Oncology, Hôpital de Jolimont, La Louvière, Belgium
| | - Ghislain Houbiers
- Department of Gastroenterology, Clinique Saint Joseph, Liège, Belgium
| | - Hassan R Kalantari
- Department of Onco-Hematology, Centre Hospitalier Pelzer-La Tourelle (CHPLT), Verviers, Belgium
| | - Stéphanie Laurent
- Department of Gastroenterology, Oncology Unit, Universiteit Gent, Gent, Belgium
| | | | - Marc De Man
- Department of Gastroenterology, Olv Ziekenhuis, Campus Aalst, Aalst, Belgium
| | - Philippe Vergauwe
- Department of Gastroenterology, AZ Groeninge -Kortrijk, Kortrijk, Belgium
| | - Marylene Clausse
- Department of Medicine, Oncology Unit, Clinique Saint-Luc Bouge, Namur, Belgium
| | | | - Lionel D'Hondt
- Department of Medical Oncology, CHU UCL Namur - Site Godinne, Yvoir, Belgium
| | - Pascal Pierre
- Department of Medical Oncology, Hôpital d'Arlon, Arlon, Belgium
| | | | - Angelique Covas
- Department of Medicine, Gastrointestinal Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Marianne Paesmans
- Department of Statistics, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Lieveke Ameye
- Department of Statistics, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Ahmad Awada
- Department of Medical Oncology, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Francesco Sclafani
- Department of Medicine, Gastrointestinal Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Alain Hendlisz
- Department of Medicine, Gastrointestinal Unit, Institut Jules Bordet, Université Libre de Bruxelles, Bruxelles, Belgium
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14
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Xu J, Wang Z, Huang Y, Wang Y, Xiang L, He X. A spirostanol saponin isolated from Tupistra chinensis Baker simultaneously induces apoptosis and autophagy by regulating the JNK pathway in human gastric cancer cells. Steroids 2020; 164:108737. [PMID: 33002483 DOI: 10.1016/j.steroids.2020.108737] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/15/2020] [Accepted: 09/21/2020] [Indexed: 12/23/2022]
Abstract
T-17, a bioactive spirostanol saponin extracted from Tupistra chinensis Baker, was previously reported with anti-inflammatory and cytotoxic activities. However, the mechanism underlying of its anti-proliferation activity remains to be elucidated. In this study, we investigated the anti-gastric cancer cell growth activity of T-17 in terms of cell viability, colony formation, cell cycle, induction of apoptosis/autophagy, and JNK pathway. T-17 showed dose-dependent cytotoxicity in SGC-7901 and AGS cell lines, it induced caspase-mediated apoptosis as well as G0/G1 phase arrest and modulation of cyclinE2 and p21 expression. In addition, T-17 promoted the cancer cell autophagy as evidenced with increased expression of Beclin-1 and decreased p62 in western blot and formation of GFP-LC3 puncta. Furthermore, T-17-induced autophagy decreased gastric cancer cell apoptosis as assessed by pharmacological autophagy inhibitors and ATG5 siRNA usage. Importantly, the activation of JNK pathway was simultaneously involved in T-17-induced apoptosis and autophagy. Taken together, the results suggest that T-17 is a promising cytotoxic agent for therapeutic treatment of human gastric adenocarcinoma, which provides a good foundation for further research and development of Tupistra chinensis Baker.
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Affiliation(s)
- Jingwen Xu
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou 510006, China
| | - Zhe Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yuying Huang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yihai Wang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou 510006, China
| | - Limin Xiang
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Xiangjiu He
- School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Engineering Research Center for Lead Compounds & Drug Discovery, Guangzhou 510006, China.
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15
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Alzeeb G, Metges JP, Corcos L, Le Jossic-Corcos C. Three-Dimensional Culture Systems in Gastric Cancer Research. Cancers (Basel) 2020; 12:E2800. [PMID: 33003476 PMCID: PMC7601358 DOI: 10.3390/cancers12102800] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 09/25/2020] [Accepted: 09/27/2020] [Indexed: 12/14/2022] Open
Abstract
Gastric cancer (GC), which includes cancer of the esophagus, the oesophagogastric junction, and the stomach fundus, is highly deadly with strong regional influence, Asia being the most affected. GC is often detected at late stages, with 30% of metastatic cases at diagnosis. Many authors have devised models to both unravel the mechanisms of GC development and to evaluate candidate therapeutics. Among these models, 2D-cell cultures are progressively replaced by 3D-cell cultures that recapitulate, much more comprehensively, tumor cellular and genetic heterogeneity, as well as responsiveness to environmental changes, such as exposure to drugs or irradiation. With respect to the specifics of GC, there are high hopes from such model systems, especially with the aim of identifying prognostic markers and novel drug targets.
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Affiliation(s)
- George Alzeeb
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
| | - Jean-Philippe Metges
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
| | - Laurent Corcos
- Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France; (G.A.); (L.C.)
- CHU de Brest, Inserm, University Brest, EFS, UMR 1078, GGB, F-29200 Brest, France;
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16
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Nakamura M, Ojima T, Katsuda M, Hayata K, Kitadani J, Nakamori M, Yamaue H. Phase 1 Study of Combined Chemotherapy of Nab-Paclitaxel, S-1, and Oxaliplatin for Gastric Cancer with Peritoneal Metastasis (NSOX Study). Oncology 2020; 99:57-61. [PMID: 32877909 DOI: 10.1159/000509396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 06/11/2020] [Indexed: 12/30/2022]
Abstract
OBJECTIVES A regimen of S-1 combined with oxaliplatin (SOX) has been widely used as the first-line regimen for advanced gastric cancer. To further improve the antitumor efficacy for gastric cancer patients with peritoneal metastasis, we added nab-paclitaxel to the established SOX regimen (NSOX). Nab-paclitaxel (nanoparticle albumin-bound paclitaxel) has effective transferability to tumor tissues and strong antitumor effects for peritoneal metastasis. We performed a phase 1 study of this regimen to determine the maximum tolerated dose (MTD) and the recommended dose (RD) in patients with gastric cancer with peritoneal metastasis. METHODS The NSOX regimen involved 21-day cycles with escalated doses of nab-paclitaxel (50 [level 1] to 80 [level 4] mg/m2 on days 1 and 8) and fixed doses of oxaliplatin (100 mg/m2 on day 1) and S-1 (80 mg/m2/day for 2 weeks). RESULTS Six patients with gastric cancer with peritoneal metastasis were enrolled. The MTD was determined to be dose level 2, as 2 of 3 patients experienced dose-limiting toxicities (DLTs), grade 4 non-hematological toxicities. One patient experienced acute myocardial infarction, and the other patient developed jejunal perforation. There were no treatment-related deaths. No patients experienced DLTs, so the RD was determined to be dose level 1. CONCLUSIONS The NSOX regimen was shown to be a tolerable regimen and may be a promising triplet therapy for patients with gastric cancer with peritoneal metastasis.
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Affiliation(s)
- Masaki Nakamura
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan,
| | - Toshiyasu Ojima
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Masahiro Katsuda
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Keiji Hayata
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Junya Kitadani
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Mikihito Nakamori
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
| | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, Wakayama, Japan
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Yamada Y. Present status and perspective of chemotherapy for patients with unresectable advanced or metastatic gastric cancer in Japan. Glob Health Med 2020; 2:156-163. [PMID: 33330800 PMCID: PMC7731092 DOI: 10.35772/ghm.2019.01025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Revised: 03/28/2020] [Accepted: 04/10/2020] [Indexed: 05/01/2023]
Abstract
Patients with unresectable advanced or recurrent gastric cancer have a poor prognosis with overall survival times increasing by only a few months after anti-cancer drug therapy in the last four decades. The survival times from previous clinical trials for untreated metastatic gastric cancer in Japan are generally better than those reported from trials in European and North or South American countries. Therefore, the proportion of Japanese patients enrolled in recent global trials of novel anti-cancer drugs should be increased in order to identify drugs that specifically prolong the survival of such patients. S-1 plus oxaliplatin (SOX) therapy is the most commonly used standard first-line treatment for advanced gastric cancer in Japan. SOX induces mild nausea and vomiting, even in elderly patients, that can be treated by maintaining oral intake with adequate anti-emetic treatment usually given in an outpatient clinic. Neutropenia, nausea, and vomiting in SOX therapy were more frequently observed in female patients compared with males. Intensive toxic chemotherapy such as triplet therapy never prolonged overall survival or maintained a favorable quality of life. The current strategies used against metastatic gastric cancer need to be modified in regard to innovative treatments with current drugs, keeping in mind each categorized treatment population. In a real world of a diverse society even if the same treatment is performed, the outcome of the individual patient is different. It is important for each society to implement established treatment, knowing that the evidence from global trials aimed at drug approval does not necessarily show external validity.
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Affiliation(s)
- Yasuhide Yamada
- Address correspondence to:Yasuhide Yamada, Comprehensive Cancer Center, National Center for Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo 162-8655, Japan. E-mail:
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18
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Moodley T, Singh M. Sterically Stabilised Polymeric Mesoporous Silica Nanoparticles Improve Doxorubicin Efficiency: Tailored Cancer Therapy. Molecules 2020; 25:E742. [PMID: 32046364 PMCID: PMC7037074 DOI: 10.3390/molecules25030742] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 02/01/2020] [Accepted: 02/05/2020] [Indexed: 01/05/2023] Open
Abstract
The fruition, commercialisation and clinical application combining nano-engineering, nanomedicine and material science for utilisation in drug delivery is becoming a reality. The successful integration of nanomaterial in nanotherapeutics requires their critical development to ensure physiological and biological compatibility. Mesoporous silica nanoparticles (MSNs) are attractive nanocarriers due to their biodegradable, biocompatible, and relative malleable porous frameworks that can be functionalized for enhanced targeting and delivery in a variety of disease models. The optimal formulation of an MSN with polyethylene glycol (2% and 5%) and chitosan was undertaken, to produce sterically stabilized, hydrophilic MSNs, capable of efficient loading and delivery of the hydrophobic anti-neoplastic drug, doxorubicin (DOX). The pH-sensitive release kinetics of DOX, together with the anticancer, apoptosis and cell-cycle activities of DOX-loaded MSNs in selected cancer cell lines were evaluated. MSNs of 36-60 nm in size, with a pore diameter of 9.8 nm, and a cumulative surface area of 710.36 m²/g were produced. The 2% pegylated MSN formulation (PCMSN) had the highest DOX loading capacity (0.98 mgdox/mgmsn), and a sustained release profile over 72 h. Pegylated-drug nanoconjugates were effective at a concentration range between 20-50 μg/mL, inducing apoptosis in cancer cells, and affirming their potential as effective drug delivery vehicles.
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Affiliation(s)
| | - Moganavelli Singh
- Nano-Gene and Drug Delivery Group, Discipline of Biochemistry, School of Life Sciences, University of Kwa-Zulu Natal, Private Bag X54001, Durban 4000, Kwa-Zulu Natal, South Africa;
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Ku GY, Ilson DH. Cancer of the Esophagus. ABELOFF'S CLINICAL ONCOLOGY 2020:1174-1196.e6. [DOI: 10.1016/b978-0-323-47674-4.00071-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Guo X, Zhao F, Ma X, Shen G, Ren D, Zheng F, Du F, Wang Z, Ahmad R, Yuan X, Zhao J, Zhao J. A comparison between triplet and doublet chemotherapy in improving the survival of patients with advanced gastric cancer: a systematic review and meta-analysis. BMC Cancer 2019; 19:1125. [PMID: 31747911 PMCID: PMC6865072 DOI: 10.1186/s12885-019-6294-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 10/25/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Chemotherapy can improve the survival of patients with advanced gastric cancer. However, whether triplet chemotherapy can further improve the survival of patients with advanced gastric cancer compared with doublet chemotherapy remains controversial. This study reviewed and updated all published and eligible randomized controlled trials (RCTs) to compare the efficacy, prognosis, and toxicity of triplet chemotherapy with doublet chemotherapy in patients with advanced gastric cancer. METHODS RCTs on first-line chemotherapy in advanced gastric cancer on PubMed, Embase, and the Cochrane Register of Controlled Trials and all abstracts from the annual meetings of the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology conferences up to October 2018 were searched. The primary outcome was overall survival, while the secondary outcomes were progression-free survival (PFS), time to progress (TTP), objective response rate (ORR), and toxicity. RESULTS Our analysis included 23 RCTs involving 4540 patients and 8 types of triplet and doublet chemotherapy regimens, and systematic review and meta-analysis revealed that triplet chemotherapy was superior compared with doublet chemotherapy in terms of improving median OS (HR = 0.92; 95% CI, 0.86-0.98; P = 0.02) and PFS (HR = 0.82; 95% CI, 0.69-0.97; P = 0.02) and TTP (HR = 0.92; 95% CI, 0.86-0.98; P = 0.02) and ORR (OR = 1.21; 95% CI, 1.12-1.31; P < 0.0001) among overall populations. Compared with doublet chemotherapy, subgroup analysis indicated that OS improved with fluoropyrimidine-based (HR = 0.80; 95% CI, 0.66-0.96; P = 0.02), platinum-based (HR = 0.75; 95% CI, 0.57-0.99; P = 0.04), and other drug-based triplet (HR = 0.79; 95% CI, 0.69-0.90; P = 0.0006) chemotherapies while not with anthracycline-based (HR = 0.70; 95% CI, 0.42-1.15; P = 0.16), mitomycin-based (HR = 0.81; 95% CI, 0.47-1.39; P = 0.44), taxane-based (HR = 0.91; 95% CI, 0.81-1.01; P = 0.07), and irinotecan-based triplet (HR = 1.01; 95% CI, 0.82-1.24; P = 0.94) chemotherapies. For different patients, compared with doublet chemotherapy, triplet chemotherapy improved OS (HR = 0.89; 95% CI, 0.81-0.99; P = 0.03) among Western patients but did not improve (HR = 0.96; 95% CI, 0.86-1.07; P = 0.47) that among Asian patients. CONCLUSIONS Compared with doublet chemotherapy, triplet chemotherapy improved OS, PFS, TTP, and ORR in patients with advanced gastric cancer in the population overall, and improved OS in Western but not in Asian patients.
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Affiliation(s)
- Xinjian Guo
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Fuxing Zhao
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Xinfu Ma
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Guoshuang Shen
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Dengfeng Ren
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Fangchao Zheng
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
- Shouguang Hospital of Traditional Chinese Medicine, Weifang, 262700, China
- Department of Medical Oncology, Cancer hospital, Chinese academy of medical sciences, Peking Union Medical College, Beijing, 100021, China
| | - Feng Du
- Peking University Cancer Hospital and Institute, Beijing, 100142, China
| | - Ziyi Wang
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Raees Ahmad
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Xinyue Yuan
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China
| | - Junhui Zhao
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
| | - Jiuda Zhao
- Affiliated Hospital of Qinghai University, Affiliated Cancer Hospital of Qinghai University, Xining, 810000, China.
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Wang T, Wang N, Ren H, Zhou H, Zhou A, Jin J, Chen Y, Zhao D. Long-term Results of Conversion Therapy for Initially Unresectable Gastric Cancer: Analysis of 122 Patients at the National Cancer Center in China. J Cancer 2019; 10:5975-5985. [PMID: 31762807 PMCID: PMC6856572 DOI: 10.7150/jca.35527] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Accepted: 08/18/2019] [Indexed: 02/07/2023] Open
Abstract
Purpose: To assess the long-term survival and prognostic factors of conversion therapy in patients with initially unresectable gastric cancer. Patients and methods: We conducted a retrospective study of clinicopathological and survival data of 122 consecutive patients who were diagnosed with initially unresectable gastric cancer and underwent the conversion surgery after systemic chemotherapy at the China National Cancer Center between May 2006 and May 2017. Results: For all the 122 patients, the 3- and 5-year overall survival (OS) rates from the date of chemotherapy initiation were 61.0% and 52.0%, respectively, with a median OS of 63.6 months. During follow-up, the recurrence was observed in 49 (40.1%) patients who underwent conversion surgery. According to the multivariate COX regression analysis, receipt of postoperative adjuvant chemotherapy (POAC) was the only significant independent predictor of a favorable OS (HR 0.40; 95% CI 0.18-0.85, P=0.017). Log-rank analysis showed that POAC group experienced a survival advantage in terms of PFS when compared with observation group (HR 0.53, 95%CI 0.31-0.92, P=0.009). Conclusions: Conversion therapy may provide long-term survival for patients with initially unresectable gastric cancer. Postoperative adjuvant chemotherapy might be recommended for patients who underwent conversion therapy.
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Affiliation(s)
- Tongbo Wang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Nianchang Wang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hu Ren
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Hong Zhou
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Aiping Zhou
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Dongbing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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22
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Ngai LL, ter Veer E, van den Boorn HG, van Herk EH, van Kleef JJ, van Oijen MGH, van Laarhoven HWM. TOXview: a novel graphical presentation of cancer treatment toxicity profiles. Acta Oncol 2019; 58:1138-1148. [PMID: 31017020 DOI: 10.1080/0284186x.2019.1601256] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background: Toxicity profiles play a crucial role in the choice between specific palliative chemotherapy regimens. To optimize the quality of life for cancer patients, patients should be adequately informed about potential toxicities before undergoing chemotherapy. Therefore, we constructed TOXviews, a novel graphical presentation and overview of toxicity profiles to improve information provision about adverse events. As an example, we analyzed first-line chemotherapy regimens for advanced esophagogastric cancer (AEGC). Methods: We searched PubMed, EMBASE, CENTRAL, ASCO and ESMO for prospective phase II or III randomized controlled trials (RCTs) on palliative first-line systemic treatment for AEGC until February 2017. We extracted proportions of Common Terminology Criteria for Adverse Events grade 1-2 (mild) and 3-4 (severe) adverse events from each chemotherapy arm and pooled these by using single-arm meta-analysis. Toxicity profiles per chemotherapy regimen were visualized in bidirectional bar charts with pooled proportions plus 95% confidence intervals. For comparative analysis, chemotherapy regimens were grouped in singlets, doublets and triplets. Results: We included 92 RCTs with a total of 16,963 patients. TOXviews for 3 fluoropyrimidine singlets, 5 cisplatin-containing doublets (C-doublets), 10 fluoropyrimidine non-cisplatin containing doublets (F-doublets), 4 anthracycline-containing triplets (A-triplets) and 5 taxane-containing triplets (T-triplets) were constructed. C-doublets, A-triplets and T-triplets all showed an increased incidence of grade 3-4 adverse events and clinically relevant grade 1-2 adverse events compared to F-doublets. Conclusion: TOXview provides a new graphical presentation and overview of chemotherapy toxicities. TOXviews can be used to educate physicians about the incidences of AEs of systemic therapy and improve informed decision-making.
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Affiliation(s)
- Lok Lam Ngai
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Emil ter Veer
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Héctor G. van den Boorn
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - E. Hugo van Herk
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Jessy Joy van Kleef
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Martijn G. H. van Oijen
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Hanneke W. M. van Laarhoven
- Department of Medical Oncology, Cancer Centre Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
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23
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Zhang F, Zhang Y, Jia Z, Wu H, Gu K. Oxaliplatin-Based Regimen is Superior to Cisplatin-Based Regimen in Tumour Remission as First-line Chemotherapy for Advanced Gastric Cancer: A Meta-Analysis. J Cancer 2019; 10:1923-1929. [PMID: 31205551 PMCID: PMC6547983 DOI: 10.7150/jca.28896] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 01/19/2019] [Indexed: 01/20/2023] Open
Abstract
Background: This study was initially designed to examine whether oxaliplatin-based regimen was superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced gastric cancer (GC). Methods: Literature in EMBASE, PUBMED, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) was searched. Only phase II or III randomized controlled trials (RCTs) comparing the effectiveness and safety between oxaliplatin-based and cisplatin-based regimens as first-line treatment for advanced GC were selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. The primary endpoints were complete remission rate (CRR), partial remission rate (PRR), objective response rate (ORR), and disease control rate (DCR). The second endpoint was the toxicity response. Results: 2,140 patients from six phase II or III RCTs were included. Compared to cisplatin-based therapy, subjects who received oxaliplatin-based treatment had significantly higher PRR (OR: 1.25, 95%CI: 1.05-1.48, P=0.01, I2=0%), ORR (OR: 1.21, 95%CI: 1.02-1.44, P=0.03, I2=0%) and DCR (OR: 1.76, 95%CI: 1.31-2.38, P=0.0002, I2=25%), but not CRR (OR: 0.70, 95%CI: 0.37-1.31, P=0.27, I2=0%). In addition, oxaliplatin-based therapy significantly decreased all grades of leukopenia, neutropenia, anemia, febrile neutropenia, nausea, stomatitis, creatinine elevation and thromboembolism, as well as grades 3-4 of leukopenia, neutropenia, anemia and febrile neutropenia than cisplatin-based regimen. However, oxaliplatin-based treatment strikingly increased the risk of thrombocytopenia, sensory neuropathy, diarrhea, fatigue and liver dysfunction. Conclusions: Oxaliplatin-based regimen is superior to cisplatin-based regimen in tumour remission as first-line chemotherapy for advanced GC, and is associated with less toxicity and better tolerability.
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Affiliation(s)
| | | | | | | | - Kangsheng Gu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, P. R. China
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24
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Multidrug delivery system based on polysaccharide nanocomplexes for controlled delivery of a combination of chemotherapeutics. J Drug Deliv Sci Technol 2019. [DOI: 10.1016/j.jddst.2019.01.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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25
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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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26
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Zurleni T, Gjoni E, Altomare M, Rausei S. Conversion surgery for gastric cancer patients: A review. World J Gastrointest Oncol 2018; 10:398-409. [PMID: 30487951 PMCID: PMC6247102 DOI: 10.4251/wjgo.v10.i11.398] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 09/25/2018] [Accepted: 10/07/2018] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is the third most common cancer-related cause of death worldwide. In locally advanced tumors, neoadjuvant chemotherapy has recently been introduced in most international Western guidelines. For metastatic and unresectable disease, there is still debate regarding correct management and the role of surgery. The standard approach for stage IV GC is palliative chemotherapy. Over the last decade, an increasing number of M1 patients who responded to palliative regimens of induction chemotherapy have been subsequently undergone surgery with curative intent. The objective of the present review is to analyze the literature regarding this approach, known as “conversion surgery”, which has become one of the most commonly adopted therapeutic options. It is defined as a treatment aiming at an R0 resection after chemotherapy in initially unresectable tumors. The 13 retrospective studies analyzed, with a total of 411 patients treated with conversion therapy, clearly show that even if standardization of unresectable and metastatic criteria, post-chemotherapy resectability evaluation and timing of surgery has not yet been established, an R0 surgery after induction chemotherapy with partial or complete response seems to offer superior survival results than chemotherapy alone. Additional larger sample-size randomized control trials are needed to identify subgroups of well-stratified patients who could benefit from this multimodal approach.
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Affiliation(s)
- Tommaso Zurleni
- Department of Surgery, ASST Valle Olona, Busto Arsizio 21052, Italy
| | - Elson Gjoni
- Department of Surgery, ASST Valle Olona, Busto Arsizio 21052, Italy
| | - Michele Altomare
- Department of Surgery, ASST Valle Olona, Busto Arsizio 21052, Italy
| | - Stefano Rausei
- Department of Surgery, ASST Valle Olona, Gallarate. 21013, Italy
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Babu KG, Chaudhuri T, Lakshmaiah KC, Dasappa L, Jacob LA, Babu M, Rudresha AH, Lokesh KN, Rajeev LK. Efficacy and safety of first-line systemic chemotherapy with epirubicin, cisplatin plus 5-fluorouracil and docetaxel, cisplatin plus 5-fluorouracil regimens in locally advanced inoperable or metastatic gastric or gastroesophageal junction adenocarcinoma: A prospective phase II study from South India. Indian J Cancer 2018; 54:47-51. [PMID: 29199662 DOI: 10.4103/ijc.ijc_168_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Patients with locally advanced inoperable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma have a poor prognosis. The maximum benefit of systemic chemotherapy is usually achieved in the first-line setting. Even though systemic chemotherapy has been used for long time, in view of unsatisfactory results, no standard regimen has been emerged. Unfortunately, till date, there is no published prospective data from India, comparing the two most commonly used triplet regimens, epirubicin, cisplatin plus 5-fluorouracil (ECF) and docetaxel, cisplatin plus 5-fluorouracil (DCF), in this patient population. MATERIALS AND METHODS The present study aimed to compare the efficacy and safety of the first-line systemic chemotherapy with ECF and DCF regimens in locally advanced inoperable or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was overall survival (OS). The secondary endpoints were overall response rate, progression-free survival (PFS), and toxicity profile. RESULTS Between January 2015 and December 2016, 58 patients were assigned and treated with ECF (n = 30) or DCF (n = 28) regimens. The median OS was 9.4 months with ECF and 12.5 months with DCF regimen (log-rank, P = 0.000), while median PFS was 5.8 and 7.5 months, respectively (log-rank, P = 0.002). Patients in the DCF arm had more frequent reductions in chemotherapy doses than those of the ECF arm (28.6% vs. 16.7%; P = 0.54). As compared with the ECF, the DCF regimen was associated with more frequent Grades 3-4 toxicities-neutropenia (16.7% vs. 39.3%, P = 0.17), febrile neutropenia (13.3% vs. 25%, P = 0.52), mucositis (6.7% vs. 17.8%, P = 0.43), and diarrhea (6.7% vs. 14.3%, P = 0.67). CONCLUSIONS In comparison to ECF, the DCF regimen was associated with a statistically significant 3.1 months longer median OS without any significant increase in Grades 3-4 toxicities. DCF can be considered as one of the reference regimens, in properly selected patients with advanced/metastatic gastric or GEJ adenocarcinoma.
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Affiliation(s)
- K G Babu
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - T Chaudhuri
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - K C Lakshmaiah
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - L Dasappa
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - L A Jacob
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - McS Babu
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - A H Rudresha
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - K N Lokesh
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
| | - L K Rajeev
- Department of Medical Oncology, Kidwai Memorial Institute of Oncology, Bengaluru, Karnataka, India
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28
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Paclitaxel, oxaliplatin, 5-fluorouracil and leucovorin combination chemotherapy in patients with recurrent or metastatic gastric cancer. TUMORI JOURNAL 2018; 104:22-29. [PMID: 28777427 DOI: 10.5301/tj.5000665] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
PURPOSE This study evaluated the efficacy and toxicity of combination chemotherapy with paclitaxel, oxaliplatin, 5-fluorouracil and leucovorin (POFL) in patients with recurrent or metastatic gastric cancer. METHODS One hundred and thirty-eight patients with histologically confirmed recurrent or metastatic gastric adenocarcinoma were treated with the POFL regimen: paclitaxel at a dose of 135 mg/m2 as a 3-hour intravenous infusion on day 1, oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 as an intravenous infusion over 2 hours on day 1, followed by 5-fluorouracil 2,400 mg/m2 as an infusion over a 46-hour period on 3 consecutive days, in a 2-week cycle. RESULTS Twelve patients could not be evaluated for response because of the absence of any measurable lesions or early discontinuation of therapy, so responses were assessed in 126 patients. The overall objective response rate was 56.3% (95% CI, 47.5%-64.9%). The median time to progression was 6.7 months (95% CI, 5.8-7.6 months), and the median overall survival was 12.6 months (95% CI, 11.3-13.9 months). The most common grade 3 and 4 toxicities were neutropenia (50.7%), peripheral neurotoxicity (16.7%) and alopecia (27.5%). CONCLUSIONS Combination chemotherapy with POFL offers a new, active and safe approach to the treatment of recurrent or metastatic gastric cancer.
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29
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Beretta E, Di Bartolomeo M, Buzzoni R, Ferrario E, Mariani L, Gevorgyan A, Bajetta E. Irinotecan, Fluorouracil and Folinic ACID (FOLFIRI) as Effective Treatment Combination for Patients with Advanced Gastric Cancer in Poor Clinical Condition. TUMORI JOURNAL 2018; 92:379-83. [PMID: 17168428 DOI: 10.1177/030089160609200502] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Aims and Background Irinotecan (CPT-11) has been tested as a single agent in several studies, and response rates of 18-23% have been reported in first-line gastric cancer therapy. In the present study we report the safety and efficacy results combining CPT-11 with 5-fluorouracil (5-FU) and folinic acid (FA). Patients and Methods Thirty consecutive patients with metastatic gastric cancer, considered in poor clinical condition, were treated with CPT-11 and 5-FU/FA according to the FOLFIRI regimen. All enrolled cases were evaluable for toxicity and drug activity. Results The main grade 3-4 toxicity (according to the NCI-CTC criteria) was neutropenia (16%, grade 4 in 1 patient); nonhematological grade 3 toxicity consisted mainly in vomiting and diarrhea reported in 1 patient. No treatment-related serious adverse events were observed. Response was obtained in 12 patients (40%), stable disease in 2 patients (7%), while progression was documented in 16 patients (53%). Conclusions These results are very promising, and suggest that the combination of CPT-11 plus 5-FU/FA is active and well tolerated and can be considered as useful treatment in patients with metastatic gastric cancer in poor clinical condition.
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Affiliation(s)
- Elena Beretta
- Medical Oncology Unit 2, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy
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30
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Rea A, Caldarola GG, Sandomenico C, Colangelo M, Filice A, Mastroianni CM, Biamonte R, Palazzo S. De Gramont Schedule is a Very Low Toxic and Effective Regimen in Low Performance Status Patients Affected by Metastatic Gastric Cancer: Preliminary Report. TUMORI JOURNAL 2018; 88:A21-4. [PMID: 12400992 DOI: 10.1177/030089160208800473] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Summary Treatment of patients affected by metastatic gastric cancer with low performance status (PS) is a very hard choice. It is mandatory to define a very well-tolerated schedule to be employed in these subgroup of patients. Patients and Methods From June 1999 to December 2001, 21 patients (pts) affected by metastatic gastric cancer with low performance status (≥2 ECOG) were treated with bimonthly “de Gramont” schedule. Treatment was planned to perform 6 courses of chemotherapy for each patient plus other 2-4 if a response had been documented. Results A total of 161 courses of de Gramont schedule was administered to the 21 pts enrolled. We observed 8 PD (38%), 8 SD (38%), 5 objective responses (24% – 2 MR, 3 PR). Duration of objective responses (OR) was 5 months, 3 months for 3 PRs and 2 and 1 months for two MRs respectively. At time of observation (June 2002) median overall survival (OS) was 14 months, median survival from the starting de Gramont schedule was 8 months. Toxicity was very mild: grade 3 leukopenia in 1 pt, grade 1-2 anemia and piastrinopenia in 3 pts, grade 1-2 nausea vomiting in 5 pts, grade 1 diarrhea in 4 pts, grade 3 mucositis in 2 pts. No other side effect was renowned. PS ameliorated in 12 (57%) pts, even if a major response was not noted. Conclusions de Gramont schedule can be safely and effectively employed in metastatic gastric cancer pts with very low performance status.
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Affiliation(s)
- Antonio Rea
- UO Oncologia, PO Mariano Santo, Azienda Ospedaliera di Cosenza
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Krug S, Michl P. Esophageal Cancer: New Insights into a Heterogenous Disease. Digestion 2018; 95:253-261. [PMID: 28384630 DOI: 10.1159/000464130] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 02/16/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Esophageal cancer represents a heterogeneous malignancy mostly diagnosed in advanced stages. Worldwide, squamous cell carcinomas (SCCs) continue to be the most prevalent subtype; however, in the Western countries, the incidence of adenocarcinomas is increasing and will exceed that of SCC in the near future. During the last decade, several landmark trials contributed to a better understanding of the disease and emphasized the importance of multimodal treatment protocols. SUMMARY With the introduction of perioperative or neoadjuvant approaches, the survival of both subtypes of esophageal cancer has significantly improved. Several trials confirmed a survival benefit for perioperative chemotherapy or neoadjuvant chemoradiation, respectively, for patients with resectable locally advanced adenocarcinomas. However, the question of whether perioperative chemotherapy or neoadjuvant chemoradiation is more effective for the long-term survival in this population has yet to be fully elucidated. In SCCs, neoadjuvant chemoradiation followed by surgery or definitive chemoradiation in case of functional inoperability represent the preferred treatment options. Compared to neoadjuvant protocols, adjuvant chemotherapy or chemoradiation have only minor effects and are associated with enhanced toxicities. Current preclinical and clinical trials investigate efficacy and tolerability of novel drugs aiming to modulate immune check-points and dual inhibition of HER2. In this "to-the-point" article, we review the current standard and summarize the most recent and encouraging therapeutic advances in esophageal cancer. Multimodal treatment approaches for esophageal cancer should be discussed in a multidisciplinary team based on histology, tumor localization, and patient performance status. Neoadjuvant chemoradiation is beneficial for patients with locally advanced SCC and adenocarcinomas of the esophagus and the gastroesophageal junction (GEJ), with perioperative chemotherapy representing a valid alternative for GEJ adenocarcinomas. Combination therapies are indicated for metastatic adenocarcinomas, while the benefit of palliative chemotherapy in SCC remains controversial. Trastuzumab is indicated in HER2+ metastatic adenocarcinomas.
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Affiliation(s)
- Sebastian Krug
- Department of Internal Medicine I, Martin-Luther University Halle-Wittenberg, Halle, Germany
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A Phase I/II Study of Docetaxel, Oxaliplatin, and Fluorouracil (D-FOX) Chemotherapy in Patients With Untreated Locally Unresectable or Metastatic Adenocarcinoma of the Stomach and Gastroesophageal Junction. Am J Clin Oncol 2018; 41:321-325. [DOI: 10.1097/coc.0000000000000271] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Zaanan A, Samalin E, Aparicio T, Bouche O, Laurent-Puig P, Manfredi S, Michel P, Monterymard C, Moreau M, Rougier P, Tougeron D, Taieb J, Louvet C. Phase III randomized trial comparing 5-fluorouracil and oxaliplatin with or without docetaxel in first-line advanced gastric cancer chemotherapy (GASTFOX study). Dig Liver Dis 2018; 50:408-410. [PMID: 29409778 DOI: 10.1016/j.dld.2018.01.119] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/10/2017] [Accepted: 01/02/2018] [Indexed: 12/11/2022]
Abstract
INTRODUCTION In advanced gastric cancer, doublet regimen including platinum salts and fluoropyrimidine is considered as a standard first-line treatment. The addition of docetaxel (75 mg/m2 q3w) to cisplatin (75 mg/m2 q3w) and 5-fluorouracil has been shown to improve efficacy. However, this regimen (DCF) was associated with frequent severe toxicities (including more complicated neutropenia), limiting its use in clinical practice. Interesting alternative docetaxel-based regimens have been developed that need to be validated. AIM GASTFOX study is a randomized phase III trial comparing FOLFOX alone or with docetaxel at 50 mg/m2 (TFOX regimen) in first-line treatment for advanced gastric cancer. In both arms, cycle is repeated every 2 weeks until disease progression or unacceptable toxicity. MATERIALS AND METHODS Main eligibility criteria: histologically proven locally advanced or metastatic gastric or esogastric junction adenocarcinoma, HER negative status, measurable disease, ECOG performance status 0 or 1, and adequate renal, hepatic and bone marrow functions. RESULTS The primary endpoint is radiological/clinical progression-free survival (PFS). A difference of 2 months for the median PFS in favor of TFOX is expected (HR = 0.73) Based on a two-sided α risk of 5% and a power of 90%, 454 events are required to show this difference. Secondary endpoints included overall survival, overall response rate, safety, quality of life and the therapeutic index. CONCLUSION This study is planned to include 506 patients to demonstrate the superiority of TFOX over FOLFOX in first-line advanced gastric cancer treatment (NCT03006432).
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Affiliation(s)
- Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes University, Sorbonne Paris Cité, France; INSERM UMR-S1147, Centre Universitaire des Saints-Pères, Paris, France.
| | - Emmanuelle Samalin
- Digestive Oncology Department, Institut du Cancer de Montpellier, Montpellier, France
| | - Thomas Aparicio
- Departement of Gastroenterology and Digestive Oncology, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Olivier Bouche
- Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France
| | - Pierre Laurent-Puig
- INSERM UMR-S1147, Centre Universitaire des Saints-Pères, Paris, France; Department of Biology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Sylvain Manfredi
- Department of Gastroenterology and Digestive Oncology, University of Bourgogne Franche-Comté, Dijon, France
| | - Pierre Michel
- Department of Digestive Oncology, Rouen University Hospital, Rouen, France
| | | | - Marie Moreau
- Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France
| | - Philippe Rougier
- Department of Hepato-Gastroenterology and Digestive Oncology, University Hospital Hotel Dieu, Nantes, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Paris Descartes University, Sorbonne Paris Cité, France
| | - Christophe Louvet
- Department of Medical Oncology, Mutualiste Montsouris Institute, Paris, France
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Gollins S, Massalha S, Mullard A, Williams RM, Lloyd A, Morris J, Garcia-Alonso A. A Prospective Phase I/II Study of Docetaxel, Cisplatin and Continuous Capecitabine in Advanced Oesophago-Gastric Cancer (NWCOG-3). Clin Oncol (R Coll Radiol) 2018; 30:409-417. [PMID: 29573846 DOI: 10.1016/j.clon.2018.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 01/24/2018] [Indexed: 10/17/2022]
Abstract
AIMS This open-label prospective phase I/II dose-escalation study determined the maximum tolerated dose (MTD) and then evaluated response, safety and feasibility of a novel combination of docetaxel, cisplatinum and capecitabine (DCC) in chemotherapy-naive patients with advanced oesophago-gastric carcinoma. MATERIALS AND METHODS Patients with adenocarcinoma or squamous cell carcinoma of the oesophagus or stomach, of good performance status, deemed too advanced for curative treatment, were given systematically increasing doses of 3 weekly DCC to ascertain the MTD. Phase II administered up to six cycles of DCC at the MTD, assessing response and toxicity. RESULTS Between November 2007 and November 2012, 15 patients were recruited into phase I and 41 into phase II. The MDT was a 21 day cycle of docetaxel 60 mg/m2 IV day 1, cisplatinum 60 mg/m2 IV day 1 and oral capecitabine 1000 mg/m2 daily in two divided doses for days 1-21. The most common phase II grade 3-4 toxicities were neutropenia 88% (10% febrile neutropenia), fatigue 15%, sensory neuropathy 10% and non-neutropenic infection 10%. The overall response rate was 51%, median progression-free survival was 7.4 months (confidence interval 6.7-9.4) and median overall survival was 10.9 months (confidence interval 7.7-13.7). CONCLUSION DCC was tolerable and feasible with promising efficacy, and may be suitable for future investigation in both first-line metastatic and neoadjuvant settings.
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Affiliation(s)
- S Gollins
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, UK.
| | - S Massalha
- Ysbyty Gwynedd, Penrhosgarnedd, Bangor, UK
| | - A Mullard
- Ysbyty Gwynedd, Penrhosgarnedd, Bangor, UK
| | | | - A Lloyd
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, UK
| | - J Morris
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, UK
| | - A Garcia-Alonso
- North Wales Cancer Treatment Centre, Glan Clwyd Hospital, Bodelwyddan, UK
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Dai X, Zhang X, Wang C, Jiang J, Wu C. Paclitaxel/oxaliplatin/fluorouracil (TOF) regimen versus S-1/oxaliplatin (SOX) regimen for metastatic gastric cancer patients. Oncotarget 2018; 8:30495-30501. [PMID: 27911869 PMCID: PMC5444759 DOI: 10.18632/oncotarget.13721] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Accepted: 10/19/2016] [Indexed: 01/25/2023] Open
Abstract
Aims and background This study was designed to compare the efficacy and safety of paclitaxel/oxaliplatin/fluorouracil (TOF) regimen and S-1/oxaliplatin (SOX) regimen for metastatic gastric cancer (GC) patients. Methods Sixty patients were divided into TOF group and SOX groups randomly. Patients in the TOF group received paclitaxel (135 mg/m2 iv) on day 1, oxaliplatin (100 mg/m2 iv) on day 1, fluorouracil (500 mg/m2 continuous iv) on day 1-5. The patients in the SOX group received oxaliplatin (130 mg/m2 iv) on day 1 and S-1 (40 mg~60mg orally twice/day based on body surface area) on days 1-14. All the treatments were repeated every 21d for 4-6 cycles. Results The ORR and DCR of TOF group was 43.3% and 60.0%, respectively while that of SOX group was 36.7% and 56.7%. There were no statistical differences between the ORRs (?2 = 0.278) and the DCRs (?2 = 0.069) of the 2 groups. The majority of adverse events of two groups were hematological and digestive ones. Most of them were grade I and II. The adverse event rate of TOF group was higher than SOX group. The PFS times of TOF and SOX groups were 6.5 and 5.8 months, respectively. There was no statistical difference between the PFSs of the 2 groups (P = 0.451). Conclusions The efficacies of TOF and SOX regimens are similar but the safety of SOX regimen better than TOF regimen.
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Affiliation(s)
- Xichao Dai
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Clinical Medical College of Yangzhou University, Jiangsu, Yangzhou, China.,Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, China
| | - Xizhi Zhang
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Clinical Medical College of Yangzhou University, Jiangsu, Yangzhou, China
| | - Chaomin Wang
- Department of Oncology, Subei People's Hospital of Jiangsu Province, Clinical Medical College of Yangzhou University, Jiangsu, Yangzhou, China
| | - Jingting Jiang
- Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, China
| | - Changping Wu
- Department of Oncology, The Third Affiliated Hospital of Soochow University, China
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Chiesa MD, Buti S, Tomasello G, Negri F, Buononato M, Brunelli A, Lazzarelli S, Brighenti M, Donati G, Passalacqua R. A Pilot Phase ii Study of Chemotherapy with Oxaliplatin, Folinic acid, 5-Fluorouracil and Irinotecan in Metastatic Gastric Cancer. TUMORI JOURNAL 2018; 93:244-7. [PMID: 17679458 DOI: 10.1177/030089160709300303] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and background Previous phase II studies have reported that combinations of oxaliplatin, folinic acid and 5-fluorouracil or irinotecan, folinic acid and 5-fluorouracil are associated with good efficacy and an acceptable safety profile in metastatic gastric cancer. The aim of this study was to evaluate chemotherapy with oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI regimen) in metastatic gastric cancer. Methods Patients received oxaliplatin (85 mg/m2 d 1), irinotecan (140 mg/m2 d 1), and L-folinic acid (200 mg/m2 d 1) followed by 5-fluorouracil bolus (400 mg/m2 d 1) and then 5-fluorouracil (2,400 mg/m2 48-h continuous infusion), every 14 days. Results Seventeen patients with metastatic gastric cancer were enrolled. Eight patients were pretreated for advanced disease. Of the 9 chemo-naïve patients, 8 were evaluated for response (1 patient was lost to follow-up): one complete response, 5 partial responses and 2 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 67%. Of the 8 pretreated patients, 6 were evaluated for response (2 patients had nonmeasurable disease): one partial response, 2 disease stabilizations and 3 progressions of disease occurred, giving an overall response rate, at intention-to-treat analysis, of 12%. Median progression-free and overall survival in chemo-naïve patients were 8.2 and 10.2 months, respectively, and in pretreated patients 2.7 and 3 months. Grade 3-4 neutropenia occurred in 55% of chemo-naïve patients. Thrombocytopenia, and anemia were observed in 18% and 29%, respectively. Grade 3 nausea/vomiting occurred in 12% and grade 3 diarrhea in 6%. Conclusions The COFFI regimen is active and well tolerated, therefore phase III studies are warranted.
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Affiliation(s)
- Matteo Dalla Chiesa
- Medical Oncology, 2Surgery Division, Azienda Istituti Ospitalieri di Cremona, Cremona, Italy.
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Farran B, Müller S, Montenegro RC. Gastric cancer management: Kinases as a target therapy. Clin Exp Pharmacol Physiol 2018; 44:613-622. [PMID: 28271563 DOI: 10.1111/1440-1681.12743] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 02/19/2017] [Accepted: 02/20/2017] [Indexed: 12/16/2022]
Abstract
The molecular diagnostics revolution has reshaped the practice of oncology by facilitating the identification of genetic, epigenetic and proteomic modifications correlated with cancer, thus delineating 'oncomaps' for various cancer types. These advances have enhanced our understanding of gastric cancer, one of the most fatal diseases worldwide, and culminated in the approval of novel molecular therapies such as trastuzumab. Gastric tumours display recurrent aberrations in key kinase oncogenes such as Her2, epidermal growth factor receptor (EGFR), PI3K, mTOR or c-Met, suggesting that these receptors are amenable to inhibition using specific drug agents. In this review, we examine the mutational landscape of gastric cancer, the use of kinase inhibitors as targeted therapies in gastric tumours and the clinical trials underway for novel inhibitors, highlighting successes, failures and future directions.
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Affiliation(s)
- Batoul Farran
- Department of Structural and Molecular Biology, University College London, London, UK
| | - Susanne Müller
- Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Frankfurt am Main, DE, Germany
| | - Raquel C Montenegro
- Drug Research and Development Center, Federal University of Ceará, Fortaleza, CE, Brazil
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Ilson DH, van Hillegersberg R. Management of Patients With Adenocarcinoma or Squamous Cancer of the Esophagus. Gastroenterology 2018; 154:437-451. [PMID: 29037469 DOI: 10.1053/j.gastro.2017.09.048] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2017] [Revised: 09/09/2017] [Accepted: 09/12/2017] [Indexed: 02/07/2023]
Abstract
Esophageal cancer is characterized by early and frequent metastasis. Surgery is the primary treatment for early-stage disease, whereas patients with patients with locally advanced disease receive perioperative chemotherapy or chemoradiotherapy. Squamous cancers can be treated with primary chemoradiotherapy without surgery, depending on their response to therapy and patient tolerance for subsequent surgery. Chemotherapy with a fluorinated pyrimidine and a platinum agent, followed by later treatment with taxanes and irinotecan, provides some benefit. Agents that inhibit the erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2), or vascular endothelial growth factor, including trastuzumab, ramucirumab, and apatinib, increase response and survival times. Esophageal adenocarcinomas have mutations in tumor protein p53 and mutations that activate receptor-associated tyrosine kinase, vascular endothelial growth factor, and cell cycle pathways, whereas esophageal squamous tumors have a distinct set of mutations. Esophageal cancers develop systems to evade anti-tumor immune responses, but studies are needed to determine how immune checkpoint modification contributes to esophageal tumor development.
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Affiliation(s)
- David H Ilson
- Memorial Sloan Kettering Cancer Center, New York, New York.
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Sawaki A, Yamada Y, Yamaguchi K, Nishina T, Doi T, Satoh T, Chin K, Boku N, Omuro Y, Komatsu Y, Hamamoto Y, Koizumi W, Saji S, Shah MA, Van Cutsem E, Kang YK, Iwasaki J, Kuriki H, Ohtsuka W, Ohtsu A. Regional differences in advanced gastric cancer: exploratory analyses of the AVAGAST placebo arm. Gastric Cancer 2018; 21:429-438. [PMID: 29058097 PMCID: PMC5906488 DOI: 10.1007/s10120-017-0773-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Accepted: 10/06/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND AVAGAST was an international, randomized, placebo-controlled phase III study of chemotherapy with or without bevacizumab as first-line therapy for patients with advanced gastric cancer. We performed exploratory analyses to evaluate regional differences observed in the trial. METHODS Analyses were performed in the placebo plus chemotherapy arm (intention-to-treat population). Chemotherapy was cisplatin 80 mg/m2 for six cycles plus capecitabine (1000 mg/m2 orally bid days 1-14) or 5-fluorouracil (800 mg/m2/day continuous IV infusion days 1-5) every 3 weeks until disease progression or unacceptable toxicity. RESULTS Overall, 387 patients were assigned to placebo plus chemotherapy (eastern Europe/South America, n = 118; USA/western Europe, n = 81; Korea/other Asia, n = 94; Japan, n = 94). At baseline, poor performance status, liver metastases, and larger tumors were most frequent in eastern Europe/South America and least frequent in Japan. Patients received subsequent chemotherapy after disease progression as follows: eastern Europe/South America (14%); USA/western Europe (37%); Korea/other Asia (61%); and Japan (77%). Hazard ratios for overall survival versus USA/western Europe were 1.47 (95% CI, 1.09-1.99) for eastern Europe/South America, 0.91 (95% CI, 0.67-1.25) for Korea/other Asia, and 0.87 (95% CI, 0.64-1.19) for Japan. CONCLUSIONS Regional differences in the healthcare environment may have contributed to the differences in overall survival observed in the AVAGAST study.
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Affiliation(s)
- Akira Sawaki
- Aichi Cancer Center Hospital, Aichi, Japan.
- Department of Medical Oncology, School of Medicine, Fujita Health University, Toyoake, Aichi, 470-1192, Japan.
| | | | - Kensei Yamaguchi
- Saitama Cancer Center Hospital, Saitama, Japan
- Cancer Institute Hospital of JFCR, Tokyo, Japan
| | | | - Toshihiko Doi
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Taroh Satoh
- Faculty of Medicine, Kinki University Hospital, Osaka, Japan
- Osaka University Hospital, Osaka, Japan
| | - Keisho Chin
- Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Narikazu Boku
- National Cancer Center Hospital, Tokyo, Japan
- Shizuoka Cancer Center, Shizuoka, Japan
| | - Yasushi Omuro
- Tokyo Metropolitan Cancer and Infectious Disease Center, Komagome Hospital, Tokyo, Japan
| | | | | | - Wasaburo Koizumi
- Kitasato University East Hospital, Kanagawa, Japan
- Kitasato University Hospital, Tokyo, Japan
| | - Shigehira Saji
- International Medical Center, Saitama Medical University, Saitama, Japan
- Fukushima Medical University, Fukushima, Japan
| | - Manish A Shah
- Weill Cornell Medical College/New York Hospital, New York, USA
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg, Leuven and KULeuven, Louvain, Belgium
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan, Seoul, South Korea
| | | | | | | | - Atsushi Ohtsu
- National Cancer Center Hospital East, Kashiwa, Japan
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Palle J, Tougeron D, Pozet A, Soularue E, Artru P, Leroy F, Dubreuil O, Sarabi M, Williet N, Manfredi S, Martin-Babau J, Rebischung C, Abdelghani MB, Evesque L, Dreanic J, Hautefeuille V, Louafi S, Sefrioui D, Savinelli F, Mabro M, Rousseau B, Lecaille C, Bouché O, Louvet C, Lecomte T, Bonnetain F, Taieb J, Zaanan A. Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study. Oncotarget 2017; 8:101383-101393. [PMID: 29254172 PMCID: PMC5731882 DOI: 10.18632/oncotarget.20711] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Accepted: 08/05/2017] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression. METHODS This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with P values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model. RESULTS From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; P=0.002) and OS (12.6 versus 6.1 months; P=0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; P=0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; P=0.004). CONCLUSION This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.
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Affiliation(s)
- Juliette Palle
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - David Tougeron
- Department of Gastroenterology, Poitiers University Hospital, Poitiers, France
| | - Astrid Pozet
- Methodology and Quality of Life in Oncology Unit, INSERM UMR 1098, Besançon University Hospital, Besançon, France
| | - Emilie Soularue
- Department of Medical Oncology, Saint Antoine Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Pascal Artru
- Department of Gastroenterology and Digestive Oncology, Jean Mermoz Hospital, Lyon, France
| | - Florence Leroy
- Department of Cancer Medicine, Gustave Roussy Institute, Villejuif, France
| | - Olivier Dubreuil
- Department of Gastroenterology and Digestive Oncology, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Matthieu Sarabi
- Department of Medical Oncology, Léon Bérard Center, Lyon, France
| | - Nicolas Williet
- Department of Gastroenterology and Digestive Oncology, Saint-Etienne University Hospital, Saint-Priest en Jarez, France
| | - Sylvain Manfredi
- Department of Gastroenterology and Digestive Oncology, Rennes University Hospital, Rennes, France
| | | | - Christine Rebischung
- Department of Oncology, Groupe Hospitalier Mutualiste of Grenoble, Grenoble, France
| | | | - Ludovic Evesque
- Department of Oncology, Antoine Lacassagne Center, Nice, France
| | - Johann Dreanic
- Department of Gastroenterology and Digestive Oncology, Cochin Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Vincent Hautefeuille
- Department of Gastroenterology and Digestive Oncology, Amiens University Hospital, Amiens, France
| | - Samy Louafi
- Department of Oncology, Oncology Federation of Essonne, Essonne, France
| | - David Sefrioui
- Department of Digestive Oncology, Rouen University Hospital, Rouen, France
| | | | - May Mabro
- Department of Oncology, Foch Hospital, Suresnes, France
| | - Benoit Rousseau
- Department of Oncology, Henri Mondor Hospital, Assistance Publique-Hôpitaux de Paris, Créteil, France
| | - Cédric Lecaille
- Department of Gastroenterology and Digestive Oncology, Polyclinique de Bordeaux Nord, Bordeaux, France
| | - Olivier Bouché
- Department of Gastroenterology and Digestive Oncology, Reims University Hospital, Reims, France
| | - Christophe Louvet
- Department of Medical Oncology, Mutualiste Montsouris Institute, Paris, France
| | - Thierry Lecomte
- Department of Gastroenterology and Digestive Oncology, Trousseau University Hospital, Tours, France
| | - Franck Bonnetain
- Methodology and Quality of Life in Oncology Unit, INSERM UMR 1098, Besançon University Hospital, Besançon, France
| | - Julien Taieb
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Aziz Zaanan
- Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
- Paris Descartes University, Sorbonne Paris Cité, Paris, France
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Wagner AD, Syn NLX, Moehler M, Grothe W, Yong WP, Tai B, Ho J, Unverzagt S. Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev 2017; 8:CD004064. [PMID: 28850174 PMCID: PMC6483552 DOI: 10.1002/14651858.cd004064.pub4] [Citation(s) in RCA: 403] [Impact Index Per Article: 50.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Gastric cancer is the fifth most common cancer worldwide. In "Western" countries, most people are either diagnosed at an advanced stage, or develop a relapse after surgery with curative intent. In people with advanced disease, significant benefits from targeted therapies are currently limited to HER-2 positive disease treated with trastuzumab, in combination with chemotherapy, in first-line. In second-line, ramucirumab, alone or in combination with paclitaxel, demonstrated significant survival benefits. Thus, systemic chemotherapy remains the mainstay of treatment for advanced gastric cancer. Uncertainty remains regarding the choice of the regimen. OBJECTIVES To assess the efficacy of chemotherapy versus best supportive care (BSC), combination versus single-agent chemotherapy and different chemotherapy combinations in advanced gastric cancer. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials, MEDLINE and Embase up to June 2016, reference lists of studies, and contacted pharmaceutical companies and experts to identify randomised controlled trials (RCTs). SELECTION CRITERIA We considered only RCTs on systemic, intravenous or oral chemotherapy versus BSC, combination versus single-agent chemotherapy and different chemotherapy regimens in advanced gastric cancer. DATA COLLECTION AND ANALYSIS Two review authors independently identified studies and extracted data. A third investigator was consulted in case of disagreements. We contacted study authors to obtain missing information. MAIN RESULTS We included 64 RCTs, of which 60 RCTs (11,698 participants) provided data for the meta-analysis of overall survival. We found chemotherapy extends overall survival (OS) by approximately 6.7 months more than BSC (hazard ratio (HR) 0.3, 95% confidence intervals (CI) 0.24 to 0.55, 184 participants, three studies, moderate-quality evidence). Combination chemotherapy extends OS slightly (by an additional month) versus single-agent chemotherapy (HR 0.84, 95% CI 0.79 to 0.89, 4447 participants, 23 studies, moderate-quality evidence), which is partly counterbalanced by increased toxicity. The benefit of epirubicin in three-drug combinations, in which cisplatin is replaced by oxaliplatin and 5-FU is replaced by capecitabine is unknown.Irinotecan extends OS slightly (by an additional 1.6 months) versus non-irinotecan-containing regimens (HR 0.87, 95% CI 0.80 to 0.95, 2135 participants, 10 studies, high-quality evidence).Docetaxel extends OS slightly (just over one month) compared to non-docetaxel-containing regimens (HR 0.86, 95% CI 0.78 to 0.95, 2001 participants, eight studies, high-quality evidence). However, due to subgroup analyses, we are uncertain whether docetaxel-containing combinations (docetaxel added to a single-agent or two-drug combination) extends OS due to moderate-quality evidence (HR 0.80, 95% CI 0.71 to 0.91, 1466 participants, four studies, moderate-quality evidence). When another chemotherapy was replaced by docetaxel, there is probably little or no difference in OS (HR 1.05; 0.87 to 1.27, 479 participants, three studies, moderate-quality evidence). We found there is probably little or no difference in OS when comparing capecitabine versus 5-FU-containing regimens (HR 0.94, 95% CI 0.79 to 1.11, 732 participants, five studies, moderate-quality evidence) .Oxaliplatin may extend (by less than one month) OS versus cisplatin-containing regimens (HR 0.81, 95% CI 0.67 to 0.98, 1105 participants, five studies, low-quality evidence). We are uncertain whether taxane-platinum combinations with (versus without) fluoropyrimidines extend OS due to very low-quality evidence (HR 0.86, 95% CI 0.71 to 1.06, 482 participants, three studies, very low-quality evidence). S-1 regimens improve OS slightly (by less than an additional month) versus 5-FU-containing regimens (HR 0.91, 95% CI 0.83 to 1.00, 1793 participants, four studies, high-quality evidence), however since S-1 is used in different doses and schedules between Asian and non-Asian population, the applicability of this finding to individual populations is uncertain. AUTHORS' CONCLUSIONS Chemotherapy improves survival (by an additional 6.7 months) in comparison to BSC, and combination chemotherapy improves survival (by an additional month) compared to single-agent 5-FU. Testing all patients for HER-2 status may help to identify patients with HER-2-positive tumours, for whom, in the absence of contraindications, trastuzumab in combination with capecitabine or 5-FU in combination with cisplatin has been shown to be beneficial. For HER-2 negative people, all different two-and three-drug combinations including irinotecan, docetaxel, oxaliplatin or oral 5-FU prodrugs are valid treatment options for advanced gastric cancer, and consideration of the side effects of each regimen is essential in the treatment decision. Irinotecan-containing combinations and docetaxel-containing combinations (in which docetaxel was added to a single-agent or two-drug (platinum/5-FUcombination) show significant survival benefits in the comparisons studied above. Furthermore, docetaxel-containing three-drug regimens have increased response rates, but the advantages of the docetaxel-containing three-drug combinations (DCF, FLO-T) are counterbalanced by increased toxicity. Additionally, oxaliplatin-containing regimens demonstrated a benefit in OS as compared to the same regimen containing cisplatin, and there is a modest survival improvement of S-1 compared to 5-FU-containing regimens.Whether the survival benefit for three-drug combinations including cisplatin, 5-FU, and epirubicin as compared to the same regimen without epirubicin is still valid when second-line therapy is routinely administered and when cisplatin is replaced by oxaliplatin and 5-FU by capecitabine is questionable. Furthermore, the magnitude of the observed survival benefits for the three-drug regimens is not large enough to be clinically meaningful as defined recently by the American Society for Clinical Oncology (Ellis 2014). In contrast to the comparisons in which a survival benefit was observed by adding a third drug to a two-drug regimen at the cost of increased toxicity, the comparison of regimens in which another chemotherapy was replaced by irinotecan was associated with a survival benefit (of borderline statistical significance), but without increased toxicity. For this reason irinotecan/5-FU-containing combinations are an attractive option for first-line treatment. Although they need to be interpreted with caution, subgroup analyses of one study suggest that elderly people have a greater benefit form oxaliplatin, as compared to cisplatin-based regimens, and that people with locally advanced disease or younger than 65 years might benefit more from a three-drug regimen including 5-FU, docetaxel, and oxaliplatin as compared to a two-drug combination of 5-FU and oxaliplatin, a hypothesis that needs further confirmation. For people with good performance status, the benefit of second-line chemotherapy has been established in several RCTs.
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Affiliation(s)
- Anna Dorothea Wagner
- Lausanne University Hospitals and ClinicsDepartment of OncologyRue du Bugnon 46LausanneSwitzerland1011
| | - Nicholas LX Syn
- National University Cancer InstituteDepartment of Haematology‐Oncology1E Kent Ridge RoadNUHS Tower Block, Level 7SingaporeSingapore119228
| | - Markus Moehler
- University Medical Center of the Johannes Gutenberg UniversityDepartment of Internal MedicineLangenbeckstrasse 1MainzGermany55131
| | - Wilfried Grothe
- Martin‐Luther‐University Halle‐WittenbergDepartment of Internal Medicine IErnst‐Grube‐Str. 40Halle/SaaleGermany06097
| | - Wei Peng Yong
- National University Cancer InstituteDepartment of Haematology‐Oncology1E Kent Ridge RoadNUHS Tower Block, Level 7SingaporeSingapore119228
| | - Bee‐Choo Tai
- National University of SingaporeSaw Swee Hock School of Public Health12 Science Drive 2#10‐03FSingaporeSingapore117549
| | - Jingshan Ho
- National University Cancer InstituteDepartment of Haematology‐Oncology1E Kent Ridge RoadNUHS Tower Block, Level 7SingaporeSingapore119228
| | - Susanne Unverzagt
- Martin‐Luther‐University Halle‐WittenbergInstitute of Medical Epidemiology, Biostatistics and InformaticsMagdeburge Straße 8Halle/SaaleGermany06097
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Abstract
OPINION STATEMENT Two cycles of neoadjuvant cisplatin and fluoropyrimidine (CF) and 6 cycles of perioperative CF with or without epirubicin are an evidence-based approach in operable esophageal and esophagogastric junctional adenocarcinomas. Three-drug regimens with anthracycline or taxane are associated with significantly higher tumor regression rates, with an expected increase in toxicity. In order to achieve an R0 resection and consequently a survival advantage, in selected patients having a risk of a threatened margin or incomplete resection, chemotherapy might be continued beyond 2 cycles if a response has been demonstrated. In metastatic setting, multidrug combination regimens have demonstrated a significant survival benefit when compared to single-agent regimes. A three-drug regimen should be considered for fit patients and/or when a response is required for symptom control. The expected increase in toxicity needs to be carefully considered and discussed with patients. The choice to use a taxane in first-line setting may limit the options of second-line treatment to irinotecan-containing regimens and also precludes the use of anthracyclines in the first line. For this reason, we prefer to reserve taxane-based therapy for the second-line setting.
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Haag GM, Stocker G, Quidde J, Jaeger D, Lordick F. Randomized controlled trial of S-1 maintenance therapy in metastatic esophagogastric cancer - the multinational MATEO study. BMC Cancer 2017; 17:509. [PMID: 28760152 PMCID: PMC5537937 DOI: 10.1186/s12885-017-3497-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 07/23/2017] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The optimal duration of firstline chemotherapy in metastatic esophagogastric cancer is unknown. In most clinical trials therapy was given until tumour progression or limiting toxicity. Maintenance concepts aiming to prolong the duration of response and maintain quality of life have been established in other tumour types but not in esophagogastric cancer. S-1 is an oral fluoropyrimidine with proven efficacy in metastatic esophagogastric cancer. METHODS The Maintenance Teysuno® (S-1) in esophagogastric cancer (MATEO) trial is a multinational, randomized phase II study that explores the role of S-1 maintenance therapy in Her-2 negative, advanced esophagogastric adenocarcinoma. After a 12-week firstline platinum-fluoropyrimidine-based chemotherapy patients without tumour progression are randomized in a 2:1 allocation to receive S-1 alone or continue with the same regimen as during the primary period. The primary endpoint is overall survival. Secondary endpoints include safety and toxicity, progression-free survival and quality of life. Correlative biomarker analyses focus on the identification of a subgroup of patients with a prolonged benefit from S-1 based maintenance therapy. DISCUSSION MATEO will be the first trial to define the role of a S-1 based maintenance therapy in patients having received a platinum-based firstline chemotherapy. TRIAL REGISTRATION NCT02128243 (date of registration: 29-04-2014).
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Affiliation(s)
- Georg-Martin Haag
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, D-69120, Heidelberg, Germany.
| | - Gertraud Stocker
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Liebigstrasse 20, D-04103, Leipzig, Germany
| | - Julia Quidde
- II. Department of Internal Medicine (Oncology/Haematology), University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246, Hamburg, Germany
| | - Dirk Jaeger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 460, D-69120, Heidelberg, Germany
| | - Florian Lordick
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Liebigstrasse 20, D-04103, Leipzig, Germany
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Duo-Ji MM, Ci-Ren BS, Long ZW, Zhang XH, Luo DL. Short-term efficacy of different chemotherapy regimens in the treatment of advanced gastric cancer: a network meta-analysis. Oncotarget 2017; 8:37896-37911. [PMID: 28099947 PMCID: PMC5514960 DOI: 10.18632/oncotarget.14664] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 11/14/2016] [Indexed: 01/13/2023] Open
Abstract
OBJECTIVE A network meta-analysis was performed to compare the short-term efficacy of different chemotherapy regimens in the treatment of advanced gastric cancer. METHODS Randomized controlled trials of different chemotherapy regimens for advanced gastric cancer were included in this study. Network meta-analysis combined direct evidence and indirect evidence to evaluate the odds ratio and draw surface under the cumulative ranking curves of different chemotherapy regimens in advanced gastric cancer. RESULTS The results of surface under the cumulative ranking curves showed that S-1 and capecitabine regimens were better than fluorouracil. As for multi-drug combination regimens, the disease control rate of cisplatin + capecitabine, docetaxel + cisplatin + fluorouracil and etoposide + cisplatin + capecitabine regimens were relatively better, while fluorouracil + adriamycin + mitomycin regimen was relatively poorer when compared with cisplatin + fluorouracil regimen. Additionally, the overall response ratio of cisplatin + capecitabine, paclitaxel + fluorouracil, docetaxel + cisplatin + fluorouracil and etoposide + cisplatin + fluorouracil regimens were relatively better, while the disease control rate of fluorouracil + adriamycin + mitomycin regimen was relatively poorer when compared with cisplatin + fluorouracil regimen. Furthermore, the results of cluster analysis demonstrated that cisplatin + capecitabine, etoposide + cisplatin + capecitabine, S-1 + paclitaxel and S-1 + irinotecan chemotherapy regimens had better disease control rate and overall response ratio for advanced gastric cancer patients. CONCLUSION This network meta-analysis clearly showed that multi-drug combination chemotherapy regimens based on capecitabine and S-1 might be the best chemotherapy regimen for advanced gastric cancer.
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Affiliation(s)
- Mi-Ma Duo-Ji
- Department of Medicine, Shigatse People's Hospital, Shigatse 857000, P.R. China
| | - Ba-Sang Ci-Ren
- Department of Medicine, Shigatse People's Hospital, Shigatse 857000, P.R. China
| | - Zi-Wen Long
- Department of Gastric Cancer and Soft-Tissue Sarcoma Sugery, Fudan University Shanghai Cancer Center, Shanghai 200032, P.R. China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China
| | - Xiao-Hua Zhang
- Department of Medicine, Shigatse People's Hospital, Shigatse 857000, P.R. China
| | - Dong-Lin Luo
- Department of Medicine, Shigatse People's Hospital, Shigatse 857000, P.R. China
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Takahari D. Second-line chemotherapy for patients with advanced gastric cancer. Gastric Cancer 2017; 20:395-406. [PMID: 28260227 DOI: 10.1007/s10120-017-0707-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/22/2017] [Indexed: 02/07/2023]
Abstract
The first choice for treating patients with metastatic gastric cancer is chemotherapy, and combination therapy with fluorouracil, platinum, and trastuzumab has been established as the standard first-line chemotherapy. For further improvement of treatment outcomes, it is important to develop second- and third-line chemotherapy. In the first decade of this century, irinotecan and taxanes, cytotoxic agents, and various molecular targeted agents began to be developed as second-line therapy. Treatment with paclitaxcel weekly in combination with ramucirumab targeting vascular endothelial growth factor receptor 2 has become the first choice for second-line therapy. Immune checkpoint inhibitors are now being developed, and the current treatment strategies for advanced gastric cancer may undergo major changes in the future. This review summarizes the transitions and future prospects of clinical developments for second-line therapy in patients with advanced gastric cancer.
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Affiliation(s)
- Daisuke Takahari
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.
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Qu D, Wang L, Liu M, Shen S, Li T, Liu Y, Huang M, Liu C, Chen Y, Mo R. Oral Nanomedicine Based on Multicomponent Microemulsions for Drug-Resistant Breast Cancer Treatment. Biomacromolecules 2017; 18:1268-1280. [PMID: 28350158 DOI: 10.1021/acs.biomac.7b00011] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Affiliation(s)
- Ding Qu
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Lixiang Wang
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Meng Liu
- State
Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of
Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals
and Biomaterials and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Shiyang Shen
- State
Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of
Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals
and Biomaterials and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Teng Li
- State
Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of
Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals
and Biomaterials and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
| | - Yuping Liu
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Mengmeng Huang
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Congyan Liu
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Yan Chen
- Affiliated
Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China
- Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing 210028, China
| | - Ran Mo
- State
Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of
Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals
and Biomaterials and Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China
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Harada K, Mizrak Kaya D, Shimodaira Y, Ajani JA. Global chemotherapy development for gastric cancer. Gastric Cancer 2017; 20:92-101. [PMID: 27718136 DOI: 10.1007/s10120-016-0655-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 09/28/2016] [Indexed: 02/07/2023]
Abstract
To combat the dismal mortality rates from metastatic gastric adenocarcinoma (GAC), new drugs and treatment strategies are needed. Today, metastatic GAC is predominantly treated by empiric chemotherapy. Combination of two cytotoxic agents has become commonplace in North America, Europe, and Asia. Human epidermal growth factor 2 (HER2) overexpression (protein or gene copy numbers) has resulted in the addition of trastuzumab in the first-line chemotherapy combination in patients whose tumor is HER2 positive. The addition of trastuzumab in this select population has provided a modest survival advantage. In this review we trace the global development of systemic therapy in patients with metastatic GAC and ponder what lies in the future.
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Affiliation(s)
- Kazuto Harada
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Dilsa Mizrak Kaya
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Yusuke Shimodaira
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd (FC10.3022), Houston, TX, 77030, USA.
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Caglevic C, Silva S, Mahave M, Rolfo C, Gallardo J. The current situation for gastric cancer in Chile. Ecancermedicalscience 2016; 10:707. [PMID: 28105078 PMCID: PMC5221643 DOI: 10.3332/ecancer.2016.707] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer is a neoplasm with a high incidence and mortality rate in Chile where more than 3000 people die every year from this type of cancer. This study shows the clinical and epidemiological considerations of this disease, information about translational research on this pathology in Chile, the contribution of Chilean doctors to the development of gastric cancer management awareness and the general situation of gastric cancer in Chile.
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Affiliation(s)
- Christian Caglevic
- Cancer Drug Research Unit, Fundación Arturo López Pérez, Santiago, Chile; Instituto Oncológico Fundación Arturo López Pérez, Rancagua 878, Providencia Santiago, Chile
| | - Shirley Silva
- Radiation Oncology, University of Valparaíso, Valparaíso, Chile; Instituto Oncológico Fundación Arturo López Pérez, Rancagua 878, Providencia Santiago, Chile
| | - Mauricio Mahave
- Medical Oncology Service, Fundación Arturo López Pérez, Santiago, Chile; Instituto Oncológico Fundación Arturo López Pérez, Rancagua 878, Providencia Santiago, Chile
| | - Christian Rolfo
- Early Drug Development Unit - Phase I, University Hospital of Antwerp, Antwerp, Belgium; Instituto Oncológico Fundación Arturo López Pérez, Rancagua 878, Providencia Santiago, Chile
| | - Jorge Gallardo
- Fundación Chilena Desarrollo Oncología, SLAGO (Latin American Symposium on Oncological Gastroenterology), Santiago, Chile.; Instituto Oncológico Fundación Arturo López Pérez, Rancagua 878, Providencia Santiago, Chile
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Fan P, Wang Q, Lu C, Chen D. Generalized high bone mineral density on bone density scanning: a case of gastric carcinoma with bone metastasis. Postgrad Med 2016; 129:299-303. [PMID: 27849427 DOI: 10.1080/00325481.2017.1261607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Generalized high bone mineral density (BMD) on Dual-energy X-ray absorptiometry (DXA) scanning most commonly reflects metabolic bone disease. However, some malignancies could also stimulate the underlying processes. We reported that a 41-year-old female was referred for lumbago. She did not complain of any symptoms in the digestive system. DXA revealed high BMD in the lumbar vertebras. Marked increase in bone mass was observed in an X-ray of chest compared with one conducted 6 months previously. Additionally, an X-ray of the axial skeleton showed diffuse sclerotic change. Laboratory data revealed hypocalcemia and high osteoblastic activity. A bone biopsy of the pelvis confirmed metastatic undifferentiated adenocarcinoma. Further research for the primary site revealed gastric signet ring cell carcinoma via endoscopic biopsy. The patient refused treatment and died 2 months after the diagnosis. In clinical practice, high BMD could be the initial feature of gastric cancer. Due to its poor prognosis, adequate clinical management is of paramount value.
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Affiliation(s)
- Pianpian Fan
- a Department of Endocrinology , West China Hospital of Sichuan University , Chengdu , Sichuan , PR China
| | - Qin Wang
- a Department of Endocrinology , West China Hospital of Sichuan University , Chengdu , Sichuan , PR China
| | - Chunyan Lu
- a Department of Endocrinology , West China Hospital of Sichuan University , Chengdu , Sichuan , PR China
| | - Decai Chen
- a Department of Endocrinology , West China Hospital of Sichuan University , Chengdu , Sichuan , PR China
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Ter Veer E, Haj Mohammad N, van Valkenhoef G, Ngai LL, Mali RMA, Anderegg MC, van Oijen MGH, van Laarhoven HWM. The Efficacy and Safety of First-line Chemotherapy in Advanced Esophagogastric Cancer: A Network Meta-analysis. J Natl Cancer Inst 2016; 108:djw166. [PMID: 27576566 DOI: 10.1093/jnci/djw166] [Citation(s) in RCA: 84] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Accepted: 05/27/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND A globally accepted standard first-line chemotherapy regimen in advanced esophagogastric cancer (AEGC) is not clearly established. We conducted a systematic review to investigate the efficacy and safety of first-line chemotherapy using Network meta-analysis (NMA). METHODS Medline, EMBASE, CENTRAL, and conferences were searched until June 2015 for randomized controlled trials that compared regimens containing: fluoropyrimidine (F), platinum (cisplatin [C] and oxaliplatin [Ox]), taxane (T), anthracycline (A), irinotecan (I), or methotrexate (M). Direct and indirect evidence for overall survival (OS) and progression-free-survival (PFS) were combined using random-effects NMA on the hazard ratio (HR) scale and calculated as combined hazard ratios and 95% credible intervals (CrIs). RESULTS The NMA incorporated 17 chemotherapy regimens with 37 direct comparisons between regimens for OS (50 studies, n = 10 249) and 29 direct comparisons for PFS (34 studies, n = 7795). Combining direct and indirect effects showed increased efficacy for fluoropyrimidine noncisplatin doublets (F-doublets) over cisplatin doublets (C-doublets): FI vs CF (combined HR = 0.85, 95% CrI = 0.71 to 0.99), FOx vs CF (combined HR = 0.83, 95% CrI = 0.71 to 0.98) in OS and FOx vs CF (combined HR = 0.82, 95% CrI = 0.66 to 0.99) in PFS. Anthracycline-containing triplets (A-triplets: ACF, AFOx, AFM) and TCF triplet showed no benefit over F-doublets in OS and PFS. The triplet FOxT showed increased PFS vs F-doublets FT (combined HR = 0.61, 95% CrI = 0.38 to 0.99), FI (combined HR = 0.62, 95% CrI = 0.38 to 0.99), and FOx (combined HR = 0.67, 95% CrI = 0.44 to 0.99). Increased grade 3 to 4 toxicity was found for CF vs F-doublets, for ACF vs FI for TCF vs CF, and for FOxT vs FOx. CONCLUSIONS Based on efficacy and toxicity, F-doublets FOx, FI, and FT are preferred as first-line treatment for AEGC compared with C-doublets, A-triplets, and TCF. FOxT is the most promising triplet.
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Affiliation(s)
- Emil Ter Veer
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Nadia Haj Mohammad
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Gert van Valkenhoef
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Lok Lam Ngai
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Rosa M A Mali
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Maarten C Anderegg
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Martijn G H van Oijen
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
| | - Hanneke W M van Laarhoven
- Affiliations of author: Department of Medical Oncology (EtV, NHM, LLN, RM, MGHvO, HWMvL) and Department of Surgery (MCA), Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands; Department of Epidemiology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands (GvV)
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