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Chen T, Xu M, Xu J, Zhan X, Zhang Y, Ying M, Wu M. The application of immunotherapy combined with taxanes in second‑line treatment of advanced HER2 negative gastric cancer. Mol Clin Oncol 2025; 22:11. [PMID: 39640912 PMCID: PMC11618035 DOI: 10.3892/mco.2024.2806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
Human epidermal growth factor receptor-2 (HER2) negative advanced gastric cancer (GC) has a high global incidence and mortality rate with limited options for second-line treatment. Monotherapy is not effective and the combination of chemotherapy and immunotherapy has not yet been included in the guidelines. The present study aimed to explore a new treatment approach by conducting a single-center, retrospective, observational real-world study. A total of 21 patients with advanced HER2-negative GC, who had progressed after receiving standard first-line regimens [tegafur, gimeracil and oteracil potassium capsules (S-1) or capecitabine plus oxaliplatin], were selected. The application of programmed cell death-1 (PD-1) inhibitor combined with taxanes was selected as the second-line treatment. The primary outcomes measured were progression-free survival (PFS), pathological complete response, objective response rate (ORR), disease control rate (DCR) and adverse reactions in the present patient cohort. The median (m)PFS in the overall population was 7.1 months, with a 95% confidence interval (CI) of 6.0-8.2 months and the median overall survival (mOS) was 11.3 months, with a 95% CI of 4.5-18.2 months. The ORR was 9.5% and the DCR was 90.5%. Univariate and multivariate analyses indicated that Ki67 <70% and tumor marker-positive status [one or two increases among carcinoembryogenic antigen (CEA), cancer antigen (CA) 199 and CA125] were independent prognostic factors for PFS and overall survival (OS) in second-line treatment. Significant statistical differences were noted in PFS (mPFS=5.3 months, 95% CI: 3.1-7.5 months vs. mPFS=9.1 months, 95% CI: 6.2-12.0 months; P=0.002) and OS (mOS=8.8 months, 95% CI: 7.0-10.7 months vs. mOS=17.2 months, 95% CI: 16.0-18.5 months; P=0.013) between the Ki67-high group (Ki67 ≥70%) and the Ki67-low group (Ki67 <70%). Significant statistical differences were noted in OS between tumor marker-negative status (CEA, CA199 and CA125 within normal range) and tumor marker-positive status (one or two increases among CEA, CA199 and CA125; mOS=17.2 months, 95% CI: 16.0-18.4 months vs. mOS=8.8 months, 95% CI: 5.3-12.4 months; P=0.018); however, no significant differences were noted in PFS between these two groups. The present study retrospectively analyzed the new second-line approach of PD-1 inhibitor combined with taxanes for HER2 negative GC which effectively improved patient PFS and OS compared with single-agent chemotherapy. The expression levels of Ki67 and the tumor marker-negative status possess potential clinical value in monitoring prognosis and guiding future individualized use of chemotherapy combined with immunotherapy.
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Affiliation(s)
- Tianran Chen
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Meng Xu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Jiajun Xu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Xianbao Zhan
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Yingyi Zhang
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Mingzhen Ying
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Meihong Wu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
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Guo M, Zhao W, Chen Y, Zou D, Peng W, Sha H, Zhou G, Fang Y, Shen B. Efficacy of rechallenge after first-line immunotherapy for advanced gastric cancer: A retrospective real-world study. Hum Vaccin Immunother 2024; 20:2423479. [PMID: 39494935 PMCID: PMC11540071 DOI: 10.1080/21645515.2024.2423479] [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: 07/19/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024] Open
Abstract
We aimed to explore the efficacy of rechallenge after first-line immunotherapy in advanced gastric cancer (AGC) and to analyze the factors affecting prognosis based on clinical characteristics. Eighty-five AGC patients who underwent rechallenged after the failure of first-line treatment with immune checkpoint inhibitors (ICIs) were retrospectively collected from July 2019 to December 2022 in Jiangsu Cancer Hospital. Potential factors affecting prognosis were analyzed by univariate and multivariate Cox analysis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Stratified factors included human epidermal growth factor receptor 2 (HER-2) and programmed cell death-ligand 1 combined positive score (PD-L1 CPS). The objective response rate (ORR) was 15.3%, and the disease control rate (DCR) was 74.1%. The median progression-free survival (PFS) was 4.8 months. Results showed that patients in the I + C group had the best response. The ORR was 20.0% VS 8.7% in the I + C group and I + C + AAD group. The DCR was 78.0% VS 65.2%, and the median PFS was 6.7 VS 4.7 months [hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.30-1.00, p = .022]. The ORR was 20.0% VS 8.3% in the I + C group and I + C + ADC group. The DCR was 78.0% VS 75.0%, and the median PFS was 6.7 VS 4.4 months (HR: 0.59, 95%CI: 0.26-1.30, p = .112). The median PFS was 4.7 VS 4.4 months in the I + C + AAD group and I + C + ADC group (HR: 1.21, 95%CI: 0.60-2.47, p = .580). Adverse events (AEs) were found in 34 patients, mainly including leukopenia 9 (10.6%), and neutropenia 8 (9.4%). The incidence of grade 3-4 AEs was 8.2%. There were no drug-related deaths and all AEs were manageable. Rechallenge after first-line immunotherapy showed good survival benefit and acceptable safety in the therapy of AGC. Especially for patients with HER-2-positive and PD-L1 CPS ≥ 1%, rechallenge may be an effective treatment modality.
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Affiliation(s)
- Mengya Guo
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenhui Zhao
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Chen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan Zou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiwei Peng
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huanhuan Sha
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoren Zhou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | | | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Li Z, Xu R, Sun P. Gastric transcatheter chemoembolization combined with systemic chemotherapy vs. systemic chemotherapy alone for patients with advanced gastric cardiac cancer presenting with dysphagia: A case control study. Oncol Lett 2024; 28:367. [PMID: 38933810 PMCID: PMC11200157 DOI: 10.3892/ol.2024.14500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Accepted: 05/17/2024] [Indexed: 06/28/2024] Open
Abstract
The present study aimed to assess the effectiveness of gastric transcatheter chemoembolization (GTC) combined with systemic chemotherapy (SYS) compared with SYS alone in managing dysphagia, and improving the quality of life (QoL) and nutritional status of patients with advanced gastric cardiac cancer (AGCC). A retrospective review was performed using data from consecutive patients with AGCC who experienced dysphagia and underwent either SYS alone or SYS combined with GTC from January 2018 to December 2022. Propensity score matching (PSM) analysis was performed to address potential confounding factors. Ogilvie dysphagia scores were used to assess dysphagia, the Functional Assessment of Cancer Therapy-General 7 (FACT-G7) was used to assess QoL, and the Patient-Generated Subjective Global Assessment (PG-SGA) was used to evaluate nutritional status. After PSM, a total of 228 patients were included in the analysis, with 114 in each group. At 4 and 8 weeks after the initial treatment, the GTC + SYS group demonstrated significantly lower median Ogilvie scores compared with the SYS alone group (P<0.001). Similarly, the median PG-SGA score at 4 weeks after the initial treatment was 2.0 in the GTC + SYS group and 6.0 in the SYS alone group. The median FACT-G7 scores in the GTC + SYS group was 13.0, compared with 10.5 in the SYS alone group. These differences remained significant at 8 weeks (P<0.001). In conclusion, the addition of GTC to SYS may more effectively and promptly relieve dysphagia, improve nutritional status and enhance QoL compared with SYS alone in patients with AGCC presenting with dysphagia.
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Affiliation(s)
- Zhenfeng Li
- Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Ran Xu
- Department of Medical Imaging, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Peng Sun
- Department of Intervention Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
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Wang F, Zhang X, Tang L, Wu Q, Cai M, Li Y, Qu X, Qiu H, Zhang Y, Ying J, Zhang J, Sun L, Lin R, Wang C, Liu H, Qiu M, Guan W, Rao S, Ji J, Xin Y, Sheng W, Xu H, Zhou Z, Zhou A, Jin J, Yuan X, Bi F, Liu T, Liang H, Zhang Y, Li G, Liang J, Liu B, Shen L, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2023. Cancer Commun (Lond) 2024; 44:127-172. [PMID: 38160327 PMCID: PMC10794017 DOI: 10.1002/cac2.12516] [Citation(s) in RCA: 63] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 12/17/2023] [Accepted: 12/18/2023] [Indexed: 01/03/2024] Open
Abstract
The 2023 update of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for Gastric Cancer focuses on standardizing cancer diagnosis and treatment in China, reflecting the latest advancements in evidence-based medicine, healthcare resource availability, and precision medicine. These updates address the differences in epidemiological characteristics, clinicopathological features, tumor biology, treatment patterns, and drug selections between Eastern and Western gastric cancer patients. Key revisions include a structured template for imaging diagnosis reports, updated standards for molecular marker testing in pathological diagnosis, and an elevated recommendation for neoadjuvant chemotherapy in stage III gastric cancer. For advanced metastatic gastric cancer, the guidelines introduce new recommendations for immunotherapy, anti-angiogenic therapy and targeted drugs, along with updated management strategies for human epidermal growth factor receptor 2 (HER2)-positive and deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) patients. Additionally, the guidelines offer detailed screening recommendations for hereditary gastric cancer and an appendix listing drug treatment regimens for various stages of gastric cancer. The 2023 CSCO Clinical Guidelines for Gastric Cancer updates are based on both Chinese and international clinical research and expert consensus to enhance their applicability and relevance in clinical practice, particularly in the heterogeneous healthcare landscape of China, while maintaining a commitment to scientific rigor, impartiality, and timely revisions.
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Affiliation(s)
- Feng‐Hua Wang
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiao‐Tian Zhang
- Department of Gastrointestinal OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Lei Tang
- Department of RadiologyPeking University Cancer HospitalBeijingP. R. China
| | - Qi Wu
- Department of Endoscopy CenterPeking University Cancer HospitalBeijingP. R. China
| | - Mu‐Yan Cai
- Department of PathologySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Yuan‐Fang Li
- Department of Gastric SurgerySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Xiu‐Juan Qu
- Department of Medical OncologyThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Hong Qiu
- Department of Medical OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Yu‐Jing Zhang
- Department of RadiotherapySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Jie‐Er Ying
- Department of Medical OncologyZhejiang Cancer HospitalHangzhouZhejiangP. R. China
| | - Jun Zhang
- Department of Medical OncologyRuijin HospitalShanghai Jiaotong University School of MedicineShanghaiP. R. China
| | - Ling‐Yu Sun
- Department of Surgical OncologyThe Fourth Affiliated Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Rong‐Bo Lin
- Department of Medical OncologyFujian Cancer HospitalFuzhouFujianP. R. China
| | - Chang Wang
- Tumor CenterThe First Hospital of Jilin UniversityChangchunJilinP. R. China
| | - Hao Liu
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Miao‐Zhen Qiu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Wen‐Long Guan
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
| | - Sheng‐Xiang Rao
- Department of RadiologyZhongshan HospitalFudan UniversityShanghaiP. R. China
| | - Jia‐Fu Ji
- Department of Gastrointestinal SurgeryPeking University Cancer HospitalBeijingP. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal TumorThe First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Wei‐Qi Sheng
- Department of PathologyZhongshan Hospital Affiliated to Shanghai Fudan UniversityShanghaiP. R. China
| | - Hui‐Mian Xu
- Department of Gastrointestinal Oncology Surgery. The First Hospital of China Medical UniversityShenyangLiaoningP. R. China
| | - Zhi‐Wei Zhou
- Department of Gastric SurgerySun Yat‐sen University Cancer Center; State Key Laboratory of Oncology in South China; Collaborative Innovation Center of Cancer MedicineGuangzhouGuangdongP. R. China
| | - Ai‐Ping Zhou
- Department of OncologyNational Cancer CenterNational Clinical Research Center for CancerCancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Jing Jin
- Department of Radiation OncologyShenzhen hospitalCancer Hospital of Chinese Academy of Medical SciencesBeijingP. R. China
| | - Xiang‐Lin Yuan
- Department of OncologyTongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and TechnologyWuhanHubeiP. R. China
| | - Feng Bi
- Department of Abdominal OncologyWest China Hospital of Sichuan UniversityChengduSichuanP. R. China
| | - Tian‐Shu Liu
- Department of Medical OncologyZhongshan Hospital Affiliated to Fudan UniversityShanghaiP. R. China
| | - Han Liang
- Department of Gastric SurgeryTianjin Medical University Cancer Institute & HospitalTianjinP. R. China
| | - Yan‐Qiao Zhang
- Department of Medical OncologyCancer Hospital of Harbin Medical UniversityHarbinHeilongjiangP. R. China
| | - Guo‐Xin Li
- Department of General SurgeryNanfang HospitalSouthern Medical UniversityGuangzhouGuangdongP. R. China
| | - Jun Liang
- Department of Medical OncologyPeking University International HospitalBeijingP. R. China
| | - Bao‐Rui Liu
- Department of Medical OncologyNanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjingP. R. China
| | - Lin Shen
- Department of GI OncologyKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer HospitalBeijingP. R. China
| | - Jin Li
- Department of OncologyEaster Hospital affiliated to Shanghai Tongji UniversityShanghaiP. R. China
| | - Rui‐Hua Xu
- Department of Medical OncologySun Yat‐sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdongP. R. China
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Nie C, Lv H, Chen B, Xu W, Wang J, Wang S, Liu Y, He Y, Zhao J, Chen X. High DCR and Better Survival in Patients with Advanced or Metastatic Gastric Cancer Receiving Anti-Angiogenic TKI plus Chemotherapy: A Real-World Study. Technol Cancer Res Treat 2023; 22:15330338221150561. [PMID: 36632666 PMCID: PMC9982383 DOI: 10.1177/15330338221150561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Objectives: This study was carried out to assess the efficacy and drug toxicity of anti-angiogenic tyrosine kinase inhibitor (TKI) plus chemotherapy as second-line or above therapeutic regime in advanced or metastatic gastric cancer patients. Methods: From November 2017 to April 2020, advanced or metastatic gastric cancer patients who have failed from prior treatment and received apatinib combined with irinotecan or irinotecan treatment were analyzed. The primary observed indicator was progression-free survival (PFS). Objective: response rate (ORR), disease control rate (DCR), overall survival (OS), and drug toxicity were also evaluated. Results: 26 patients received apatinib combined with irinotecan and 29 patients received irinotecan. The ORR in the combination therapy and monotherapy population was 26.9% and 17.2%, respectively. The DCR in the apatinib combined with irinotecan group was higher than in irinotecan monotherapy population (80.8% vs 55.2%, P = .043). Median PFS was 4.2 months in the combination group and 3.3 months in the monotherapy group (P = .020). Median OS was 8.0 months in the combination group and 5.9 months in the monotherapy group (P = .048). Except for ECOG PS 2, PFS and OS were generally consistent across subgroups by sex, age, number of metastatic sites and primary tumor site. The incidence of Grade 3-4 adverse events in combination and monotherapy group was 23.1% and 20.7%, respectively. In apatinib combined with irinotecan group, adverse events that were attributed to apatinib were secondary hypertension (in seven patients, 26.9%), hand-foot syndrome (5,19.2%), and proteinuria (5, 19.2%). Univariate analysis demonstrated that secondary hypertension was considered to be a favorable factor (P = .040) for longer OS in combination therapy group. Conclusions: Compared with chemotherapy alone, anti-angiogenic TKI plus chemotherapy showed better PFS, OS and DCR in advanced or metastatic gastric cancer as second-line or above therapy, with a tolerable and manageable safety profile.
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Affiliation(s)
- Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Beibei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Saiqi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Yingjun Liu
- Department of General Surgery, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China
| | - Xiaobing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of
Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China,State Key Laboratory of Esophageal Cancer Prevention &
Treatment, Zhengzhou University, Zhengzhou, China,Henan Engineering Research Center of Precision Therapy of
Gastrointestinal Cancer, Zhengzhou, China,Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal
Cancer, Zhengzhou, China,Xiaobing Chen, Department of Medical
Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer
Hospital, No. 127 Dongming Road, Jinshui District, Zhengzhou City, Henan
Province 450008, China.
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6
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Nie C, Xu W, Lv H, Gao X, Li G, Chen B, Wang J, Liu Y, Zhao J, He Y, Wang S, Chen X. Tailoring second-line or above therapy for patients with advanced or metastatic gastric cancer: A multicenter real-world study. Front Pharmacol 2022; 13:1043217. [DOI: 10.3389/fphar.2022.1043217] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/08/2022] [Indexed: 11/18/2022] Open
Abstract
Background: There is currently still a lack of effective therapeutic manner after the failure of first-line therapy for patients with advanced or metastatic gastric cancer. The present study aimed to evaluate the clinical efficacy and safety of different treatment strategies as second-line or above therapy for patients with advanced or metastatic gastric cancer.Methods: This was an observational multicenter real-world study. From January 2018 to December 2020, advanced or metastatic gastric cancer patients who have failed prior therapy were enrolled and treated with chemotherapy, anti-angiogenic TKIs (tyrosine kinase inhibitors) + chemotherapy or TKIs + ICIs (immune checkpoint inhibitors). In this study, progression free survival (PFS) was the primary end-point. Other evaluation indicators were objective response rate (ORR), disease control rate (DCR), overall survival (OS) and drug toxicities.Results: 162 patients were enrolled, of which 61 patients received chemotherapy, 47 patients received TKIs plus chemotherapy, and 54 patients received TKIs + ICIs. No statistically significant difference existed in ORR among groups (16.4% vs. 19.1% vs. 18.5%, p = 0.924). Patients who received TKIs plus chemotherapy obtained better DCR compared with the chemotherapy group (78.7% vs. 54.1%, p = 0.008), and simultaneously, the median PFS (3.3 m vs. 2.8 m, p = 0.001) and OS (8.0 m vs. 5.8 m, p = 0.005) in TKIs plus chemotherapy group were superior to chemotherapy group. Consistent results were observed in subgroup analysis, including sex, age, ECOG, number of metastatic sites and treatment line. No statistically differences were found between TKIs + ICIs and the chemotherapy group concerning DCR (63.0% vs. 54.1%, p = 0.336), median PFS (3.0 m vs. 2.8 m, p = 0.051) and OS (5.2 m vs. 5.8 m, p = 0.260). Different treatment manner present a special spectrum of adverse events (AEs), and the incidence of Grade 3–4 AEs were 31.1%, 38.3% and 18.5%, respectively.Conclusion: Compared with chemotherapy, anti-angiogenic TKIs plus chemotherapy demonstrated superior second-line or above therapeutic efficacy for advanced or metastatic gastric cancer with well tolerated toxicity. However, TKIs + ICIs failed to demonstrate a clinical advantage over chemotherapy.
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Wang J, He Y, Zhang B, Lv H, Nie C, Chen B, Xu W, Zhao J, Cheng X, Li Q, Tu S, Chen X. The Efficacy and Safety of Sintilimab Combined With Nab-Paclitaxel as a Second-Line Treatment for Advanced or Metastatic Gastric Cancer and Gastroesophageal Junction Cancer. Front Oncol 2022; 12:924149. [PMID: 35719979 PMCID: PMC9198424 DOI: 10.3389/fonc.2022.924149] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/02/2022] [Indexed: 12/19/2022] Open
Abstract
Background Unresectable advanced or recurrent gastric cancer patients have a poor prognosis. PD-1 monotherapy regimen and PD-1 combined chemotherapy regimen have become the standard third- and first-line treatment for advanced gastric cancer, respectively. However, the status of immune checkpoint inhibitors in the second-line treatment for advanced gastric cancer has not been established. The combination of chemotherapy and anti-PD-1 antibody has been demonstrated to have a synergistic effect. In this study, we aimed to evaluate the efficacy and safety of sintilimab combined with nab-paclitaxel in the second-line treatment for advanced gastric cancer (GC)/gastroesophageal junction (GEJ) cancer patients. Patients and Methods We retrospectively analyzed patients with advanced GC/GEJ cancer that progressed after first-line systemic therapies with sintilimab combined with nab-paclitaxel from April 1, 2019 to December 31, 2021. The primary endpoint was progression-free survival (PFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Results Thirty-nine patients were enrolled and eligible for response assessment. Complete response (CR) was not observed, 15 patients achieved partial response (PR), 16 patients had stable disease (SD) and 9 patients had progressive disease (PD). The ORR and DCR were 15 (38.5%) and 31 (79.5%), respectively. Median PFS was 5.4 months (95%CI: 3.072-7.728). PFSs between different subgroups were analyzed. The results showed that gender, age, Human epidermal growth factor receptors 2 (HER2) status, PD-L1 expression, primary tumor site and chemotherapy cycles had no significant effect on PFS. Most of the adverse events (AEs) were of grade 1-2 and manageable. The common treatment-related adverse events of grade 3 or 4 included anemia (12.8%), neutropenia (12.8%), leukopenia (10.3%), hand-foot syndrome (7.7%), thrombocytopenia (7.7%). The potential immune-related adverse events (irAEs) were grade 1 pneumonia (1 pts [2.6%]) and grade 4 hepatitis (1 pts [2.6%]). There were no treatment-related deaths. Conclusion These results indicate that sintilimab combined with nab-paclitaxel exhibits good anti-tumor activity and an acceptable safety profile as a second-line treatment for advanced or metastatic gastric cancer. These results warrant further investigation and evaluation to identify patients who can benefit more from the combined treatment strategy.
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Affiliation(s)
- Jianzheng Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Baiwen Zhang
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Huifang Lv
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
| | - Xiaojiao Cheng
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qingli Li
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Shuiping Tu
- Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xiaobing Chen
- Department of Medical Oncology, The Affiliated Cancer Hospital of Zhengzhou, University and Henan Cancer Hospital, Zhengzhou, China
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8
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Wang F, Zhang X, Li Y, Tang L, Qu X, Ying J, Zhang J, Sun L, Lin R, Qiu H, Wang C, Qiu M, Cai M, Wu Q, Liu H, Guan W, Zhou A, Zhang Y, Liu T, Bi F, Yuan X, Rao S, Xin Y, Sheng W, Xu H, Li G, Ji J, Zhou Z, Liang H, Zhang Y, Jin J, Shen L, Li J, Xu R. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Commun (Lond) 2021; 41:747-795. [PMID: 34197702 PMCID: PMC8360643 DOI: 10.1002/cac2.12193] [Citation(s) in RCA: 401] [Impact Index Per Article: 100.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 02/05/2023] Open
Abstract
There exist differences in the epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selections between gastric cancer patients from the Eastern and Western countries. The Chinese Society of Clinical Oncology (CSCO) has organized a panel of senior experts specializing in all sub-specialties of gastric cancer to compile a clinical guideline for the diagnosis and treatment of gastric cancer since 2016 and renews it annually. Taking into account regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted expert consensus judgment on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes in China. The 2021 CSCO Clinical Practice Guidelines for Gastric Cancer covers the diagnosis, treatment, follow-up, and screening of gastric cancer. Based on the 2020 version of the CSCO Chinese Gastric Cancer guidelines, this updated guideline integrates the results of major clinical studies from China and overseas for the past year, focused on the inclusion of research data from the Chinese population for more personalized and clinically relevant recommendations. For the comprehensive treatment of non-metastatic gastric cancer, attentions were paid to neoadjuvant treatment. The value of perioperative chemotherapy is gradually becoming clearer and its recommendation level has been updated. For the comprehensive treatment of metastatic gastric cancer, recommendations for immunotherapy were included, and immune checkpoint inhibitors from third-line to the first-line of treatment for different patient groups with detailed notes are provided.
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9
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Schokker S, van der Woude SO, van Kleef JJ, van Zoen DJ, van Oijen MGH, Mearadji B, Beenen LFM, Stroes CI, Waasdorp C, Jibodh RA, Creemers A, Meijer SL, Hooijer GKJ, Punt CJA, Bijlsma MF, van Laarhoven HWM. Phase I Dose Escalation Study with Expansion Cohort of the Addition of Nab-Paclitaxel to Capecitabine and Oxaliplatin (CapOx) as First-Line Treatment of Metastatic Esophagogastric Adenocarcinoma (ACTION Study). Cancers (Basel) 2019; 11:cancers11060827. [PMID: 31207904 PMCID: PMC6627561 DOI: 10.3390/cancers11060827] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 05/31/2019] [Accepted: 06/11/2019] [Indexed: 02/07/2023] Open
Abstract
First-line triplet chemotherapy including a taxane may prolong survival in patients with metastatic esophagogastric cancer. The added toxicity of the taxane might be minimized by using nab-paclitaxel. The aim of this phase I study was to determine the feasibility of combining nab-paclitaxel with the standard of care in the Netherlands, capecitabine and oxaliplatin (CapOx). Patients with metastatic esophagogastric adenocarcinoma received oxaliplatin 65 mg/m2 on days 1 and 8, and capecitabine 1000 mg/m2 bid on days 1-14 in a 21-day cycle, with nab-paclitaxel on days 1 and 8 at four dose levels (60, 80, 100, and 120 mg/m2, respectively), using a standard 3 + 3 dose escalation phase, followed by a safety expansion cohort. Baseline tissue and serum markers for activated tumor stroma were assessed as biomarkers for response and survival. Twenty-six patients were included. The first two dose-limiting toxicities (i.e., diarrhea and dehydration) occurred at dose level 3. The resulting maximum tolerable dose (MTD) of 80 mg/m2 was used in the expansion cohort, but was reduced to 60 mg/m2 after three out of eight patients experienced diarrhea grade 3. The objective response rate was 54%. The median progression-free (PFS) and overall survival were 8.0 and 12.8 months, respectively. High baseline serum ADAM12 was associated with a significantly shorter PFS (p = 0.011). In conclusion, albeit that the addition of nab-paclitaxel 60 mg/m2 to CapOx may be better tolerated than other taxane triplets, relevant toxicity was observed. There is a rationale for preserving taxanes for later-line treatment. ADAM12 is a potential biomarker to predict survival, and warrants further investigation.
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Affiliation(s)
- Sandor Schokker
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Stephanie O van der Woude
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Jessy Joy van Kleef
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Daan J van Zoen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Martijn G H van Oijen
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Banafsche Mearadji
- Department of Radiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Ludo F M Beenen
- Department of Radiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Charlotte I Stroes
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Cynthia Waasdorp
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - R Aarti Jibodh
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Aafke Creemers
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Sybren L Meijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Gerrit K J Hooijer
- Department of Pathology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Cornelis J A Punt
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Maarten F Bijlsma
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
| | - Hanneke W M van Laarhoven
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, The Netherlands.
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10
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Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, Tang L, Xin Y, Jin J, Zhang YJ, Yuan XL, Liu TS, Li GX, Wu Q, Xu HM, Ji JF, Li YF, Wang X, Yu S, Liu H, Guan WL, Xu RH. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Commun (Lond) 2019; 39:10. [PMID: 30885279 PMCID: PMC6423835 DOI: 10.1186/s40880-019-0349-9] [Citation(s) in RCA: 304] [Impact Index Per Article: 50.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Accepted: 02/01/2019] [Indexed: 02/08/2023] Open
Abstract
China is one of the countries with the highest incidence of gastric cancer. There are differences in epidemiological characteristics, clinicopathological features, tumor biological characteristics, treatment patterns, and drug selection between gastric cancer patients from the Eastern and Western countries. Non-Chinese guidelines cannot specifically reflect the diagnosis and treatment characteristics for the Chinese gastric cancer patients. The Chinese Society of Clinical Oncology (CSCO) arranged for a panel of senior experts specializing in all sub-specialties of gastric cancer to compile, discuss, and revise the guidelines on the diagnosis and treatment of gastric cancer based on the findings of evidence-based medicine in China and abroad. By referring to the opinions of industry experts, taking into account of regional differences, giving full consideration to the accessibility of diagnosis and treatment resources, these experts have conducted experts' consensus judgement on relevant evidence and made various grades of recommendations for the clinical diagnosis and treatment of gastric cancer to reflect the value of cancer treatment and meeting health economic indexes. This guideline uses tables and is complemented by explanatory and descriptive notes covering the diagnosis, comprehensive treatment, and follow-up visits for gastric cancer.
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Affiliation(s)
- Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120 P. R. China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Han Liang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Tianjin’s Clinical Research Cancer for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060 P. R. China
| | - Xiao-Tian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Lei Tang
- Medical Imaging Department, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yan Xin
- Pathology Laboratory of Gastrointestinal Tumor, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jing Jin
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Yu-Jing Zhang
- Department of Radiotherapy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xiang-Lin Yuan
- Department of Medical Oncology, Tongji Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, 430030 Hubei P. R. China
| | - Tian-Shu Liu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Guo-Xin Li
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Qi Wu
- Department of Endoscopy Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Hui-Mian Xu
- Department of Surgical Oncology, The First Hospital of China Medical University, Shenyang, 110001 Liaoning P. R. China
| | - Jia-Fu Ji
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, 100142 P. R. China
| | - Yuan-Fang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Xin Wang
- Department of Radiation Oncology, National Cancer Center, China and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
| | - Shan Yu
- Department of Medical Oncology, Zhongshan Hospital Affiliated to Fudan University, Shanghai, 200032 P. R. China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital Affiliated to Southern Medical University, Guangzhou, 510515 Guangdong P. R. China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060 Guangdong P. R. China
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11
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Guo Y, Tang J, Huang XE, Cao J. Efficacy and toxicity of apatinib combined with or without chemotherapy for patients with advanced or metastatic chemotherapy-refractory gastric adenocarcinoma: A prospective clinical study. Medicine (Baltimore) 2019; 98:e13908. [PMID: 30732125 PMCID: PMC6380695 DOI: 10.1097/md.0000000000013908] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Apatinib (Jiangsu HengRui Medicine Co. Ltd), a vascular endothelial growth factor receptor 2 (VEGFR-2) tyrosine kinase inhibitor, has been proven to be safe and to significantly prolong survival in advanced chemotherapy-refractory gastric cancer. This study aimed to assess and compare the efficacy and safety of apatinib combined with chemotherapy with that of chemotherapy alone as second- or higher-line treatment in patients with advanced and metastatic gastric or those with metastatic gastroesophageal junction adenocarcinoma (mGC).Patients with chemotherapy-refractory mGC at Jiangsu Cancer Hospital & Research Institute were prospectively enrolled and assigned into 2 groups at a 2:1 ratio. The first group (combination group) comprised patients with combination treatment (apatinib + chemotherapy), while the second group comprised patients treated with chemotherapy alone (chemotherapy group). The dose of apatinib was 500 mg/d, and the chemotherapy regimens were based on fluoropyrimidine, platinum, and paclitaxel or irinotecan. The primary end points were progression-free survival (PFS).Between November 2014 and December 2016, 175 patients were enrolled. PFS was significantly improved in the combination group compared with that in the chemotherapy group (8.5 months [95% confidence interval [CI], 6.45-10.54] vs 7.0 months [95% CI, 5.12-8.88] P = .021; hazard ratio (HR): 0.645 [95% CI: 0.429-0.969] P = .035). The disease control rate (DCR) was also higher in the combination group than that in the chemotherapy group (58.4% vs 41.9%, P = .041). Moreover, the incidence of Grade 3 to 4 hand-foot syndrome, proteinuria, and hypertension was significantly different between the 2 groups. Combined therapy (P = .040) and metastatic sites <2 (P = .008) were the independent prognostic factors for disease progression.Compared with chemotherapy alone, the addition of apatinib to chemotherapy could better improve PFS and DCR with an acceptable safety profile for mGC refractory to 1 or more line of prior chemotherapy.
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Affiliation(s)
- Yesong Guo
- Department of Radiotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research &The Affiliated Cancer Hospital of Nanjing Medical University
| | - Jinhai Tang
- Department of General Surgery, The First Affiliated Hospital With Nanjing Medical University
| | | | - Jie Cao
- Department of Chemotherapy, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research &The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
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12
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Zhang B, Wang X, Li Q, Mo H, Wang X, Song Y, Xu J, Qu T, Huang J. Efficacy of irinotecan-based chemotherapy after exposure to an anti-PD-1 antibody in patients with advanced esophageal squamous cell carcinoma. Chin J Cancer Res 2019; 31:910-917. [PMID: 31949393 PMCID: PMC6955162 DOI: 10.21147/j.issn.1000-9604.2019.06.07] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Objective Several anti-programmed cell death 1 (anti-PD-1) antibodies have demonstrated potential efficacy in the treatment of advanced esophageal squamous cell cancer (ESCC). However, the response to subsequent chemotherapy after the failure of PD-1 blockade in ESCC patients has not been reported, and the optimal sequencing of immunotherapy and chemotherapy remains controversial. The aim of the present study was to evaluate responses to irinotecan-based subsequent chemotherapy in advanced ESCC patients who had progressed after treatment with camrelizumab (SHR-1210), a novel anti-PD-1 antibody. Methods We retrospectively reviewed the medical records of patients with advanced ESCC treated with camrelizumab at a single institution. Consecutive patients who received subsequent irinotecan-based chemotherapy were selected for data collection and analysis. Results Overall, a total of 28 patients were included. All patients had received at least two lines of systemic treatment prior to irinotecan salvage. The most common regimen that was administered after PD-1 blockade was irinotecan in combination with 5-fluorouracil (5-Fu) (or its derivatives), which was given to 19 patients. The objective response rate (ORR) and disease control rate (DCR) were 17.9% (5/28) and 64.3% (18/28), respectively, with 5 (17.9%) patients achieving a partial response and 13 (46.4%) having stable disease. The median progression-free survival (PFS) was 3.18 [95% confidence interval (95% CI), 2.48−3.88] months and the median overall survival (OS) was 6.23 (95% CI, 4.71−7.75) months. No new safety issues, either immune-related or otherwise, were observed. Conclusions Our results suggested that the response to irinotecan-based chemotherapy after PD-1 blockade in advanced ESCC patients appeared similar to that previously observed in patients who had not received PD-1 antibodies, and further study in larger cohorts or randomized trials is warranted to verify our observation.
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Affiliation(s)
- Bo Zhang
- 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
| | - Xi Wang
- 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
| | - Qun Li
- 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
| | - Hongnan Mo
- 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
| | - Xingyuan Wang
- 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
| | - Yan Song
- 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
| | - Jianping Xu
- 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
| | - Tao Qu
- 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 Huang
- 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
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13
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Bruera G, Massacese S, Galvano A, Mas AD, Guadagni S, Calvisi G, Ciacco E, Russo A, Ricevuto E. Dose-finding study of intensive weekly alternating schedule of docetaxel, 5-fluorouracil, and oxaliplatin, FD/FOx regimen, in metastatic gastric cancer. Oncotarget 2018; 9:20339-20350. [PMID: 29755655 PMCID: PMC5945545 DOI: 10.18632/oncotarget.24861] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 03/07/2018] [Indexed: 01/13/2023] Open
Abstract
INTRODUCTION Proper administration timing, dose-intensity, efficacy/toxicity ratio of triplet docetaxel (DTX), 5-fluorouracil (5-FU), and oxaliplatin (OXP) should be improved to safely perform three-drugs intensive first line in advanced gastric cancer (GC). This dose-finding study investigated recommended 5-FU and OXP doses, safety of triplet regimen and preliminary activity. METHODS Schedule: 12h-timed-flat-infusion 5-FU 700-1000 mg/m2/d 1-2, 8-9, 15-16, 22-23, with 100 mg/m2/d increase for dose level; DTX 50 mg/m2 d 1, 15 fixed dose, OXP at three increasing dose-levels 60-70-80 mg/m2 d 8, 22, every 4 weeks. Intra- and inter-patients dose-escalation was planned. RESULTS Ten fit <75 years patients were enrolled: median age 59; young-elderly 4 (40%). From first to fifth dose level, 5 patients (1 per cohort) were enrolled according to intra-patient dose escalation, no dose-limiting toxicity (DLT) were reported. At sixth level, 1 DLT, G2 diarrhea, was reported, thus other 2 patients were enrolled, DLT 1/3 patients (33%). Maximum tolerated dose (MTD) was not reached. 5-FU and OXP recommended doses (RD) were 1000 mg/m2/d and 80 mg/m2, respectively. To confirm RD, other 3 patients were enrolled, without DLT. Cumulative G3-4 toxicities were: neutropenia 50%, leucopenia 20%, hypoalbuminemia 10%, mucositis 10%, asthenia 20%. Limiting toxicity syndromes were 30%, 25% in young-elderly, all multiple site. Objective response rate intent-to-treat 60%, disease control rate 90%. After 15 months follow-up, progression-free and overall survival, 6 and 17 months, respectively. CONCLUSIONS First line intensive FD/FOx regimen adding DXT/5-FU/OXP can be safely administered at recommended doses in advanced GC, with promising high activity and efficacy.
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Affiliation(s)
- Gemma Bruera
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Silvia Massacese
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Antonio Galvano
- Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Antonella Dal Mas
- Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy
| | - Stefano Guadagni
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- University General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
| | - Giuseppe Calvisi
- Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy
| | - Eugenio Ciacco
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Antonio Russo
- Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Enrico Ricevuto
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - on behalf of Oncology Network ASL1 Abruzzo, Italy
- Oncology Territorial Care, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
- Medical Oncology, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
- Pathology, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L'Aquila, Italy
- University General Surgery, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L'Aquila, L'Aquila, Italy
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Chen Z, Liu Z, Huang W, Li Z, Zou J, Wang J, Lin X, Li B, Chen D, Hu Y, Ji J, Gao J, Shen L. Gimatecan exerts potent antitumor activity against gastric cancer in vitro and in vivo via AKT and MAPK signaling pathways. J Transl Med 2017; 15:253. [PMID: 29237470 PMCID: PMC5729429 DOI: 10.1186/s12967-017-1360-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 12/06/2017] [Indexed: 02/08/2023] Open
Abstract
Background We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models. Methods GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed. Results Gimatecan inhibited the proliferation of GC cells in vitro in a dose- and time-dependent manner by inducing apoptosis, and gimatecan had greater inhibitory effects than irinotecan. In addition, both gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2). Conclusions For the first time, we have shown that the antitumor activity of gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that gimatecan might be an alternative to irinotecan in the treatment of GC. Electronic supplementary material The online version of this article (10.1186/s12967-017-1360-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Zuhua Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Zhentao Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Wenwen Huang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Zhongwu Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jianling Zou
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jingyuan Wang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Xiaoting Lin
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Beifang Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Dongshao Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Yanting Hu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China
| | - Jiafu Ji
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jing Gao
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
| | - Lin Shen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
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15
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Multicenter phase II study of apatinib treatment for metastatic gastric cancer after failure of second-line chemotherapy. Oncotarget 2017; 8:104552-104559. [PMID: 29262660 PMCID: PMC5732826 DOI: 10.18632/oncotarget.21053] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Accepted: 08/17/2017] [Indexed: 12/31/2022] Open
Abstract
Apatinib is a tyrosine kinase inhibitor and vascular endothelial growth factor receptor 2 (VEGFR-2) targeted drug. A phase I clinical trial showed that this agent has antitumor activity in Chinese patients with metastatic gastric cancer (mGC). The aim of this study was to investigate the safety and efficacy of apatinib treatment in patients with mGC. This was an open-label, multicenter, single-arm study involving four institutions in China. We enrolled 42 patients from March 2015 to October 2015 who experienced tumor progression after second-line chemotherapy and had no other treatment options that clearly conferred a survival benefit. Oral apatinib (850 mg daily) was administered within 30 min of eating breakfast, lunch, or dinner on days 1 through 28 of each 4-week cycle. The median progression-free survival (PFS) time and median overall survival (OS) time were 4.0 months (95% CI, 2.85-5.15) and 4.50 months (95% CI, 4.03-4.97), respectively. The disease control rate (DCR) and objective response rate (ORR) were, respectively, 78.57% and 9.52% after 2 cycles and 57.14% and 19.05% after 4 cycles. The main adverse events (AEs) were secondary hypertension, elevated aminotransferase, and hand-foot syndrome, with incidences of 35.71%, 45.24%, and 40.48%, respectively. The most common grade 3 to 4 AEs were secondary hypertension and elevated aminotransferase, with incidences of 7.14% each. Apatinib is effective and safe in heavily pretreated patients with mGC who fail to respond to two or more prior chemotherapy regimens. Toxicities were tolerable or could be clinically managed.
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Wang H, Chen J, Xu C, Shi L, Tayier M, Zhou J, Zhang J, Wu J, Ye Z, Fang T, Han W. Cancer Nanomedicines Stabilized by π-π Stacking between Heterodimeric Prodrugs Enable Exceptionally High Drug Loading Capacity and Safer Delivery of Drug Combinations. Am J Cancer Res 2017; 7:3638-3652. [PMID: 29109766 PMCID: PMC5667338 DOI: 10.7150/thno.20028] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2017] [Accepted: 07/18/2017] [Indexed: 02/05/2023] Open
Abstract
Combination therapy using distinct mode-of-action drugs has sparked a rapidly growing interest because this paradigm holds promise for improving the therapeutic efficacy of anticancer therapy. However, the current drug combination therapy refers to administering individual drugs together, which is far from a perfect regimen for cancer patients. The aim of this work was to demonstrate that synergistic delivery of two chemotherapeutic drugs in a single nanoparticle reservoir could be achieved through the rational chemical ligation of the drugs followed by supramolecular nano-assembly via blending of the drugs with a minimal amount of matrix. Choosing 7-ethyl-10-hydroxycamptothecin and taxanes, which are rich in aromatic structures, as model compounds, we show that the heterodimeric conjugates of the two agents are miscible with lipids to form systemically injectable nanomedicines. The compatibility between the prodrug conjugates and lipid carriers is substantially augmented by the intermolecular π-π stacking and alleviated polarity, thus enabling an exceptionally high drug loading (DL) capacity (~92%) and a gratifyingly long drug retention time within the micellar core. We further observed superior therapeutic outcomes in a mouse tumor model without detecting accompanying systemic toxicity. This structure-based, self-assembled cancer nanomedicine increased the potency and drug tolerability in animals and thus offers a robust strategy for simultaneously formulating two or more drugs in single nanovehicles.
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17
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Apatinib: A novel receptor tyrosine kinase inhibitor for the treatment of gastric cancer. Cancer Lett 2016; 372:187-91. [PMID: 26797419 DOI: 10.1016/j.canlet.2016.01.014] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 01/11/2016] [Accepted: 01/12/2016] [Indexed: 12/11/2022]
Abstract
Metastatic gastric cancer is a lethal disease characterized by a very short overall survival, underlining a critical need of new therapeutic options. Unfortunately, although several molecular targets have been investigated, only very few recently approved agents, such as trastuzumab in the HER2-positive setting and ramucirumab, led to a clinical improvement in the outcome of metastatic gastric cancer patients. VEGF (vascular endothelial growth factor) is one of the most potent angiogenic factors and is a signalling molecule secreted by many solid tumours. Since high VEGF expression is one of the characteristic features of gastric carcinomas, targeting VEGF is therefore considered as a promising therapeutic strategy for gastric cancer. In the scenario of possible new target therapies with particular regard to angiogenesis, apatinib is a novel receptor tyrosine kinase inhibitor selectively targeting VEGFR-2. It is an orally-bioavailable agent currently being studied in several solid tumour types showing a promising activity in gastric cancer. Due to the recent positive results as a third line of treatment for metastatic gastric cancer patients, apatinib may be an interesting and novel type of targeted treatment for metastatic gastric cancer in several lines of therapy. In this review, we summarize the available data of apatinib, mainly focused on the clinical aspect, in advanced/metastatic gastric cancer.
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18
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Wang X, Wang X, Huang J. Irinotecan plus fluorouracil-based regimen as second or third-line chemotherapy for recurrent or metastatic esophageal squamous cell carcinoma. Thorac Cancer 2015; 7:246-50. [PMID: 27042229 PMCID: PMC4773301 DOI: 10.1111/1759-7714.12323] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Accepted: 10/21/2015] [Indexed: 01/31/2023] Open
Abstract
Background No standard second‐line regimen exists for the treatment of advanced esophageal squamous cell carcinoma (ESCC). The aim of this study was to evaluate the efficacy and safety of irinotecan and fluorouracil‐based chemotherapy as a second or third‐line regimen for advanced ESCC patients. Methods We retrospectively reviewed a cohort of 27 consecutive patients with advanced ESCC in one institute, treated with a combination of irinotecan plus fluorouracil‐based regimens after the failure of first‐line platinum‐based therapy. Nine patients were treated with 150–160 mg/m2 irinotecan and 400 mg/m2 fluorouracil (5‐FU) on day 1, followed by 2000 mg/m2 5‐FU during a 48‐hour infusion every two weeks. Eighteen patients received 150–160 mg/m2 irinotecan on day 1 and 80–120 mg/day S‐1 on days 1–10 every two weeks. The S‐1 dose was based on the patients' body surface area. Results Twenty‐four of the 27 patients were assessable for response. One (3.7%) patient achieved complete response, seven (25.9%) achieved partial response, eight (29.6%) had stable disease, and eight (29.6%) had progressive disease. The median progression‐free and overall survival were 4.8 (95% confidence interval [CI]: 1.2–8.4) and 10.5 months (95% CI: 8.4–12.7), respectively. Grade 3 neutropenia and diarrhea were detected in four (15%) and one (4%) patient, respectively. No grade 4 toxicity was noted. Conclusions Our study indicates that an irinotecan plus 5‐FU‐based regimen is effective and well‐tolerated as a second or third‐line chemotherapy for patients with advanced ESCC.
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Affiliation(s)
- Xi Wang
- Department of Medical Oncology, Cancer Institute & Hospital Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC) Beijing China
| | - Xinwei Wang
- Department of Medical Oncology, Cancer Institute & Hospital Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC) Beijing China
| | - Jing Huang
- Department of Medical Oncology, Cancer Institute & Hospital Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC) Beijing China
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19
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Kim SM, Park SH. Chemotherapy beyond second-line in advanced gastric cancer. World J Gastroenterol 2015; 21:8811-6. [PMID: 26269670 PMCID: PMC4528023 DOI: 10.3748/wjg.v21.i29.8811] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Revised: 03/23/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
Patients with advanced gastric cancer (AGC) can be treated with multiple lines of chemotherapy. Although several randomized trials have demonstrated the benefit of second-line chemotherapy compared with best supportive care, there is no evidence that further lines of chemotherapy will result in substantial prolongation of survival. Despite this, the practice of offering chemotherapy beyond second-line agents to AGC patients is not uncommon if their performance status is well-preserved and they are willing to receive subsequent active treatments. The choice of chemotherapeutic agents depends on the patient's prior regimens. However, there are important controversial issues in the salvage setting of AGC, including a subset of patients who may benefit from chemotherapy, that still remain unanswered. This report reviews the available evidence regarding the impact of third- and subsequent lines of chemotherapy on survival and quality of life in patients with AGC.
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20
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Liu L, Yu H, Huang L, Shao F, Bai J, Lou D, Chen F. Progression-free survival as a surrogate endpoint for overall survival in patients with third-line or later-line chemotherapy for advanced gastric cancer. Onco Targets Ther 2015; 8:921-8. [PMID: 25960663 PMCID: PMC4410904 DOI: 10.2147/ott.s82365] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The correlation between overall survival (OS) and progression-free survival (PFS) has been evaluated in patients with metastatic or advanced gastric cancer who have received first-line and/or second-line chemotherapy. However, no corresponding analysis has been done for patients who have undergone third-line or later-line chemotherapy. METHODS A total of 303 patients from the Phase II/III studies of apatinib were pooled (the Phase II study as a training data set, the Phase III study as a testing data set). Landmark analyses of PFS at 2 months from randomization were performed to minimize lead time bias. The Cox proportional hazard model was used to test for the significance effect of PFS rate at 2 months in predicting OS. Additionally, the PFS/OS correlations were evaluated by the normal induced copula (National Institute for Health and Care Excellence) estimation model. RESULTS The median OS was 3.37 months (95% confidence interval 2.63-3.80) in patients who experienced progression at 2 months and 5.67 months in patients who did not (95% confidence interval 4.83-6.67; P<0.0001). Compared with patients who did not progress at 2 months, the adjusted hazard ratio for death was 3.39 (95% confidence interval 1.79-6.41; P<0.0001) for patients who experienced progression at 2 months. Moreover, the correlation of PFS/OS was 0.84 (95% confidence interval 0.74-0.90). Similar results were found in the testing data set. CONCLUSION These results indicate that PFS correlates strongly with OS, suggesting PFS may be a useful early endpoint for patients with advanced gastric cancer who have undergone third-line or later-line chemotherapy. These observations require prospective validation.
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Affiliation(s)
- Liya Liu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Hao Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Lihong Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Fang Shao
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Jianling Bai
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Donghua Lou
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Feng Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
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Murphy A, Kelly RJ. From molecular classification to targeted therapeutics: the changing face of systemic therapy in metastatic gastroesophageal cancer. Gastroenterol Res Pract 2015; 2015:896560. [PMID: 25784931 PMCID: PMC4346691 DOI: 10.1155/2015/896560] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 01/15/2015] [Indexed: 01/14/2023] Open
Abstract
Histological classification of adenocarcinoma or squamous cell carcinoma for esophageal cancer or using the Lauren classification for intestinal and diffuse type gastric cancer has limited clinical utility in the management of advanced disease. Germline mutations in E-cadherin (CDH1) or mismatch repair genes (Lynch syndrome) were identified many years ago but given their rarity, the identification of these molecular alterations does not substantially impact treatment in the advanced setting. Recent molecular profiling studies of upper GI tumors have added to our knowledge of the underlying biology but have not led to an alternative classification system which can guide clinician's therapeutic decisions. Recently the Cancer Genome Atlas Research Network has proposed four subtypes of gastric cancer dividing tumors into those positive for Epstein-Barr virus, microsatellite unstable tumors, genomically stable tumors, and tumors with chromosomal instability. Unfortunately to date, many phase III clinical trials involving molecularly targeted agents have failed to meet their survival endpoints due to their use in unselected populations. Future clinical trials should utilize molecular profiling of individual tumors in order to determine the optimal use of targeted therapies in preselected patients.
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Affiliation(s)
- Adrian Murphy
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
| | - Ronan J. Kelly
- Upper Aerodigestive Malignancies Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA
- Gastroesophageal Cancer Therapeutics Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Room G93, Baltimore, MD 21231, USA
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22
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Hultman B, Mahteme H, Sundbom M, Ljungman M, Larsson R, Nygren P. Benchmarking of gastric cancer sensitivity to anti-cancer drugs ex vivo as a basis for drug selection in systemic and intraperitoneal therapy. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2014; 33:110. [PMID: 25528067 PMCID: PMC4304126 DOI: 10.1186/s13046-014-0110-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 12/11/2014] [Indexed: 12/13/2022]
Abstract
Background The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC. Methods Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mitomycin C, doxorubicin and docetaxel as well as for the targeted drugs bortezomib, sorafenib, sunitinib and rapamycin using a short-term in vitro assay based on retention of viable tumor cells of fluorescent fluorescein. Samples of normal mononuclear cells, chronic lymphocytic leukemia, ovarian cancer and colorectal cancer were included for comparison. Results The GC samples were essentially as sensitive to the standard drugs and the TDs as those from colorectal cancer whereas the ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the clinically used standard drugs. In GC, cisplatin was cross-resistant to oxaliplatin and 5-fluorouracil which, on the other hand, was not cross-resistant to the other cytotoxic drugs. The activity of sunitinib did not obviously correlate to that of the standard drugs. Conclusion Ex vivo assessment of drug sensitivity of tumor cells from patients with GC is feasible and may provide information that could be useful for selection of drugs for treatment. Drug sensitivity varies considerably between and within individual samples arguing for individualized selection of drugs for chemotherapy.
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Affiliation(s)
- Bo Hultman
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
| | - Haile Mahteme
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
| | - Magnus Sundbom
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.
| | - Martin Ljungman
- Surgery Department, Västmanlands Hospital, SE-721 89, Västerås, Sweden.
| | - Rolf Larsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
| | - Peter Nygren
- Department of Radiology, Oncology and Radiation Sciences, Uppsala University, SE-751 85, Uppsala, Sweden.
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Yoon JH, Kwon MM, Park HJ, Park SY, Lim KY, Joo J, Park BK. A study of docetaxel and irinotecan in children and young adults with recurrent or refractory Ewing sarcoma family of tumors. BMC Cancer 2014; 14:622. [PMID: 25164234 PMCID: PMC4155244 DOI: 10.1186/1471-2407-14-622] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Accepted: 08/19/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patients with Ewing sarcoma family of tumors (ESFT) who are resistant even to salvage chemotherapy, have dismal prognoses and few therapeutic options. Because the docetaxel/irinotecan (DI) combination has not been previously evaluated in ESFT, we prospectively evaluated its use in patients with recurrent or refractory ESFT. METHODS Patients aged <30 years with ESFT, who failed ≥ third-line therapy, were eligible. They received docetaxel 100 mg/m(2) intravenously on day 1, and irinotecan 80 mg/m(2) on days 1 and 8, of a 21-day cycle up to 15 cycles or until disease progressed. The primary objective was objective response rate (ORR); secondary objectives were progression-free survival (PFS) and safety. RESULTS We enrolled nine patients (median age: 13 years); four were male. Two patients had recurrent disease and seven had progressive disease. This group had undergone a median of four prior chemotherapy regimens (range: 3-6), and received a total of 51 DI cycles (median: three cycles/per person; range: 1-15 cycles). The nine patients showed one complete response (CR), two partial responses (PRs), one stable disease, and five progressive diseases, for an ORR (CR + PR) of 3/9 (33.3%). Two patients with PR achieved CR with subsequent surgery. Overall median PFS was 2.2 months (range: 0.5-16.9 months). All nine patients had grade 4 neutropenia (100%); grade 3 diarrhea or grade 2/3 neuropathy each occurred in two patients (22%). All toxicities were manageable without serious morbidities or treatment-related mortality. CONCLUSIONS The DI combination may be effective and tolerable for patients with heavily pre-treated ESFT. TRIAL REGISTRATION NCT01380275. Registered June 21, 2011.
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Affiliation(s)
| | | | | | | | | | | | - Byung-Kiu Park
- Center for Pediatric Oncology, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 410-769, Korea.
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Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N, Cheng Y, Wang Z, Zheng L, Tao M, Zhu X, Ji D, Liu X, Yu H. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol 2013; 31:3219-25. [PMID: 23918952 DOI: 10.1200/jco.2013.48.8585] [Citation(s) in RCA: 411] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC. PATIENTS AND METHODS Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C). RESULTS We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare. CONCLUSION Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.
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Affiliation(s)
- Jin Li
- Jin Li, Weijian Guo, Xiaodong Zhu, Dongmei Ji, and Xin Liu, Shanghai Cancer Center and Shanghai Medical College, Fudan University; Liwei Wang, Shanghai First People's Hospital; Leizhen Zheng, XinHua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai; Shukui Qin, The 81 Hospital of PLA, Nanjing; Hao Yu, School of Public Health, Nanjing Medical University, Nanjing; Jianming Xu, The 307 Hospital of the Academy of Military Medical Sciences, Beijing; Jianping Xiong, The First Affiliated Hospital of Nanchang University, Nanchang; Yuxian Bai, The Third Affiliated Hospital of Harbin Medical University, Harbin; Guoping Sun, The First Affiliated Hospital of Anhui Medical University, Hefei; Yan Yang, Gansu Cancer Hospital, Lanzhou; Nong Xu, The First Affiliated Hospital of Zhejiang University, Hangzhou; Ying Cheng, Jilin Cancer Hospital, Changchun; Zhehai Wang, Shandong Cancer Hospital, Jinan; and Min Tao, The First Affiliated Hospital of Soochow University, Suzhou, China
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Abstract
Answer questions and earn CME/CNE Esophageal adenocarcinoma (EAC) is characterized by 6 striking features: increasing incidence, male predominance, lack of preventive measures, opportunities for early detection, demanding surgical therapy and care, and poor prognosis. Reasons for its rapidly increasing incidence include the rising prevalence of gastroesophageal reflux and obesity, combined with the decreasing prevalence of Helicobacter pylori infection. The strong male predominance remains unexplained, but hormonal influence might play an important role. Future prevention might include the treatment of reflux or obesity or chemoprevention with nonsteroidal antiinflammatory drugs or statins, but no evidence-based preventive measures are currently available. Likely future developments include endoscopic screening of better defined high-risk groups for EAC. Individuals with Barrett esophagus might benefit from surveillance, at least those with dysplasia, but screening and surveillance strategies need careful evaluation to be feasible and cost-effective. The surgery for EAC is more extensive than virtually any other standard procedure, and postoperative survival, health-related quality of life, and nutrition need to be improved (eg, by improved treatment, better decision-making, and more individually tailored follow-up). Promising clinical developments include increased survival after preoperative chemoradiotherapy, the potentially reduced impact on health-related quality of life after minimally invasive surgery, and the new endoscopic therapies for dysplastic Barrett esophagus or early EAC. The overall survival rates are improving slightly, but poor prognosis remains a challenge.
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Affiliation(s)
- Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
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26
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Roy A, Cunningham D, Hawkins R, Sörbye H, Adenis A, Barcelo JR, Lopez-Vivanco G, Adler G, Canon JL, Lofts F, Castanon C, Fonseca E, Rixe O, Aparicio J, Cassinello J, Nicolson M, Mousseau M, Schalhorn A, D'Hondt L, Kerger J, Hossfeld DK, Garcia Giron C, Rodriguez R, Schoffski P, Misset JL. Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study. Br J Cancer 2012; 107:435-41. [PMID: 22767144 PMCID: PMC3405223 DOI: 10.1038/bjc.2012.286] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Revised: 05/18/2012] [Accepted: 05/30/2012] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. METHODS Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). RESULTS A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). CONCLUSION Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.
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Affiliation(s)
- A Roy
- Department of Medicine, Royal Marsden Hospital, Sutton, London, SM25PT, UK
| | - D Cunningham
- Department of Medicine, Royal Marsden Hospital, Sutton, London, SM25PT, UK
| | - R Hawkins
- Department of Medical Oncology, University of Manchester, Manchester, M20 4BX UK
| | - H Sörbye
- Department of Medical Oncology, Haukeland University Hospital, Bergen, Norway
| | - A Adenis
- Department of Gastrointestinal Oncology, Centre Oscar Lambret, Lille, France
| | - J-R Barcelo
- Department of Oncology, Hospital de Cruces Osakidetza, Basque Country, Spain
| | - G Lopez-Vivanco
- Department of Oncology, Hospital de Cruces Osakidetza, Basque Country, Spain
| | - G Adler
- Department of Medicine, University of Ulm, Robert-Koch-Strasse 8 D-89081, Ulm, Germany
| | - J-L Canon
- Oncologie Médicale, Grand Hopital de Charleroi, 3, Grand’Rue Charleroi, 6000, Belgium
| | - F Lofts
- Department of Oncology, St George’s Hospital NHS Trust, London, UK
| | - C Castanon
- Department of Medical Oncology, Hospital Clinico de Salamanca, Salamanca, Spain
| | - E Fonseca
- Department of Medical Oncology, Hospital Universitario Paseo de San Vicente, Salamanca, Spain
| | - O Rixe
- Department of Medical Oncology, Salpêtrière Hospital, Paris, France
| | - J Aparicio
- Department of Medical Oncology, Hospital Universitario La Fe, Valencia, Spain
| | - J Cassinello
- Department of Medical Oncology, Hospital General Universitario de Guadalajara, Guadalajara, Spain
| | - M Nicolson
- Department of Oncology, Aberdeen Royal Infirmary, Aberdeen, UK
| | - M Mousseau
- Department of Oncology and Haematology, University Hospital, CHU de Grenoble, Grenoble, France
| | - A Schalhorn
- Klinikum der Universität München Grosshadern, Munich, Germany
| | - L D'Hondt
- Chu Mont Godinne, Avenue Docteur G. Thérasse, Yvoir 1 – 5530, Belgium
| | - J Kerger
- Chu Mont Godinne, Avenue Docteur G. Thérasse, Yvoir 1 – 5530, Belgium
| | - D K Hossfeld
- Department of Oncology-Haematology, Medical University Clinic, Hamburg, Germany
| | - C Garcia Giron
- Department of Medical Oncology, Hospital General Yagüe, del Cid, Burgos 96 09005, Spain
| | - R Rodriguez
- Department of Medical Oncology, Complejo Hospitalario de Orense, Orense, Spain
| | - P Schoffski
- Department of Medical Oncology, Leuven Cancer Institute, University Hospitals, Leuven, Belgium
| | - J-L Misset
- Médicale Hôpital St Louis, 1 av. Claude Vellefaux, Paris 75010, France
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