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Ardizzone A, Bulzomì M, De Luca F, Silvestris N, Esposito E, Capra AP. Dihydropyrimidine Dehydrogenase Polymorphism c.2194G>A Screening Is a Useful Tool for Decreasing Gastrointestinal and Hematological Adverse Drug Reaction Risk in Fluoropyrimidine-Treated Patients. Curr Issues Mol Biol 2024; 46:9831-9843. [PMID: 39329936 PMCID: PMC11430620 DOI: 10.3390/cimb46090584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/19/2024] [Accepted: 09/03/2024] [Indexed: 09/28/2024] Open
Abstract
Although the risk of fluoropyrimidine toxicity may be decreased by identifying poor metabolizers with a preemptive dihydropyrimidine dehydrogenase (DPYD) test, following international standards, many patients with wild-type (WT) genotypes for classic variations may still exhibit adverse drug reactions (ADRs). Therefore, the safety of fluoropyrimidine therapy could be improved by identifying new DPYD polymorphisms associated with ADRs. This study was carried out to assess whether testing for the underestimated c.2194G>A (DPYD*6 polymorphism, rs1801160) is useful, in addition to other well-known variants, in reducing the risk of ADRs in patients undergoing chemotherapy treatment. This retrospective study included 132 patients treated with fluoropyrimidine-containing regimens who experienced ADRs such as gastrointestinal, dermatological, hematological, and neurological. All subjects were screened for DPYD variants DPYD2A (IVS14+1G>A, c.1905+1G>A, rs3918290), DPYD13 (c.1679T>G, rs55886062), c.2846A>T (rs67376798), c.1236G>A (rs56038477), and c.2194G>A by real-time polymerase chain reaction (RT-PCR). In this cohort, the heterozygous c.2194G>A variant was present in 26 patients, while 106 individuals were WT; both subgroups were compared for the incidence of ADRs. This assessment revealed a high incidence of gastrointestinal and hematological ADRs in DPYD6 carriers compared to WT. Moreover, we have shown a higher prevalence of ADRs in females compared to males when stratifying c.2194G>A carrier individuals. Considering that c.2194G>A was linked to clinically relevant ADRs, we suggest that this variant should also be assessed preventively to reduce the risk of fluoropyrimidine-related ADRs.
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Affiliation(s)
- Alessio Ardizzone
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (A.A.); (M.B.); (F.D.L.); (A.P.C.)
| | - Maria Bulzomì
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (A.A.); (M.B.); (F.D.L.); (A.P.C.)
| | - Fabiola De Luca
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (A.A.); (M.B.); (F.D.L.); (A.P.C.)
| | - Nicola Silvestris
- Medical Oncology Unit, Department of Human Pathology “G. Barresi”, University of Messina, 98125 Messina, Italy;
| | - Emanuela Esposito
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (A.A.); (M.B.); (F.D.L.); (A.P.C.)
- Genetics and Pharmacogenetics Unit, “Gaetano Martino” University Hospital, Via Consolare Valeria 1, 98125 Messina, Italy
| | - Anna Paola Capra
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Ferdinando Stagno D’Alcontres, 31, 98166 Messina, Italy; (A.A.); (M.B.); (F.D.L.); (A.P.C.)
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Mimansa, Zafar MA, Verma DK, Das R, Agrewala JN, Shanavas A. Shielding against breast tumor relapse with an autologous chemo-photo-immune active Nano-Micro-Sera based fibrin implant. NANOSCALE 2024; 16:14006-14019. [PMID: 38989622 DOI: 10.1039/d4nr01076k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2024]
Abstract
Local recurrence post-surgery in early-stage triple-negative breast cancer is a major challenge. To control the regrowth of a residual tumor, we have developed an autologous therapeutic hybrid fibrin glue for intra-operative implantation. Using autologous serum proteins as stabilizers, we have optimized high drug-loaded lapatinib-NanoSera (Lap-NS; ∼66% L.C.) and imiquimod-MicroSera (IMQ-MS; ∼92% L.C). Additionally, plasmonic nanosera (PNS) with an ∼67% photothermal conversion efficiency under 980 nm laser irradiation was also developed. While localized monotherapy with either Lap-NS or PNS reduced the tumor regrowth rate, their combination with IMQ-MS amplified the effect of immunogenic cell death with a high level of tumor infiltration by immune cells at the surgical site. The localized combination immunotherapy with a Nano-MicroSera based hybrid fibrin implant showed superior tumor inhibition and survival with significant promise for clinical translation.
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Affiliation(s)
- Mimansa
- Inorganic & Organic Nanomedicine (ION) Lab, Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Punjab 140306, India.
| | - Mohammad Adeel Zafar
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Dinesh Kumar Verma
- All India Institute of Medical Sciences Bilaspur, Changar Palasiyan, Noa, Himachal Pradesh, 174001, India
| | - Reena Das
- Department of Haematology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
| | - Javed Naim Agrewala
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, Rupnagar, Punjab 140001, India
| | - Asifkhan Shanavas
- Inorganic & Organic Nanomedicine (ION) Lab, Chemical Biology Unit, Institute of Nano Science and Technology, Sector-81, Knowledge City, Sahibzada Ajit Singh Nagar, Punjab 140306, India.
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Liu R, Hu X, Lai C. Effectiveness and safety of intraoperative intraperitoneal 5-Fu drug implantation in patients with colorectal cancer: a retrospective cohort study. J Cancer Res Clin Oncol 2024; 150:92. [PMID: 38349419 PMCID: PMC10864533 DOI: 10.1007/s00432-023-05523-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 12/06/2023] [Indexed: 02/15/2024]
Abstract
PURPOSE The purpose of this clinical study was to evaluate the efficacy and safety of intraoperative chemotherapy (IOC) with intraoperative intraperitoneal implantation of 5-fluorouracil (5-FU) in colorectal cancer (CRC) patients. METHODS In this study, 165 patients who underwent colorectal radical surgery were selected, of whom 111 in the experimental group received surgical treatment with an intraperitoneal 5-fluorouracil (5-FU) implantation. Fifty-four patients who did not undergo intraperitoneal implantation of 5-FU were matched to compare the progression-free survival (PFS) and overall survival (OS) with the former. RESULTS We also studied the differences in the changes of different biochemical indicators between the two groups before and after surgery, and there were significant differences in leukocytes, neutrophils, and lymphocytes before and after (P < 0.05), while for sodium ions, potassium ions, platelets, alanine transaminase, aspartate transaminase, creatinine, urea, and albumin, there were no significant differences. This may be related to the intraperitoneal chemotherapy implant entering the blood circulation. For 5-year OS, there were 85/111 (76.58%) in the 5-FU group (P = 0.013) and 35/54 (64.81%) in the control group; for 5-year PFS, there were 84/111 (75.68%) in the 5-FU group and 29/54 (53.70%) in the control group (P = 0.02). All the experimental groups were better than the control group with a significant difference in the experimental results. CONCLUSION For CRC surgery patients, intraperitoneal implantation of slow-release 5-FU drugs, which is a safe and simple procedure, can improve the prognosis of the patients. CLINICAL TRIAL REGISTRATION No clinical trials were performed in the study.
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Affiliation(s)
- Renchao Liu
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital Central South University, Changsha, Hunan, China
- International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Changsha, China
| | - Xianqin Hu
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital Central South University, Changsha, Hunan, China
- International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Changsha, China
| | - Chen Lai
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital Central South University, Changsha, Hunan, China.
- International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Changsha, China.
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Chen W, Shi K, Liu J, Yang P, Han R, Pan M, Yuan L, Fang C, Yu Y, Qian Z. Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer. Bioact Mater 2023; 23:1-15. [PMID: 36406247 PMCID: PMC9650011 DOI: 10.1016/j.bioactmat.2022.10.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/02/2022] [Accepted: 10/03/2022] [Indexed: 11/09/2022] Open
Abstract
Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.
Intraoperative chemotherapy could reduce the recurrence and metastasis after surgical resection of gastroenteric tumors. 5-FU and DDP co-delivery system based on PLEL was developed for intraoperative combination chemotherapy of gastric cancer. This dual-drug loaded hydrogel helped to improve synergistic anti-tumor effects and reduce adverse side effects in vivo. 5-FU+DDP/PLEL could inhibit recurrence of orthotopic tumors and growth of abdominal metastatic tumors in gastric cancer.
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He P, Xu S, Guo Z, Yuan P, Liu Y, Chen Y, Zhang T, Que Y, Hu Y. Pharmacodynamics and pharmacokinetics of PLGA-based doxorubicin-loaded implants for tumor therapy. Drug Deliv 2022; 29:478-488. [PMID: 35147071 PMCID: PMC8843208 DOI: 10.1080/10717544.2022.2032878] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/08/2023] Open
Abstract
The traditional systemic chemotherapy through intravenous infusion of doxorubicin (DOX) has many side effects. The aim of this study was to develop a PLGA-based DOX-loaded implant and to evaluate the efficacy and drug metabolism distribution of the implant in intratumoral chemotherapy for osteosarcoma (OS). In this study, implants containing DOX, poly(d,l-lactide-co-glycolide), and polyethylene glycol 4000 were prepared by melt-molding method. Then, the antitumor activity and systemic drug distribution of the implants were tested in a K7M2 OS bearing mouse model. The scanning electron microscope images showed that DOX was uniformly dispersed in the polymer matrix. Both the in vitro and in vivo release profiles of implants are characterized by three-phase release. Implantation of DOX-loaded implants into tumors can inhibit tumor growth in a dose-dependent manner. The pharmacokinetic behavior shows that intratumor chemotherapy through implants has a much higher drug concentration in tumors than in normal tissues, which may be the reason for improving antitumor activity and reducing systemic side effects. In summary, the drug release of the implants prepared in this study is sustained and stable, which promotes long-term local accumulation of drugs in tumors, improves the efficacy of chemotherapy and has low toxicity to normal tissues.
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Affiliation(s)
- Peng He
- Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Shenglin Xu
- Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zehao Guo
- Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Peng Yuan
- Department of Orthopedics, Fuyang Hospital of Anhui Medical University, Fuyang, China
| | - Yulei Liu
- Department of Orthopedics, Fuyang Hospital of Anhui Medical University, Fuyang, China
| | - Yu Chen
- Department of Pharmacy, Anqing Medical College, Anqing, China
| | - Tiantian Zhang
- Laboratory of Pharmaceutical Research, Anhui Zhongren Science and Technology Co., Ltd, Hefei, China
| | - Yukang Que
- Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yong Hu
- Department of Orthopedics, First Affiliated Hospital of Anhui Medical University, Hefei, China
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Wu YZ, Wu M, Zheng XH, Wang BZ, Xue LY, Ding SK, Yang L, Ren JS, Tian YT, Xie YB. No long-term survival benefit with sustained-release 5-fluorouracil implants in patients with stages II and III gastric cancer. World J Gastroenterol 2022; 28:5589-5601. [PMID: 36304092 PMCID: PMC9594009 DOI: 10.3748/wjg.v28.i38.5589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 09/10/2022] [Accepted: 09/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The prognosis of gastric cancer in an advanced stage remains poor. The exact efficacy of the use of intraoperative sustained-release chemotherapy with 5-fluorouracil (5-FU) in advanced-stage gastric cancer is still unelucidated. AIM To explore the long-term survival benefit of using sustained-release 5-FU implants in stage II and stage III gastric cancer patients. METHODS Patients with gastric cancer in a locally advanced stage and who underwent an R0 radical resection between Jan 2014, to Dec 2016, in this single institution were included. Patients with pathological diagnoses other than adenocarcinoma were excluded. All included patients were grouped according to whether intraoperative sustained-release (SR) chemotherapy with 5-FU was used or not (NSR). The primary end-point was 5-year overall survival. Kaplan-Meier method with log-rank test was used to analyze the overall survival of patients and Cox analysis was used to analyze prognosis factors of these patients. RESULTS In total, there were 563 patients with gastric cancer with locally advanced stage, who underwent an R0 radical resection. 309 patients were included in the final analysis. 219 (70.9%) were men, with an average age of 58.25 years. Furthermore, 56 (18.1%) received neoadjuvant chemotherapy, and 191 (61.8%) were in TNM stage III. In addition, 158 patients received intraoperative sustained-release chemotherapy with 5-FU and were included in the SR group, while the other 161 patients were included in the NSR group. The overall complication rate was 12.94% in the whole group and 10.81%, 16.46% in SR and NSR groups, respectively. There were no significant differences between the two groups in overall survival and complication rate (P > 0.05). The multivariate cox analysis indicated that only N Stage and neoadjuvant therapy were independent influencing factors of survival. CONCLUSION Intraoperative sustained-release chemotherapy usage with 5-FU, did not improve the survival of patients who underwent an R0 radical resection in locally advanced stage of gastric cancer.
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Affiliation(s)
- Yun-Zi Wu
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ming Wu
- Department of Gastrointestinal Surgery, Yun Cheng Center Hospital, Yuncheng 044000, Shanxi Province, China
| | - Xiao-Hao Zheng
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Bing-Zhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Li-Yan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Shi-Kang Ding
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jian-Song Ren
- Office of Cancer Screening, 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-Tao Tian
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yi-Bin Xie
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang 065001, Hebei Province, China
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Xu Y, Zhang R, Li C, Sun Z, Deng J, Wang X, Ding X, Wang B, Xue Q, Ke B, Zhan H, Liu N, Liu Y, Wang X, Liang H, Xue Y, Xu H. Intraperitoneal Chemotherapy Using Fluorouracil Implants Combined With Radical Resection and Postoperative Adjuvant Chemotherapy for Stage III Gastric Cancer: A Multi-Center, Randomized, Open-Label, Controlled Clinical Study. Front Oncol 2021; 11:670651. [PMID: 34307140 PMCID: PMC8298064 DOI: 10.3389/fonc.2021.670651] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 06/22/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Reducing peritoneal recurrence after radical surgery is an important choice to improve the prognosis of patients with advanced gastric cancer. Intraoperative intraperitoneal chemotherapy has the potential to be a promising treatment strategy. In the present study, we conducted a multi-center, randomized, controlled clinical study to evaluate the efficacy and safety of intraoperative intraperitoneal chemotherapy using sustained-release fluorouracil implants plus radical gastrectomy and adjuvant chemotherapy for cTNM stage III gastric cancer. METHODS The patients were randomized into intraperitoneal chemotherapy group (sustained-release fluorouracil implants administration after standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy) and control group (standard D2 radical gastrectomy, and followed by XELOX adjuvant chemotherapy). A total of 122 patients from three centers were enrolled from September 2015 to February 2017. RESULTS One hundred and two eligible patients completed the treatment course. The median follow-up time was 41.7 months (36.1-52.9 months). The 3-year progression-free survival rate and overall survival of patients in the intraperitoneal chemotherapy group were 43.9% and 49.1%, respectively, which were significantly better than those of the control group, 31.0% and 38.4%. In the intraperitoneal chemotherapy group, the number of cases with peritoneal recurrence was significantly less than that of the control group, 9 cases (17.3%) vs. 19 cases (44.2%). There were neither significant differences between the groups in the incidence of hematogenous metastasis, lymph node metastasis, nor local metastasis. CONCLUSION For cTNM stage III gastric cancer, intraoperative sustained-release fluorouracil implants after radical resection combined with postoperative adjuvant chemotherapy, could significantly reduce the risk of peritoneal recurrence and prolong PFS.Clinical Trial Registration: https://clinicaltrials.gov/, identifier (NCT02269904).
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Affiliation(s)
- Yan Xu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Rupeng Zhang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Chunfeng Li
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Zhe Sun
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Jingyu Deng
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Xiaona Wang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Xuewei Ding
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Baogui Wang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Qiang Xue
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Bin Ke
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Hongjie Zhan
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Ning Liu
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Yong Liu
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Xuejun Wang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Han Liang
- Department of Gastric Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Cancer for Cancer, Tianjin, China
| | - Yingwei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huimian Xu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Shenyang, China
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Ge J, Liu T, Lei T, Li X, Song K, Azizi S, Liu H, Tang M. Retrospective Cohort Study of Intraoperative Administration of Sustained-Release 5-Fluorouracil Implants in Advanced Gastric Cancer Patients. Front Pharmacol 2021; 12:659258. [PMID: 33927633 PMCID: PMC8076801 DOI: 10.3389/fphar.2021.659258] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/08/2021] [Indexed: 12/13/2022] Open
Abstract
Background: 5-fluorouracil (5-FU) is basically used in the field of postoperative chemotherapy of gastric cancer (GC), the goal of this study was to evaluate improvement of long-term survival rate among GC patients after the 5-FU implants treatment. Methods: The study included 145 patients with gastric cancer who received postoperative chemotherapy with 5-FU implants and had complete follow-up information. According to the sex, age and clinical stage of 5-FU implants group, 74 patients were matched as the control group at the same time. In the study, we compared the 5-year overall survival rate with progression-free survival rate in the two groups, and the drug safety for both groups during the treatment was also compared. Results: The median follow-up time was 85 months (range 60–116 months). 31 patients (21.38%) died of tumor recurrence in 5-FU implants group and 21 (28.38%) in control group. In the control group, metastatic lesions were found in the small intestine, left adrenal gland and peritoneum in three patients. The 5-year progression-free survival (PFS) rate was 79.71% in 5-FU group and 67.12% in control (p = 0.0045). The 5-year overall survival (OS) rate was 77.68% in 5-FU implants group and 64.87% in control (p = 0.0159). Both the 5-years OS and PFS rates in 5-FU group were better than control group without significant side effect. Conclusions: 5-FU implants may improve 5-years OS and PFS rates after surgery in gastric cancer patients, while good safety profile suggests it could be reliable.
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Affiliation(s)
- Jie Ge
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Ting Liu
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Xuan Li
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Kun Song
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Samim Azizi
- Department of Cardiothoracic and Vascular Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, China
| | - Mimi Tang
- Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, China
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Does Intraperitoneal Chemotherapy Increase the Incidence of Anastomotic Leakage after Colorectal Cancer Surgery: A Systematic Review and Meta-Analysis. Gastroenterol Res Pract 2021; 2021:9204373. [PMID: 33564302 PMCID: PMC7850836 DOI: 10.1155/2021/9204373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 01/13/2021] [Indexed: 12/28/2022] Open
Abstract
Purpose To identify and evaluate the influence of intraperitoneal chemotherapy without hyperthermia (ICwh) to the incidence of anastomotic leakage (AL) after colorectal cancer surgery. Methods A systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses in order to review all studies investigating the relationship between ICwh and AL in patients undergoing colorectal surgery. The primary outcome was overall incidence rate of anastomotic leakage. Results Four studies were included in the final review. ICwh was associated with an overall increased risk of anastomotic leakage [OR 2.05 (1.06, 3.98), P = 0.03]. But there was no significant increased incidence rate when fluorouracil was implanted into the abdominal cavity for ICwh [OR 2.48 (0.55, 11.10), P = 0.24]. Conclusions This meta-analysis provides some evidence to suggest ICwh may increase the incidence of postoperative AL in colorectal cancer. However, fluorouracil implantation for ICwh does not increase the risk of AL, which seems to be a relatively safe method of ICwh.
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A Retrospective Study of Risk Factors for Symptomatic Anastomotic Leakage after Laparoscopic Anterior Resection of the Rectal Cancer without a Diverting Stoma. Gastroenterol Res Pract 2020; 2020:4863542. [PMID: 32351555 PMCID: PMC7174905 DOI: 10.1155/2020/4863542] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 03/21/2020] [Indexed: 02/06/2023] Open
Abstract
Background Anastomotic leakage (AL) is a common and devastating postoperative issue for patients who have undergone anterior resection of rectal carcinoma and can lead to increased short-term morbidity and mortality. Moreover, it might be associated with a worse oncological prognosis of tumors. This study is aimed at exploring the risk factors for symptomatic AL after laparoscopic anterior resection (LAR) for rectal tumors without a preventive diverting stoma. Materials and Methods This case control study retrospectively reviewed the data of 496 consecutive patients who underwent LAR of the rectum without a preventive diverting stoma at the Cancer Hospital, Chinese Academy of Medical Sciences between September 2016 and September 2017. All patients were divided into an AL group and a control group based on the occurrence of postoperative symptomatic AL. Factors regarding patient-related variables, operation-related variables, and tumor-related variables were collected and assessed between the two groups through univariate and multivariate logistic regression analyses to identify independent risk factors for AL. Results In total, 18 (3.6%) patients developed postoperative symptomatic AL. Univariate analysis showed that a synchronous primary malignancy of the left hemicolon (P = 0.047), intraoperative chemotherapy (P = 0.003), and level of anastomosis (P = 0.033) were significantly related with AL. Multivariate analysis was subsequently performed to adjust for confounding biases and confirmed that a synchronous primary malignancy of the left hemicolon (odds ratio (OR), 12.225; 95% confidence interval (CI), 1.764-84.702; P = 0.011), intraoperative chemotherapy (OR, 3.931; 95% CI, 1.334-11.583; P = 0.013), and level of anastomosis (OR, 3.224; 95% CI, 1.124-9.249; P = 0.030) were independent risk factors for symptomatic AL for patients who received LAR for rectal neoplasms without a preventive diverting stoma. Conclusions Synchronous primary malignancy of the left hemicolon, intraoperative chemotherapy, and a low anastomotic level can increase the risks of postoperative symptomatic AL after LAR of the rectum without a protective diverting stoma.
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Wang ZJ, Tao JH, Chen JN, Mei SW, Shen HY, Zhao FQ, Liu Q. Intraoperative intraperitoneal chemotherapy increases the incidence of anastomotic leakage after anterior resection of rectal tumors. World J Gastrointest Oncol 2019; 11:538-550. [PMID: 31367273 PMCID: PMC6657222 DOI: 10.4251/wjgo.v11.i7.538] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 05/01/2019] [Accepted: 05/29/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Intraoperative intraperitoneal chemotherapy is an emerging treatment modality for locally advanced rectal neoplasms. However, its impacts on postoperative complications remain unknown. Anastomotic leakage (AL) is one of the most common and serious complications associated with the anterior resection of rectal tumors. Therefore, we designed this study to determine the effects of intraoperative intraperitoneal chemotherapy on AL.
AIM To investigate whether intraoperative intraperitoneal chemotherapy increases the incidence of AL after the anterior resection of rectal neoplasms.
METHODS This retrospective cohort study collected information from 477 consecutive patients who underwent an anterior resection of rectal carcinoma using the double stapling technique at our institution from September 2016 to September 2017. Based on the administration of intraoperative intraperitoneal chemotherapy or not, the patients were divided into a chemotherapy group (171 cases with intraperitoneal implantation of chemotherapy agents during the operation) or a control group (306 cases without intraoperative intraperitoneal chemotherapy). Clinicopathologic features, intraoperative treatment, and postoperative complications were recorded and analyzed to determine the effects of intraoperative intraperitoneal chemotherapy on the incidence of AL. The clinical outcomes of the two groups were also compared through survival analysis.
RESULTS The univariate analysis showed a significantly higher incidence of AL in the patients who received intraoperative intraperitoneal chemotherapy, with 13 (7.6%) cases in the chemotherapy group and 5 (1.6%) cases in the control group (P = 0.001). As for the severity of AL, the AL patients who underwent intraoperative intraperitoneal chemotherapy tended to be more severe cases, and 12 (92.3%) out of 13 AL patients in the chemotherapy group and 2 (40.0%) out of 5 AL patients in the control group required a secondary operation (P = 0.044). A multivariate analysis was subsequently performed to adjust for the confounding factors and also showed that intraoperative intraperitoneal chemotherapy increased the incidence of AL (odds ratio = 5.386; 95%CI: 1.808-16.042; P = 0.002). However, the survival analysis demonstrated that intraoperative intraperitoneal chemotherapy could also improve the disease-free survival rates for patients with locally advanced rectal cancer.
CONCLUSION Intraoperative intraperitoneal chemotherapy can improve the prognosis of patients with locally advanced rectal carcinoma, but it also increases the risk of AL following the anterior resection of rectal neoplasms.
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Affiliation(s)
- Zhi-Jie Wang
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Jin-Hua Tao
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Jia-Nan Chen
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Shi-Wen Mei
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Hai-Yu Shen
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Fu-Qiang Zhao
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union College, Beijing 100021, China
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Leelakanok N, Geary SM, Salem AK. Antitumor Efficacy and Toxicity of 5-Fluorouracil-Loaded Poly(Lactide Co-glycolide) Pellets. J Pharm Sci 2017; 107:690-697. [PMID: 29031952 DOI: 10.1016/j.xphs.2017.10.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 10/03/2017] [Accepted: 10/04/2017] [Indexed: 02/02/2023]
Abstract
The aim of this study was to formulate a biodegradable implant capable of imparting local antitumor activity through the sustained release of the chemotherapeutic agent, 5-fluorouracil (5-FU). Thus, injectable pellets (<1.2 mm diameter) made from poly(lactide co-glycolide) (PLGA) and loaded with 5-FU at varying drug:polymer ratios were fabricated using hot-melt extrusion and tested for their ability to provide sustained release of 5-FU in in vitro and in vivo settings. In addition, these formulations were compared against soluble 5-FU for their antitumor activity in vivo as well as for their toxicity. It was demonstrated that the release rate of 5-FU from PLGA pellets was directly related to the percentage of 5-FU in the pellets. PLGA pellets loaded with 50% w/w 5-FU exhibited comparable, and significantly enhanced, antitumor activity (as measured by tumor volumes and survival) in vivo in a thymoma and colon cancer model, respectively, when compared to an equivalent bolus dose (120 mg/kg) of soluble 5-FU. We concluded that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections and therefore may prove to be of benefit as an intraoperative adjunct therapy for patients with cancers that are sensitive to 5-FU and who are undergoing tumor resection.
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Affiliation(s)
- Nattawut Leelakanok
- Division of Pharmaceutics and Translational Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa 52242
| | - Sean M Geary
- Division of Pharmaceutics and Translational Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa 52242
| | - Aliasger K Salem
- Division of Pharmaceutics and Translational Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa 52242.
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Zhu JF, Zeng W, Ge L, Wang HJ. Inhibitory effect of intraperitoneal chemotherapy with sustained-release fluorouracil vs fluorouracil injection on peritoneally transplanted MKN-45 tumors in nude mice. Shijie Huaren Xiaohua Zazhi 2016; 24:4684-4690. [DOI: 10.11569/wcjd.v24.i35.4684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To compare the inhibitory effect of sustained-release fluorouracil (Sinofuan) and fluorouracil injection on peritoneally transplanted MKN-45 tumors in nude mice.
METHODS Fifty-one nude mice peritoneally transplanted with MKN-45 cells were randomly divided into three groups: control group, fluorouracil injection group (2 mg/nude mouse), and sustained-release fluorouracil group (2 mg/nude mouse). The general status of the nude mice, body mass changes and survival were observed. Ascites volume was measured, the number of tumor cells per milliliter of ascites was counted, and tumor cell apoptosis was detected.
RESULTS Compared with the control group, the general status of nude mice from the fluorouracil injection group and sustained-release fluorouracil group were better with regard to slower weight gain, delayed systemic symptoms and prolonged survival (P < 0.05). The median survival of mice in the sustained-release fluorouracil group was prolonged compared with the fluorouracil injection group (25 d vs 19 d, P < 0.01). Ascites volume in the sustained-release fluorouracil group was less than that in the fluorouracil injection group [(5.66 mL ± 1.00 mL) vs (8.78 mL ± 1.19 mL), P < 0.01], but the difference in the number of ascitic tumor cells per milliliter between the two groups was not statistically significant [(2.75 × 108/mL ± 0.71 × 108/mL) vs (3.46 × 108/mL ± 0.69 × 108/mL)]. Tumor cell apoptosis rate was significantly higher in the sustained-release fluorouracil group than in the fluorouracil injection group (14.49% ± 0.80% vs 2.03% ± 0.64%, P < 0.01).
CONCLUSION Sustained-release fluorouracil is better than fluorouracil injection in intraperitoneal chemotherapy for peritoneally transplanted MKN-45 tumors in nude mice.
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