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Van der Speeten K, Kusamura S, Villeneuve L, Piso P, Verwaal VJ, González-Moreno S, Glehen O. The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: HIPEC Technologies. Ann Surg Oncol 2024; 31:7090-7110. [PMID: 39037523 DOI: 10.1245/s10434-024-15513-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Accepted: 05/09/2024] [Indexed: 07/23/2024]
Abstract
This manuscript reports the results of an international consensus on technologies of hyperthermic intraperitoneal perioperative chemotherapy (HIPEC) performed with the following goals: To provide recommendations for the technological parameters to perform HIPEC. To identify the role of heat and its application forms in treating peritoneal metastases. To provide recommendations regarding the correct dosimetry of intraperitoneal chemotherapy drugs and their carrier solutions. To identify for each intraperitoneal chemotherapy regimen the best dosimetry and fractionation. To identify areas of future research pertaining to HIPEC technology and regimens. This consensus was performed by the Delphi technique and comprised two rounds of voting. In total, 96 of 102 eligible panelists replied to both Delphi rounds (94.1%) with a consensus of 39/51 questions on HIPEC technical aspects. Among the recommendations that met with the strongest consensus were those concerning the dose of HIPEC drug established in mg/m2, a target temperature of at least 42°C, and the use of at least three temperature probes to pursue hyperthermia. Ninety minutes as the ideal HIPEC duration seemed to make consensus. These results should be considered when designing new clinical trials in patients with peritoneal surface malignancies.
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Affiliation(s)
- Kurt Van der Speeten
- Department of Surgical Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium.
- Faculty of Life Sciences, BIOMED Research Institute, University Hasselt, Hasselt, Belgium.
| | - Shigeki Kusamura
- Department of Surgical Oncology, PSM unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Laurent Villeneuve
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France
| | - Pompiliu Piso
- Department of General and Visceral Surgery, Hospital Barmherzige Brüder, Regensburg, Germany
| | - Vic J Verwaal
- Peritoneal Surface Malignancy and HIPEC Institute for Regional Sundhedforskning, Syddansk University, Odense, Sweden
| | | | - Olivier Glehen
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France
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Bhatt A, Glehen O, Zivanovic O, Brennan D, Nadeau C, Van Driel W, Bakrin N. The 2022 PSOGI International Consensus on HIPEC Regimens for Peritoneal Malignancies: Epithelial Ovarian Cancer. Ann Surg Oncol 2023; 30:8115-8137. [PMID: 37561343 DOI: 10.1245/s10434-023-13932-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 06/27/2023] [Indexed: 08/11/2023]
Abstract
BACKGROUND AND AIM We report the results of an international consensus on hyperthermic intraperitoneal chemotherapy (HIPEC) regimens for epithelial ovarian cancer (EOC) performed with the following goals: To define the indications for HIPEC To identify the most suitable HIPEC regimens for each indication in EOC To identify areas of future research on HIPEC To provide recommendations for some aspects of perioperative care for HIPEC METHODS: The Delphi technique was used with two rounds of voting. There were three categories of questions: evidence-based recommendations [using the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system with the patient, intervention, comparator, and outcome (PICO) method], an opinion survey, and research recommendations. RESULTS Seventy-three (67.5%) of 108 invited experts responded in round I, and 68 (62.9%) in round II. Consensus was achieved for 34/38 (94.7%) questions. However, a strong positive consensus that would lead to inclusion in routine care was reached for only 6/38 (15.7%) questions. HIPEC in addition to interval cytoreductive surgery (CRS) received a strong positive recommendation that merits inclusion in routine care. Single-agent cisplatin was the only drug recommended for routine care, and OVHIPEC-1 was the most preferred regimen. The panel recommended performing HIPEC for a minimum of 60 min with a recommended minimum intraabdominal temperature of 41°C. Nephroprotection with sodium thiosulfate should be used for cisplatin HIPEC. CONCLUSIONS The results of this consensus should guide clinical decisions on indications of HIPEC and the choice and various parameters of HIPEC regimens and could fill current knowledge gaps. These outcomes should be the basis for designing future clinical trials on HIPEC in EOC.
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Affiliation(s)
- Aditi Bhatt
- Department of Surgical Oncology, KD Hospital, Ahmedabad, India.
| | - Olivier Glehen
- Department of Surgical Oncology, Centre Hospitalier, Lyon-sud, Lyon, France
| | - Oliver Zivanovic
- Department of Gynecological Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Donal Brennan
- UCD Gynaecological Oncology Group, UCD School of Medicine, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Cedric Nadeau
- Department of Gynecological Oncology, CHU de Poitiers, Poitiers, Cedex, France
| | - Willemien Van Driel
- Department of Gynecological Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Naoual Bakrin
- Department of Surgical Oncology, Centre Hospitalier, Lyon-sud, Lyon, France
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Dai W, Chen Y, Xue Y, Wan M, Mao C, Zhang K. Progress in the Treatment of Peritoneal Metastatic Cancer and the Application of Therapeutic Nanoagents. ACS APPLIED BIO MATERIALS 2023; 6:4518-4548. [PMID: 37916787 DOI: 10.1021/acsabm.3c00662] [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] [Indexed: 11/03/2023]
Abstract
Peritoneal metastatic cancer is a cancer caused by the direct growth of cancer cells from the primary site through the bloodstream, lymph, or peritoneum, which is a difficult part of current clinical treatment. In the abdominal cavity of patients with metastatic peritoneal cancer, there are usually nodules of various sizes and malignant ascites. Among them, nodules of different sizes can obstruct intestinal movement and form intestinal obstruction, while malignant ascites can cause abdominal distension and discomfort, and even cause patients to have difficulty in breathing. The pathology and physiology of peritoneal metastatic cancer are complex and not fully understood. The main hypothesis is "seed" and "soil"; i.e., cells from the primary tumor are shed and implanted in the peritoneal cavity (peritoneal metastasis). In the last two decades, the main treatment modalities used clinically are cytoreductive surgery (CRS), systemic chemotherapy, intraperitoneal chemotherapy, and combined treatment, all of which help to improve patient survival and quality of life (QOL). However, the small-molecule chemotherapeutic drugs used clinically still have problems such as rapid drug metabolism and systemic toxicity. With the rapid development of nanotechnology in recent years, therapeutic nanoagents for the treatment of peritoneal metastatic cancer have been gradually developed, which has improved the therapeutic effect and reduced the systemic toxicity of small-molecule chemotherapeutic drugs to a certain extent. In addition, nanomaterials have been developed not only as therapeutic agents but also as imaging agents to guide peritoneal tumor CRS. In this review, we describe the etiology and pathological features of peritoneal metastatic cancer, discuss in detail the clinical treatments that have been used for peritoneal metastatic cancer, and analyze the advantages and disadvantages of the different clinical treatments and the QOL of the treated patients, followed by a discussion focusing on the progress, obstacles, and challenges in the use of therapeutic nanoagents in peritoneal metastatic cancer. Finally, therapeutic nanoagents and therapeutic tools that may be used in the future for the treatment of peritoneal metastatic cancer are prospected.
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Affiliation(s)
- Wenjun Dai
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Yidan Chen
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yunxin Xue
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Ke Zhang
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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Tu L, Zhang W, Ni L, Xu Z, Yang K, Gou H, Zhu Q, Liu M, Yang Y, Hu J, Qiu M. Study of SOX combined with intraperitoneal high-dose paclitaxel in gastric cancer with synchronous peritoneal metastasis: A phase II single-arm clinical trial. Cancer Med 2023; 12:4161-4169. [PMID: 36161282 PMCID: PMC9972103 DOI: 10.1002/cam4.5277] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 06/23/2022] [Accepted: 07/22/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Intraperitoneal paclitaxel is proved to be efficient for peritoneal metastasis of gastric cancer. It remains uncertain the efficacy and safety of the triplets regimen which combined intraperitoneal high-dose paclitaxel with systemic SOX in gastric cancer patients with peritoneal metastasis. This study aimed to evaluate the efficacy and safety of intraperitoneal administration of high-dose paclitaxel, intravenous oxaliplatin and S-1 in patients with peritoneal metastatic gastric cancer. METHODS This single-center, prospective, single-arm phase II study was conducted between January 2017 and May 2019 in West China Hospital, Sichuan University. Patients diagnosed with primary gastric cancer by histopathology and confirmed synchronous peritoneal metastasis were enrolled. This study aimed to evaluate efficacy and safety of intraperitoneal administration of high-dose paclitaxel (80 mg/m2 , d1), intravenous oxaliplatin (100 mg/m2 , d1), and S-1 (80 mg/m2 , d1-14) of patients. The primary endpoint was 1-year overall survival rate, and the second endpoints were progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and adverse events. RESULTS In this single-arm phase II clinical trial, 49 patients received SOX combined intraperitoneal high-dose paclitaxel treatment. One-year survival rate was 81.6% (95% CI, 68.6-90.0%). Median PFS and OS were 6.50 months (95% CI, 2.89-10.11) and 16.9 months (95% CI, 13.58 to 20.22), respectively; ORR was 55.3% (95% CI, 41.3-68.6) and DCR was 76.6% (95% CI, 62.8-86.4). Thirteen patients underwent second laparoscopic detection, but only nine ultimately underwent radical gastrectomy. Subgroup analysis showed that sPCI ≤12 was a good index for a favorable prognosis. The most frequent grade 3/4 toxicities were neutropenia (40.8%), anemia (22.4%), leukopenia (18.4%), nausea (14.3%), and vomiting (12.2%). None of the patients had any intraperitoneal catheter-related complications. CONCLUSIONS Intraperitoneal high-dose paclitaxel with systemic SOX is an effective and tolerable first-line treatment for patients with peritoneal metastatic gastric cancer and patients with sPCI≤12 scores might be recommended crowd for this regimen as conversion therapy.
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Affiliation(s)
- Li Tu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Weihan Zhang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Lu Ni
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Zihan Xu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Kun Yang
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Hongfeng Gou
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Qing Zhu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Liu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Yu Yang
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jiankun Hu
- Department of Gastrointestinal Surgery and Laboratory of Gastric Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China
| | - Meng Qiu
- Department of Medical Oncology, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
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Guchelaar NAD, Noordman BJ, Koolen SLW, Mostert B, Madsen EVE, Burger JWA, Brandt-Kerkhof ARM, Creemers GJ, de Hingh IHJT, Luyer M, Bins S, van Meerten E, Lagarde SM, Verhoef C, Wijnhoven BPL, Mathijssen RHJ. Intraperitoneal Chemotherapy for Unresectable Peritoneal Surface Malignancies. Drugs 2023; 83:159-180. [PMID: 36633826 PMCID: PMC9908703 DOI: 10.1007/s40265-022-01828-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2022] [Indexed: 01/13/2023]
Abstract
Malignancies of the peritoneal cavity are associated with a dismal prognosis. Systemic chemotherapy is the gold standard for patients with unresectable peritoneal disease, but its intraperitoneal effect is hampered by the peritoneal-plasma barrier. Intraperitoneal chemotherapy, which is administered repeatedly into the peritoneal cavity through a peritoneal implanted port, could provide a novel treatment modality for this patient population. This review provides a systematic overview of intraperitoneal used drugs, the performed clinical studies so far, and the complications of the peritoneal implemental ports. Several anticancer drugs have been studied for intraperitoneal application, with the taxanes paclitaxel and docetaxel as the most commonly used drug. Repeated intraperitoneal chemotherapy, mostly in combination with systemic chemotherapy, has shown promising results in Phase I and Phase II studies for several tumor types, such as gastric cancer, ovarian cancer, colorectal cancer, and pancreatic cancer. Two Phase III studies for intraperitoneal chemotherapy in gastric cancer have been performed so far, but the results regarding the superiority over standard systemic chemotherapy alone, are contradictory. Pressurized intraperitoneal administration, known as PIPAC, is an alternative way of administering intraperitoneal chemotherapy, and the first prospective studies have shown a tolerable safety profile. Although intraperitoneal chemotherapy might be a standard treatment option for patients with unresectable peritoneal disease, more Phase II and Phase III studies focusing on tolerability profiles, survival rates, and quality of life are warranted in order to establish optimal treatment schedules and to establish a potential role for intraperitoneal chemotherapy in the approach to unresectable peritoneal disease.
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Affiliation(s)
- Niels A. D. Guchelaar
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Bo J. Noordman
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Stijn L. W. Koolen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
- Department of Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Bianca Mostert
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Eva V. E. Madsen
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | | | - Alexandra R. M. Brandt-Kerkhof
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Geert-Jan Creemers
- Department of Medical Oncology, Catharina Cancer Institute, Eindhoven, The Netherlands
| | - Ignace H. J. T. de Hingh
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands
- Department of Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Misha Luyer
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands
| | - Sander Bins
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Esther van Meerten
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
| | - Sjoerd M. Lagarde
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Cornelis Verhoef
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Bas P. L. Wijnhoven
- Department of Surgery, Division of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ron. H. J. Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands
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Mehta S, Kammar P, Patel A, Goswami G, Shaikh S, Sukumar V, Trivedi E, Bhatt A. Feasibility and Safety of Taxane-PIPAC in Patients with Peritoneal Malignancies-a Retrospective Bi-institutional Study. Indian J Surg Oncol 2022; 14:1-9. [PMID: 36091624 PMCID: PMC9451111 DOI: 10.1007/s13193-022-01641-4] [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: 07/19/2022] [Accepted: 08/31/2022] [Indexed: 11/30/2022] Open
Abstract
Taxanes have a favorable pharmacokinetic profile for intraperitoneal application. We report our initial experience with taxane-PIPAC (pressurized intraperitoneal chemotherapy) for unresectable peritoneal metastases from different primary sites in terms of safety, feasibility, response rate, and conversion to resectability. In this retrospective study, PIPAC was performed alone or in combination with systemic chemotherapy. Paclitaxel was used as a single agent, whereas docetaxel was used in combination with cisplatin-adriamycin or oxaliplatin-adriamycin. From December 2019 to December 2021, 47 patients underwent 82 PIPAC procedures (1 PIPAC in 55.3%, 2 in 29.7%, 3 in 14.8%). The most common primary sites were ovarian cancer (31.9%), gastric cancer (23.4%), and colorectal cancer (21.2%). Docetaxel-cisplatin-adriamycin was used in 33 (70.2%) patients, docetaxel-oxaliplatin-adriamycin in 12 (25.5%), and paclitaxel alone in 2 (4.2%) patients. Grade 1-2 complications were observed in 24 (51%) and grade 3-4 complications in 6 (12.7%) patients (8.5% of 82 PIPACs). 16/47 (34.0%) patients had a clinical response to PIPAC. The mean PCI was 25.9 ± 9.2 for the first PIPACs and 22.4 ± 9 for the subsequent PIPACs with an average reduction of 3.6 points [change in PCI ranged from - 14 to + 8]. The PRGS was 1/2 in 4/47 (8.5%) patients (19.0% patients with > 1 PIPAC). A reduction in ascites was observed in 35.4% presenting with ascites. Nine (19.1%) patients had conversion to operability leading to a subsequent cytoreductive surgery in 8 (17%) patients. PIPAC with docetaxel is feasible and safe. The role of PIPAC with both docetaxel and paclitaxel either alone or in combination with other drugs should be investigated in prospective studies.
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Affiliation(s)
- Sanket Mehta
- Department of Surgical Oncology, Saifee Hospital, Mumbai, India
| | - Praveen Kammar
- Department of Surgical Oncology, Saifee Hospital, Mumbai, India
| | - Ankita Patel
- Department of Surgical Oncology, Zydus Hospital, Thaltej, Ahmedabad, 380054 India
| | - Gaurav Goswami
- Department of Radiology, Zydus Hospital, Ahmedabad, India
| | - Sakina Shaikh
- Department of Surgical Oncology, Zydus Hospital, Thaltej, Ahmedabad, 380054 India
| | - Vivek Sukumar
- Department of Surgical Oncology, Saifee Hospital, Mumbai, India
| | - Esha Trivedi
- Department of Surgical Oncology, Saifee Hospital, Mumbai, India
| | - Aditi Bhatt
- Department of Surgical Oncology, Zydus Hospital, Thaltej, Ahmedabad, 380054 India
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Zhang Y, Wang S, Duan X, Xu X, Gao Y, Zhou J, Xu X, Li J. mPEG-PDLLA Micelles Potentiate Docetaxel for Intraperitoneal Chemotherapy in Ovarian Cancer Peritoneal Metastasis. Front Pharmacol 2022; 13:861938. [PMID: 35462938 PMCID: PMC9019464 DOI: 10.3389/fphar.2022.861938] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/14/2022] [Indexed: 01/10/2023] Open
Abstract
Ovarian cancer is the second most common cause of gynecological cancer death in women. It is usually diagnosed late and accompanied by peritoneal metastasis. For ovarian cancer with peritoneal metastasis, intraperitoneal (IP) chemotherapy can maintain a high drug concentration in the abdominal cavity and reduce local and systemic toxicity. Recently, docetaxel (DTX) has shown broad-spectrum antitumor activity against various malignant tumors, including ovarian cancer with peritoneal metastasis. However, DTX has limited clinical applications due to its poor water solubility, predisposition to hypersensitivity, fluid retention, and varying degrees of neurotoxicity. In this study, we prepared methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-PDLLA) micelles loaded with DTX and developed an alternative, less toxic, more effective DTX formulation, without Tween 80, and evaluated its pharmacokinetics in the abdominal cavity and its efficacy in ovarian cancer with peritoneal metastasis. The mean diameter of DTX-mPEG-PDLLA was about 25 nm, and the pharmacokinetics of BALB/c mice via IP showed that the plasma exposure of DTX-mPEG-PDLLA was about four times lower than that of DTX. Importantly, DTX-mPEG-PDLLA was significantly more effective than DTX and prolonged the survival period in a SKOV-3 ovarian cancer peritoneal metastasis model. Moreover, the apoptosis rate was significantly increased in vitro. Based on these findings, it is expected that DTX-mPEG-PDLLA can enhance efficacy against ovarian cancer peritoneal metastasis, while reducing toxic side effects, and has the potential to be used in the clinical treatment of peritoneal metastatic cancer.
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Affiliation(s)
- Yumei Zhang
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- Department of VIP Clinic, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shunli Wang
- Department of Pathology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaofan Duan
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaoxiao Xu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yuan Gao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiuli Zhou
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaolin Xu
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jin Li
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Jin Li,
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Bhatt A, de Hingh I, Van Der Speeten K, Hubner M, Deraco M, Bakrin N, Villeneuve L, Kusamura S, Glehen O. HIPEC Methodology and Regimens: The Need for an Expert Consensus. Ann Surg Oncol 2021; 28:9098-9113. [PMID: 34142293 DOI: 10.1245/s10434-021-10193-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 05/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hyperthermic intraperitoneal chemotherapy (HIPEC) is performed with a wide variation in methodology, drugs, and other elements vital to the procedure. Adoption of a limited number of regimens could increase the collective experience of peritoneal oncologists, make comparison between studies more meaningful, and lead to a greater acceptance of results from randomized trials. This study aimed to determine the possibility of standardizing HIPEC methodology and regimens and to identify the best method of performing such a standardization. METHODS A critical review of preclinical and clinical studies evaluating the pharmacokinetic aspects of different HIPEC drugs and drug regimens, the impact of hyperthermia, and the efficacy of various HIPEC regimens as well as studies comparing different regimens was performed. RESULTS The preclinical and clinical data were limited, and studies comparing different regimens were scarce. Many of the regimens were neither supported by preclinical rationale or data nor validated by a dose-escalating formal phase 1 trial. All the regimens were based on pharmacokinetic data and did not take chemosensitivity of peritoneal metastases into account. Personalized medicine approaches such as patient-derived tumor organoids could offer a solution to this problem, although clinical validation is likely to be challenging. CONCLUSIONS Apart from randomized trials, more translational research and phases 1 and 2 studies are needed. While waiting for better preclinical and clinical evidence, the best way to minimize heterogeneity is by an expert consensus that aims to identify and define a limited number of regimens for each indication and primary site. The choice of regimen then can be tailored to the patient profile and its expected toxicity and the methodology according regional factors.
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Affiliation(s)
- Aditi Bhatt
- Department of Surgical Oncology, Zydus Hospital, Ahmedabad, India
| | - Ignace de Hingh
- Department of Surgical Oncology, Catharina Hospital, Eidhoven, The Netherlands
| | | | - Martin Hubner
- Department of Visceral Surgery, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - Marcello Deraco
- Department of Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Naoual Bakrin
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France
| | - Laurent Villeneuve
- Department of Clinical Research, Hospices Civils de Lyon, Centre Hospitalier Lyon-sud, Lyon, France
| | - Shigeki Kusamura
- Department of Surgical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Olivier Glehen
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France.
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Therapeutic efficacy of a paclitaxel-loaded nanofibrillated bacterial cellulose (PTX/NFBC) formulation in a peritoneally disseminated gastric cancer xenograft model. Int J Biol Macromol 2021; 174:494-501. [PMID: 33545180 DOI: 10.1016/j.ijbiomac.2021.01.201] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 01/23/2021] [Accepted: 01/29/2021] [Indexed: 12/31/2022]
Abstract
Nano-fibrillated bacterial cellulose (NFBC) is a safe, biocompatible material that can be prepared by culturing a cellulose-producing bacterium in a culture supplemented with carboxymethylcellulose (CMC) or hydroxypropylcellulose (HPC). CM-NFBC and HP-NFBC, prepared using CMC or HPC, show hydrophilicity and amphiphilicity, respectively, and thus they could be useful carriers for hydrophobic anticancer agents such as paclitaxel (PTX). In the present study, we prepared novel PTX formulations for intraperitoneal administration by associating PTX with either CM-NFBC or HP-NFBC and studied their therapeutic efficacy on peritoneally disseminated gastric cancer in a xenograft nude mouse model. Freeze-dried PTX formulations (PTX/CM-NFBC and PTX/HP-NFBC) were quickly reconstituted with saline without any foaming, compared to nanoparticle albumin-bound PTX (nab-PTX, Abraxane®). Both PTX/NFBC formulations extended the mean survival times in our xenograft murine models compared with either free PTX or nab-PTX. The PTX/NFBC formulations reduced systemic side effects of free PTX relating to weight loss. In our disseminated gastric peritoneal cancer model, the PTX/NFBC formulation increased the therapeutic index for PTX by increasing the therapeutic efficacy and decreasing toxicity. NFBCs should receive consideration as improved carriers for the clinical delivery of hydrophobic anticancer drugs such as PTX in malignancies in the abdominal cavity with peritoneal metastasis and dissemination.
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Koemans WJ, van der Kaaij RT, Wassenaar ECE, Grootscholten C, Boot H, Boerma D, Los M, Imhof O, Schellens JHM, Rosing H, Huitema ADR, van Sandick JW. Systemic exposure of oxaliplatin and docetaxel in gastric cancer patients with peritonitis carcinomatosis treated with intraperitoneal hyperthermic chemotherapy. Eur J Surg Oncol 2020; 47:486-489. [PMID: 32800401 DOI: 10.1016/j.ejso.2020.07.037] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 07/28/2020] [Indexed: 12/27/2022] Open
Abstract
In the PERISCOPE I study, gastric cancer patients with limited peritoneal dissemination were treated with systemic chemotherapy followed by (sub)total gastrectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) with 460 mg/m2 hyperthermic oxaliplatin followed by normothermic docetaxel in escalating doses (0, 50, 75 mg/m2). In total, 25 patients completed the study protocol. Plasma samples were collected before the start of the HIPEC procedure, after oxaliplatin washing, after docetaxel washing and the following morning. Median peak plasma concentrations were 5.5∗10-3 mg/ml for oxaliplatin, 89∗10-6 mg/ml for docetaxel (dose 50 mg/m2) and 113∗10-6 mg/ml for docetacel (dose 75 mg/m2). The following morning median plasma concentrations were 32% and 4% of the measured peak concentrations for oxaliplatin and docetaxel, respectively. For both cytostatic agents, no correlation was found between intraperitoneal fluid concentration and peak plasma concentration. High doses oxaliplatin and docetaxel can be given intraperitoneally without causing potentially toxic systemic concentrations.
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Affiliation(s)
- W J Koemans
- Department of Surgical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - R T van der Kaaij
- Department of Surgical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - E C E Wassenaar
- Departments of Surgery, Sint Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands
| | - C Grootscholten
- Department of Gastrointestinal Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - H Boot
- Department of Gastrointestinal Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - D Boerma
- Departments of Surgery, Sint Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands
| | - M Los
- Department of Medical Oncology, Sint Antonius Hospital, Koekoekslaan 1, 3435 CM, Nieuwegein, the Netherlands
| | - O Imhof
- Clinical Perfusion, Heartbeat. Kerkstraat 3a, 3755 CK, Eemnes, the Netherlands
| | - J H M Schellens
- Department of Clinical Pharmacology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - H Rosing
- Department of Pharmacy, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands
| | - A D R Huitema
- Department of Pharmacy, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands; Department of Clinical Pharmacy, University Medical Center Utrecht. Heidelberglaan 100, 3584 CX, Utrecht, the Netherlands
| | - J W van Sandick
- Department of Surgical Oncology, the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
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11
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Carina V, Costa V, Sartori M, Bellavia D, De Luca A, Raimondi L, Fini M, Giavaresi G. Adjuvant Biophysical Therapies in Osteosarcoma. Cancers (Basel) 2019; 11:cancers11030348. [PMID: 30871044 PMCID: PMC6468347 DOI: 10.3390/cancers11030348] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 02/28/2019] [Accepted: 03/08/2019] [Indexed: 12/22/2022] Open
Abstract
Osteosarcoma (OS) is a primary bone sarcoma, manifesting as osteogenesis by malignant cells. Nowadays, patients’ quality of life has been improved, however continuing high rates of limb amputation, pulmonary metastasis and drug toxicity, remain unresolved issues. Thus, effective osteosarcoma therapies are still required. Recently, the potentialities of biophysical treatments in osteosarcoma have been evaluated and seem to offer a promising future, thanks in this field as they are less invasive. Several approaches have been investigated such as hyperthermia (HT), high intensity focused ultrasound (HIFU), low intensity pulsed ultrasound (LIPUS) and sono- and photodynamic therapies (SDT, PDT). This review aims to summarize in vitro and in vivo studies and clinical trials employing biophysical stimuli in osteosarcoma treatment. The findings underscore how the technological development of biophysical therapies might represent an adjuvant role and, in some cases, alternative role to the surgery, radio and chemotherapy treatment of OS. Among them, the most promising are HIFU and HT, which are already employed in OS patient treatment, while LIPUS/SDT and PDT seem to be particularly interesting for their low toxicity.
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Affiliation(s)
- Valeria Carina
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Viviana Costa
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Maria Sartori
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Daniele Bellavia
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Angela De Luca
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Lavinia Raimondi
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Milena Fini
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
| | - Gianluca Giavaresi
- IRCCS-Istituto Ortopedico Rizzoli, via Di Barbiano 1/10, 40136 Bologna, Italy.
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12
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Preparation of Folic Acid-Targeted Temperature-Sensitive Magnetoliposomes and their Antitumor Effects In Vitro and In Vivo. Target Oncol 2018; 13:481-494. [DOI: 10.1007/s11523-018-0577-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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13
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de Bree E, Michelakis D, Stamatiou D, Romanos J, Zoras O. Pharmacological principles of intraperitoneal and bidirectional chemotherapy. Pleura Peritoneum 2017; 2:47-62. [PMID: 30911633 PMCID: PMC6405033 DOI: 10.1515/pp-2017-0010] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Accepted: 04/05/2017] [Indexed: 12/19/2022] Open
Abstract
Intraperitoneal chemotherapy is associated with a significant pharmacokinetic and pharmacodynamic benefit and can, alone or in combination with systemic chemotherapy (bidirectional chemotherapy), be used for treating primary and secondary peritoneal surface malignancies. Due to the peritoneal-plasma barrier, high intraperitoneal drug concentration can be achieved by intraperitoneal chemotherapy, whereas systemic concentration remains low. Bidirectional chemotherapy may provide in addition adequate drug concentrations from the side of the subperitoneal space to the peritoneal tumour nodules. Major pharmacological problems of intraperitoneal chemotherapy are limited tissue penetration and poor homogeneity of drug distribution to the entire seroperitoneal surface. Significant pharmacological determinants of intraperitoneal chemotherapy are choice of drug, drug dosage, solution volume, carrier solution, intra-abdominal pressure, temperature, duration, mode of administration, extent of peritonectomy and interindividual variability. Drugs most commonly applied for intraperitoneal chemotherapy include mitomycin C, cisplatin, carboplatin, oxaliplatin, irinotecan, 5-fluoruracil, gemcitabine, paclitaxel, docetaxel, doxorubicin, premetrexed and melphalan. The drugs and their doses that are used vary widely among centres. While the adequate drug choice for intraperitoneal and bidirectional chemotherapy is essential, randomized clinical trials to determine the most optimal drug or drug combination are lacking, and only eight retrospective comparative clinical studies are available. Further clinical pharmacological studies are required to determine the most effective drug regimen for intraperitoneal and bidirectional chemotherapy in various indications. In the future, reliable drug sensitivity testing and genetic profiling of peritoneal metastases will be needed for enabling patient-specific therapy.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Dimosthenis Michelakis
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Dimitris Stamatiou
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - John Romanos
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
| | - Odysseas Zoras
- Department of Surgical Oncology, Medical School of Crete University Hospital, Heraklion, Greece
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14
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Pouliquen DL, Nawrocki-Raby B, Nader J, Blandin S, Robard M, Birembaut P, Grégoire M. Evaluation of intracavitary administration of curcumin for the treatment of sarcomatoid mesothelioma. Oncotarget 2017; 8:57552-57573. [PMID: 28915695 PMCID: PMC5593667 DOI: 10.18632/oncotarget.15744] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Accepted: 02/06/2017] [Indexed: 12/15/2022] Open
Abstract
A rat model of sarcomatoid mesothelioma, mimicking some of the worst clinical conditions encountered, was established to evaluate the therapeutic potential of intracavitary curcumin administration. The M5-T1 cell line, selected from a collection established from F344 rats induced with asbestos, produces tumors within three weeks, with extended metastasis in normal tissues, after intraperitoneal inoculation in syngeneic rats. The optimal concentration/time conditions for killing M5-T1 cells with curcumin were first determined in vitro. Secondly, the potential of intraperitoneal curcumin administration to kill tumor cells in vivo was evaluated in tumor-bearing rats, in comparison with a reference epigenetic drug, SAHA. Both agents administered at days 21 and 26 after tumor challenge produced necrosis within the solid tumors at day 28. However, tumor tissue necrosis induced with curcumin was much more extensive than with SAHA, and was characterized by infiltration with mononuclear phagocytic cells. In contrast, tumor tissue treated with SAHA contained foci of resistant cells and was infiltrated by many isolated CD8+ cells. The treatment of tumor-bearing rats with 1.5 mg/kg curcumin on days 7, 9, 11 and 14 after tumor challenge dramatically reduced the mean total tumor mass at day 16. Clusters of CD8+ T lymphocytes were observed at the periphery of small residual tumor masses in the peritoneal cavity, which presented a significant reduction in mitotic index, IL6 and vimentin expression compared with tumors in untreated rats. These data open up interesting new prospects for the therapy of sarcomatoid mesothelioma with curcumin and its derivatives.
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Affiliation(s)
- Daniel L Pouliquen
- INSERM, UMR 1232, Nantes, France.,Université de Nantes, Nantes, France.,CNRS ERL, Nantes, France
| | - Béatrice Nawrocki-Raby
- INSERM, UMR-S 903, Reims, France.,Université de Reims Champagne-Ardenne, Reims, France.,SFR CAP-Santé, Reims, France
| | - Joëlle Nader
- INSERM, UMR 1232, Nantes, France.,Université de Nantes, Nantes, France.,CNRS ERL, Nantes, France
| | - Stéphanie Blandin
- Université de Nantes, Nantes, France.,Plate-forme MicroPICell, SFR François Bonamy, Nantes, France
| | - Myriam Robard
- Université de Nantes, Nantes, France.,Plate-forme MicroPICell, SFR François Bonamy, Nantes, France
| | - Philippe Birembaut
- INSERM, UMR-S 903, Reims, France.,Université de Reims Champagne-Ardenne, Reims, France.,SFR CAP-Santé, Reims, France.,Laboratory of Biopathology, CHU Reims, Reims, France
| | - Marc Grégoire
- INSERM, UMR 1232, Nantes, France.,Université de Nantes, Nantes, France.,CNRS ERL, Nantes, France
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15
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Oršolić N, Car N. Quercetin and hyperthermia modulate cisplatin-induced DNA damage in tumor and normal tissues in vivo. Tumour Biol 2014; 35:6445-54. [DOI: 10.1007/s13277-014-1843-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Accepted: 03/12/2014] [Indexed: 11/30/2022] Open
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16
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Pu C, Chang S, Sun J, Zhu S, Liu H, Zhu Y, Wang Z, Xu RX. Ultrasound-mediated destruction of LHRHa-targeted and paclitaxel-loaded lipid microbubbles for the treatment of intraperitoneal ovarian cancer xenografts. Mol Pharm 2013; 11:49-58. [PMID: 24237050 DOI: 10.1021/mp400523h] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Ultrasound-targeted microbubble destruction (UTMD) is a promising technique to facilitate the delivery of chemotherapy in cancer treatment. However, the process typically uses nonspecific microbubbles, leading to low tumor-to-normal tissue uptake ratio and adverse side effects. In this study, we synthesized the LHRH receptor-targeted and paclitaxel (PTX)-loaded lipid microbubbles (TPLMBs) for tumor-specific binding and enhanced therapeutic effect at the tumor site. An ovarian cancer xenograft model was established by injecting A2780/DDP cells intraperitoneally in BALB/c nude mice. Microscopic imaging of tumor sections after intraperitoneal injection of TPLMBs showed effective binding of the microbubbles with cancer cells. Ultrasound mediated destruction of the intraperitoneally injected TPLMBs yielded a superior therapeutic outcome in comparison with other treatment options. Immunohistochemical analyses of the dissected tumor tissue further confirmed the increased tumor apoptosis and reduced angiogenesis. Our experiment suggests that ultrasound-mediated intraperitoneal administration of the targeted drug-loaded microbubbles may be a useful method for the treatment of ovarian cancer.
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Affiliation(s)
- Caixiu Pu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shufang Chang
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Jiangchuan Sun
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Shenyin Zhu
- Department of Pharmacy, First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Hongxia Liu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Yi Zhu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Zhigang Wang
- Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China
| | - Ronald X Xu
- Department of Obstetrics and Gynecology, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.,Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA
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17
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Lotti M, Busci LM, Campanati L, Catena F, Coccolini F, Bakrin N, Iaco PD, Ercolani G, Grosso G, Pisano M, Poiasina E, Rossetti D, Rossi M, Zamagni C, Bertoli P, Pinna AD, Frigerio L, Ansaloni L. Cytoreductive surgery and HIPEC after neoadjuvant chemotherapy for advanced epithelial ovarian cancer. World J Obstet Gynecol 2013; 2:167-175. [DOI: 10.5317/wjog.v2.i4.167] [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] [Received: 02/21/2013] [Revised: 04/23/2013] [Accepted: 07/11/2013] [Indexed: 02/05/2023] Open
Abstract
AIM: To reduce postoperative complications and to make possible an optimal cytoreduction, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery has been applied with encouraging results.
METHODS: Between December 2009 and February 2012, patients with stage IIIC-IV epithelial ovarian cancer (EOC) underwent diagnostic laparoscopy, to assess the feasibility of optimal debulking surgery. The modified Fagotti score was applied to assess the feasibility of resection with zero residual tumor. Patients who were not candidate for upfront debulking surgery were submitted to NACT, then reassessed according to the RECIST 1.1 criteria and submitted to cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) if they showed clinical response or stable disease. The remaining cycles of adjuvant systemic chemotherapy (ASCT) were administered postoperatively, to complete 6 cycles of systemic chemotherapy.
RESULTS: Nine patients were included. Clinical response to NACT was complete in 3 patients and partial in 5 patients; one patient had stable disease. All patients underwent CRS resulting in CC0 disease prior to HIPEC. Average operative time was 510 min. Average intensive care unit stay was 2 d. Average postoperative hospital stay was 25 d. No postoperative mortality was observed. One patient experienced pelvic abscess. One patient refused ASCT. The remaining 8 patients started ASCT. Average time to chemotherapy was 36 d. All patients are alive, with an average follow up of 11 mo. Eight patients are disease-free at follow up.
CONCLUSION: HIPEC after CRS for advanced EOC is feasible with acceptable morbidity and mortality. NACT may increase the chance for achieving complete cytoreduction. Phase 3 studies are needed to determine the effects of HIPEC on survival.
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18
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Oršolić N, Car N, Lisičić D, Benković V, Knežević AH, Dikić D, Petrik J. Synergism between propolis and hyperthermal intraperitoneal chemotherapy with cisplatin on ehrlich ascites tumor in mice. J Pharm Sci 2013; 102:4395-405. [PMID: 24136132 DOI: 10.1002/jps.23755] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 09/17/2013] [Accepted: 09/25/2013] [Indexed: 12/14/2022]
Abstract
We investigated antitumor, genotoxic, chemopreventive, and immunostimulative effects of local chemoimmunotherapy and hyperthermal intraperitoneal chemotherapy (HIPEC) in a mouse-bearing Ehrlich ascites tumor (EAT). Mice were treated with water-soluble derivative of propolis (WSDP) at a dose of 50 mg kg(-1) , 7 and 3 days before implantation of EAT cells, whereas cisplatin (5 or 10 mg kg(-1) ) was injected 3 days after implantation of EAT cells at 37°C and 43°C. The following variables were analyzed: the total number of cells, differential count of the cells present in the peritoneal cavity, functional activity of macrophages, comet assay, and micronucleus assay. The combination of WSDP + CIS 5 mg kg(-1) at 37°C resulted in tumor growth inhibition and increased the survival of mice by additional 115.25%. WSDP with HIPEC increased the survival of mice by additional 160.3% as compared with HIPEC. WSDP reduced cisplatin toxic and genotoxic effect to normal cells without affecting cisplatin cytotoxicity on EAT cells. In addition, WSDP with HIPEC increased the cytotoxic actions of macrophages to tumor cells. Water-soluble derivative of propolis increases macrophage activity and sensitivity of tumor cells to HIPEC and reduces cisplatin toxicity to normal cells.
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Affiliation(s)
- Nada Oršolić
- Department of Animal Physiology, Faculty of Science, University of Zagreb, Zagreb, 10000, Croatia
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19
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Oršolic N, Car N. WITHDRAWN: Quercetin enhances the effect of hyperthermal intraperitoneal chemotherapy with cisplatin in mice. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2013:S1383-5718(13)00265-9. [PMID: 24060507 DOI: 10.1016/j.mrgentox.2013.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Revised: 06/06/2013] [Accepted: 07/05/2013] [Indexed: 06/02/2023]
Abstract
The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1177/0960327113499048. The duplicate article has therefore been withdrawn.
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Affiliation(s)
- Nada Oršolic
- Department of Animal Physiology, Faculty of Science, University of Zagreb, Rooseveltov trg 6, 10 000 Zagreb, Croatia.
| | - Nikola Car
- Pliva Croatia Ltd., Prilaz baruna Filipovica 25, 10 000 Zagreb, Croatia
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20
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Huang T, Gong W, Li X, Zou C, Jiang G, Li X, Feng D. Enhancement of osteosarcoma cell sensitivity to cisplatin using paclitaxel in the presence of hyperthermia. Int J Hyperthermia 2013; 29:248-55. [PMID: 23527624 DOI: 10.3109/02656736.2013.775511] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
PURPOSE This paper aimed to evaluate the effects of a combination of paclitaxel and cisplatin on osteosarcoma (OS) cell lines in the presence of hyperthermia and to investigate the related mechanism. MATERIALS AND METHODS Two types of OS cell lines (OS732 and MG63) were treated with paclitaxel and cisplatin in the presence of hyperthermia. The survival rate was measured by MTT assay, and the clonogenic rate was measured by a clonogenic assay. The cellular changes were observed with an inverted phase contrast microscope and a fluorescence microscope. The apoptotic effect was analysed with flow cytometry (FCM). Fas expression by the OS cell lines was measured by western blot. Fas expression in OS tissue was measured by immunohistochemistry. RESULTS Our study indicated that 1 h after the application of a combination of 10 μg/mL paclitaxel and 5 μg/mL cisplatin to OS cells at 43 °C, the survival rate of the OS cells was 11.96%, which was significantly lower than when either 10 μg/mL paclitaxel (45.02%) or 5 μg/mL cisplatin (48.69%) was applied alone (p < 0.01). Additionally, the clonogenic assay demonstrated that the clonogenic survival rate in the OS cells of the combination group was lower than that in the individual groups. Moreover, the cellular changes and apoptosis rates indicated that apoptosis in the combined application group was much greater than when either drug was applied individually. Fas expression by OS cell lines was increased by the combination of paclitaxel and cisplatin under hyperthermic conditions. More importantly, our study revealed low Fas expression in OS, which better explained the up-regulation of Fas achieved by the combination of paclitaxel and cisplatin in the presence of hyperthermia. CONCLUSIONS The combination of paclitaxel and cisplatin increases the effects of thermochemotherapy on OS cell lines, primarily through the induction of apoptosis by the up-regulation of Fas expression.
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Affiliation(s)
- Tao Huang
- Department of Orthopaedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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21
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Huang T, Gong WH, Li XC, Zou CP, Jiang GJ, Li XH, Feng DP. Synergistic increase in the sensitivity of osteosarcoma cells to thermochemotherapy with combination of paclitaxel and etoposide. Mol Med Rep 2012; 6:1013-7. [PMID: 22948360 DOI: 10.3892/mmr.2012.1058] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2012] [Accepted: 08/06/2012] [Indexed: 11/05/2022] Open
Abstract
Osteosarcoma is a malignant bone tumor which is found most commonly in adolescents and young adults. Local perfusion thermochemotherapy has long been proposed as an alternative strategy for the treatment of osteosarcoma. As a standard anticancer drug, paclitaxel plays a significant role in the treatment of a number of tumors; however, little is known concerning its ability to promote thermochemotherapy. The aim of this study was to evaluate the cytotoxic effects of a combination of paclitaxel and etoposide on an osteosarcoma cell line in the presence of hyperthermia and to investigate the related mechanism. Our study indicated that 1 h after the application of a combination of 10 µg/ml paclitaxel and 5 µg/ml etoposide to OS732 cells at 43˚C, the survival rate of the cells was 14.52% which was significantly lower than when either 10 µg/ml paclitaxel (45.83%) or 5 µg/ml etoposide (43.31%) was applied alone (P<0.01). Moreover, changes in cellular morphology and apoptotic rates indicated that the apoptosis-inducing effect of the combination was much stronger than that of either drug applied individually. Fas expression levels in the OS732 cells were increased by the combination of paclitaxel and etoposide in the presence of hyperthermia. Therefore, paclitaxel enhances the thermochemotherapy of the osteosarcoma cell line and this is primarily accomplished by the upregulation of Fas expression and the induction of apoptosis.
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Affiliation(s)
- T Huang
- Department of Orthopedics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, PR China.
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22
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Huang T, Gong WH, Li XC, Zou CP, Jiang GJ, Li XH, Feng DP. Induction of apoptosis by a combination of paclitaxel and carboplatin in the presence of hyperthermia. Asian Pac J Cancer Prev 2012; 13:81-5. [PMID: 22502718 DOI: 10.7314/apjcp.2012.13.1.081] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
PURPOSE To study enhancing effects of paclitaxel in the thermochemotherapy of osteosarcoma cell lines and related mechanisms. MATERIALS AND METHODS Paclitaxel and carboplatin were used alone or jointly on OS732 cell lines in the presence of hyperthermia. Inhibition of proliferation was measured by MTT assay and cellular changes were assessed with inverted phase contrast and fluorescence microscopy. Apoptosis was analyzed with flow cytometry (FCM) and Fas expression by immunocytochemistry. RESULTS At 43 degrees C, one hour after the application of 10 μg/ml paclitaxel and 5 μg/ml carboplatin on OS732 cells jointly, the survival rate was 15.8% which was significantly lower than with 10 μg/ml paclitaxel (45.8%) and 5 μg/ml carboplatin (47.7%) respectively (P<0.01). Moreover, changes of morphology and apoptotic rates indicated that the apoptosis-inducing effect of combined application was also much enhanced, as evident also regarding Fas expression. CONCLUSION Paclitaxel is conducive to thermochemotherapy of osteosarcoma cell lines, possibly accomplished by up-regulation of Fas expression with induction of apoptosis.
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Affiliation(s)
- Tao Huang
- Department of Orthopedics, First Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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23
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de Bree E, Helm CW. Hyperthermic intraperitoneal chemotherapy in ovarian cancer: rationale and clinical data. Expert Rev Anticancer Ther 2012; 12:895-911. [PMID: 22845405 DOI: 10.1586/era.12.72] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
The outcome of ovarian cancer remains poor with conventional therapy. Intraperitoneal chemotherapy has some advantages over systemic chemotherapy, including favorable pharmacokinetics and optimal treatment timing. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) provides improved exposure of the entire seroperitoneal surface to the agent and utilizes the direct cytoxic and drug-enhancing effect of hyperthermia. While standard normothermic, nonintraoperative, intraperitoneal chemotherapy has been demonstrated to be beneficial in randomized trials and meta-analyses, there are no data from randomized HIPEC trials available yet. Cautious extrapolation of data from standard normothermic, nonintraoperative, intraperitoneal chemotherapy and data from Phase II and nonrandomized comparative studies suggest that HIPEC delivered at the time of surgery for ovarian cancer has definite potential. Data from ongoing randomized HIPEC trials to adequately answer the question of whether the addition of HIPEC actually prolongs survival in patients with peritoneal dissemination of primary and recurrent ovarian cancer are awaited in the near future.
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Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete-University Hospital, PO Box 1352, 71110 Heraklion, Greece.
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Muller M, Chérel M, Dupré PF, Gouard S, Collet M, Classe JM. The Cytotoxic Effect of Combined Hyperthermia and Taxane Chemotherapy on Ovarian Cancer Cells: Results of an in vitro Study. Eur Surg Res 2012; 48:55-63. [DOI: 10.1159/000333393] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2011] [Accepted: 07/20/2011] [Indexed: 11/19/2022]
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Zahedi P, Stewart J, De Souza R, Piquette-Miller M, Allen C. An injectable depot system for sustained intraperitoneal chemotherapy of ovarian cancer results in favorable drug distribution at the whole body, peritoneal and intratumoral levels. J Control Release 2011; 158:379-85. [PMID: 22154933 DOI: 10.1016/j.jconrel.2011.11.025] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Revised: 11/17/2011] [Accepted: 11/21/2011] [Indexed: 11/28/2022]
Abstract
The current study characterizes the impact of docetaxel (DTX) distribution on efficacy following sustained intraperitoneal (IP) chemotherapy in murine models of ovarian cancer. A polymer-lipid biodegradable depot (PoLigel) was used to deliver DTX in a sustained manner over 21-days following IP administration. Distribution and efficacy studies were carried out in SCID mice bearing SKOV3 IP solid tumors or C57BL/6 mice with ID8 IP ascites fluid. In addition, a subcutaneous (SC) SKOV3 model was used to determine whether systemic drug levels that result from IP administration of the PoLigel influence antitumor efficacy. Immunostained IP and SC SKOV3 tumor sections were used to study cell death, intratumoral drug distribution and tumor penetration. Sustained concentrations of DTX were observed in plasma, tissue, tumor and ascites over the entire study period. Drug accumulation was several fold greater in tumors and ascites when compared to plasma levels. Sustained chemotherapy resulted in significant reduction in tumor burden and ascites volume. IP tumors showed greater cell death compared to the SC tumors as seen by higher TUNEL and caspase-3 expression. At the intratumoral level, DTX distributed more towards the core of IP tumors compared to the SC tumors. Tumor penetration of drug from nearest blood vessel was 1.5 fold greater in the IP tumors than the SC tumors. Overall, favorable drug distribution at the whole-body, peritoneal and intratumoral levels in combination with local and systemic sustained drug exposure contribute to the high efficacy observed. These results encourage the clinical use of IP sustained chemotherapy for ovarian cancer.
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Affiliation(s)
- Payam Zahedi
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
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Crane LMA, van Oosten M, Pleijhuis RG, Motekallemi A, Dowdy SC, Cliby WA, van der Zee AGJ, van Dam GM. Intraoperative imaging in ovarian cancer: fact or fiction? Mol Imaging 2011; 10:248-57. [PMID: 21521557 PMCID: PMC3763956 DOI: 10.2310/7290.2011.00004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Accepted: 10/09/2010] [Indexed: 02/06/2023] Open
Abstract
Tumor-targeted fluorescence imaging for cancer diagnosis and treatment is an evolving field of research that is on the verge of clinical implementation. As each tumor has its unique biologic profile, selection of the most promising targets is essential. In this review, we focus on target finding in ovarian cancer, a disease in which fluorescence imaging may be of value in both adequate staging and in improving cytoreductive efforts, and as such may have a beneficial effect on prognosis. Thus far, tumor-targeted imaging for ovarian cancer has been applied only in animal models. For clinical implementation, the five most prominent targets were identified: folate receptor α, vascular endothelial growth factor, epidermal growth factor receptor, chemokine receptor 4, and matrix metalloproteinase. These targets were selected based on expression rates in ovarian cancer, availability of an antibody or substrate aimed at the target approved by the Food and Drug Administration, and the likelihood of translation to human use. The purpose of this review is to present requirements for intraoperative imaging and to discuss possible tumor-specific targets for ovarian cancer, prioritizing for targets with substrates ready for introduction into the clinic.
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Affiliation(s)
- Lucia M A Crane
- Department of Surgery, Division of Surgical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Muñoz-Casares FC, Rufián S, Arjona-Sánchez Á, Rubio MJ, Díaz R, Casado Á, Naranjo Á, Díaz-Iglesias CJ, Ortega R, Muñoz-Villanueva MC, Muntané J, Aranda E. Neoadjuvant intraperitoneal chemotherapy with paclitaxel for the radical surgical treatment of peritoneal carcinomatosis in ovarian cancer: a prospective pilot study. Cancer Chemother Pharmacol 2011; 68:267-74. [PMID: 21499894 DOI: 10.1007/s00280-011-1646-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2010] [Accepted: 04/01/2011] [Indexed: 12/17/2022]
Abstract
PURPOSE The admitted benefits of intraperitoneal chemotherapy during postoperative administration for the treatment of peritoneal carcinomatosis from ovarian origin are limited by their associated morbidity and restricted diffusion by the presence of multiple intra-abdominal adherences. The purpose of the study was to evaluate the security, effectiveness, and cytoreduction optimization of intraperitoneal paclitaxel administration previously to radical surgery/peritonectomy/HIPEC (hyperthermic intraoperative intraperitoneal chemotherapy) either in monotherapy or combined with intravenous carboplatin. METHODS Prospective pilot study of 10 patients with ovarian peritoneal carcinomatosis in stage IIIc-FIGO without previous treatment. After staging of the diseases by laparoscopy, five patients received paclitaxel by weekly intraperitoneal administration (60 mg/m(2), 10 cycles), and other five patients additionally received intravenous carboplatin every 21 days (AUC 6, 4 cycles). Subsequently radical surgery/peritonectomy with HIPEC was performed. RESULTS The presence of moderate abdominal pain was the most common (70%) side effect associated with neoadjuvant paclitaxel intraperitoneal administration. The intravenous carboplatin administration was not associated with significant increase in adverse effects. It boosted intraperitoneal paclitaxel-associated antitumoral activity with a high average decrease in Index Cancer Peritoneal (21.2 vs. 14.4, P = 0.066) and CA 125(1,053 vs. 346, P = 0.043). All the patients who received combined neoadjuvant chemotherapy obtained R0 cytoreduction. Five-year overall survival was 62%. CONCLUSIONS The intraperitoneal paclitaxel weekly administration combined with intravenous carboplatin administration prior to radical surgery/peritonectomy with HIPEC is a safe and effective option in the treatment of ovarian peritoneal carcinomatosis. This study shows the possibility to investigate other forms of intraperitoneal chemotherapy and their combinations thoroughly.
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Affiliation(s)
- Francisco C Muñoz-Casares
- Department of General Surgery. Surgical Oncology Unit, Reina Sofía University Hospital, Avda. Menéndez Pidal s/n, 14004 Córdoba, Spain.
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van Oosten M, Crane LM, Bart J, van Leeuwen FW, van Dam GM. Selecting Potential Targetable Biomarkers for Imaging Purposes in Colorectal Cancer Using TArget Selection Criteria (TASC): A Novel Target Identification Tool. Transl Oncol 2011; 4:71-82. [PMID: 21461170 PMCID: PMC3069650 DOI: 10.1593/tlo.10220] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2010] [Revised: 10/23/2010] [Accepted: 11/01/2010] [Indexed: 12/19/2022] Open
Abstract
Peritoneal carcinomatosis (PC) of colorectal origin is associated with a poor prognosis. However, cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is available for a selected group of PC patients, which significantly increases overall survival rates up to 30%. As a consequence, there is substantial room for improvement. Tumor targeting is expected to improve the treatment efficacy of colorectal cancer (CRC) further through 1) more sensitive preoperative tumor detection, thus reducing overtreatment; 2) better intraoperative detection and surgical elimination of residual disease using tumor-specific intraoperative imaging; and 3) tumor-specific targeted therapeutics. This review focuses, in particular, on the development of tumor-targeted imaging agents. A large number of biomarkers are known to be upregulated in CRC. However, to date, no validated criteria have been described for the selection of the most promising biomarkers for tumor targeting. Such a scoring system might improve the selection of the correct biomarker for imaging purposes. In this review, we present the TArget Selection Criteria (TASC) scoring system for selection of potential biomarkers for tumor-targeted imaging. By applying TASC to biomarkers for CRC, we identified seven biomarkers (carcinoembryonic antigen, CXC chemokine receptor 4, epidermal growth factor receptor, epithelial cell adhesion molecule, matrix metalloproteinases, mucin 1, and vascular endothelial growth factor A) that seem most suitable for tumor-targeted imaging applications in colorectal cancer. Further cross-validation studies in CRC and other tumor types are necessary to establish its definitive value.
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Affiliation(s)
- Marleen van Oosten
- Department of Surgery, Division of Surgical Oncology, Surgical Research Laboratory/BioOptical Imaging Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Kamei T, Kitayama J, Yamaguchi H, Soma D, Emoto S, Konno T, Ishihara K, Ishigami H, Kaisaki S, Nagawa H. Spatial distribution of intraperitoneally administrated paclitaxel nanoparticles solubilized with poly (2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) in peritoneal metastatic nodules. Cancer Sci 2011; 102:200-5. [PMID: 20942868 PMCID: PMC11158943 DOI: 10.1111/j.1349-7006.2010.01747.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Intraperitoneal (i.p.) administration of paclitaxel nanoparticles (PTX-30W) prepared by solubulization with the amphiphilic copolymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate can efficiently suppress the growth of peritoneal metastasis. In this study, we characterized the drug distribution of i.p. injected PTX-30W in peritoneal tumor and liver in a mouse model using MKN45, human gastric cancer cells. Oregon green-conjugated PTX-30W showed perivascular accumulation in MKN45 tumor in the peritoneum at 24 h after intravenous (i.v.) injection; however, the amount of PTX in tumor was markedly less than that in liver. In contrast, a larger amount of PTX accumulated in the peripheral area of disseminated nodules at 1 h after i.p. injection and the area gradually enlarged. The depth of PTX infiltration reached 1 mm from the tumor surface at 48 h after i.p. injection, and the fluorescence intensity was markedly greater than that in liver. Interestingly, i.p. injected PTX preferentially accumulated in relatively hypovascular areas, and many tumor cells in the vicinity of PTX accumulation showed apoptosis. This unique accumulation pattern and lesser washout in hypovascular areas are thought to be attributable to the superior penetrating activity of PTX-30W, and thus, PTX-30W is considered to be highly suitable for i.p. chemotherapy for peritoneal dissemination.
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Affiliation(s)
- Takao Kamei
- Department of Surgery, Division of Surgical Oncology, University of Tokyo, Tokyo, Japan
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De Stefano I, Battaglia A, Zannoni GF, Prisco MG, Fattorossi A, Travaglia D, Baroni S, Renier D, Scambia G, Ferlini C, Gallo D. Hyaluronic acid–paclitaxel: effects of intraperitoneal administration against CD44(+) human ovarian cancer xenografts. Cancer Chemother Pharmacol 2010; 68:107-16. [DOI: 10.1007/s00280-010-1462-2] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 09/02/2010] [Indexed: 01/11/2023]
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Yan TD, Cao CQ, Munkholm-Larsen S. A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy. World J Gastrointest Oncol 2010; 2:109-16. [PMID: 21160929 PMCID: PMC2999163 DOI: 10.4251/wjgo.v2.i2.109] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2009] [Revised: 07/23/2009] [Accepted: 07/30/2009] [Indexed: 02/05/2023] Open
Abstract
Perioperative intraperitoneal chemotherapy in combination with cytoreductive surgery has been shown to be of benefit for treating selected patients with peritoneal surface malignancy. It has become a new standard of care in the management of diffuse malignant peritoneal mesothelioma and peritoneal dissemination of appendiceal malignancy. Numerous recent publications on carcinomatosis from colorectal cancer and gastric cancer identify groups of patients that would benefit from this local-regional approach for prevention and treatment of carcinomatosis. This review focuses on pharmacological information regarding intraperitoneal chemotherapeutic agents commonly used in gastrointestinal oncology.
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Affiliation(s)
- Tristan D Yan
- Tristan D Yan, Stine Munkholm-Larsen, Department of Cardiothoracic Surgery, University of Sydney, Royal Prince Alfred Hospital, 50 Missenden Road, Camperdown, NSW 2050, Australia
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Muñoz-Casares FC, Rufián S, Rubio MJ, Díaz CJ, Díaz R, Casado Á, Arjona Á, Muñoz-Villanueva MC, Muntané J. The role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinomatosis in recurrent ovarian cancer. Clin Transl Oncol 2009; 11:753-9. [DOI: 10.1007/s12094-009-0438-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Soma D, Kitayama J, Konno T, Ishihara K, Yamada J, Kamei T, Ishigami H, Kaisaki S, Nagawa H. Intraperitoneal administration of paclitaxel solubilized with poly(2-methacryloxyethyl phosphorylcholine-co n-butyl methacrylate) for peritoneal dissemination of gastric cancer. Cancer Sci 2009; 100:1979-85. [PMID: 19604244 PMCID: PMC11159799 DOI: 10.1111/j.1349-7006.2009.01265.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Intraperitoneal (i.p.) administration of paclitaxel (PTX) is a hopeful therapeutic strategy for peritoneal malignancy. Intravenously (i.v.) injected nanoparticle anticancer drugs are known to be retained in the blood stream for a long time and favorably extravasated from vessels into the interstitium of tumor tissue. In this study, we evaluated the effect of i.p. injection of PTX (PTX-30W), which was prepared by solubulization with water-soluble amphiphilic polymer composed of PMB-30W, a co-polymer of 2-methacryloxyethyl phosphorylcholine and n-butyl methacrylate, for peritoneal dissemination of gastric cancer. In a peritoneal metastasis model with transfer of MKN45P in nude mice, the effect of i.p. administration of PTX-30W was compared with conventional PTX dissolved in Cremophor EL (PTX-Cre). The drug accumulation in peritoneal nodules was evaluated with intratumor PTX concentration and fluorescence microscopic observation. PTX-30W reduced the number of metastatic nodules and tumor volume significantly more than did conventional PTX dissolved in Cremophor EL (PTX-Cre), and prolonged the survival time (P < 0.05). PTX concentration in disseminated tumors measured by HPLC was higher in the PTX-30W than in the PTX-Cre group up to 24 h after i.p. injection. Oregon green-conjugated PTX-30W, i.p. administered, preferentially accumulated in relatively hypovascular areas in the peripheral part of disseminated nodules, which was significantly greater than the accumulation of PTX-Cre. I.p. administration of PTX-30W may be a promising strategy for peritoneal dissemination, due to its superior characteristics to accumulate in peritoneal lesions.
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Affiliation(s)
- Daisuke Soma
- Department of Surgery, Division of Surgical Oncology, School of Engineering, University of Tokyo, Tokyo, Japan
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Abstract
Regional chemotherapy was developed in the 1950s and continues to play an integral part in the development of newer therapies for advanced solid malignancies. Regional therapies have evolved in complexity but are still based on the pharmacokinetics of drug delivery to solid malignancies. Newer techniques demonstrate that the combination of regional therapies, hyperthermia, and surgery is essential in promoting improved patient outcomes.
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35
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Issels RD. Hyperthermia adds to chemotherapy. Eur J Cancer 2008; 44:2546-54. [PMID: 18789678 DOI: 10.1016/j.ejca.2008.07.038] [Citation(s) in RCA: 358] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Revised: 07/17/2008] [Accepted: 07/24/2008] [Indexed: 01/11/2023]
Abstract
The hallmarks of hyperthermia and its pleotropic effects are in favour of its combined use with chemotherapy. Preclinical research reveals that for heat killing and synergistic effects the thermal dose is most critical. Thermal enhancement of drug cytotoxicity is accompanied by cellular death and necrosis without increasing its oncogenic potential. The induction of genetically defined stress responses can deliver danger signals to activate the host's immune system. The positive results of randomised trials have definitely established hyperthermia in combination with chemotherapy as a novel clinical modality for the treatment of cancer. Hyperthermia targets the action of chemotherapy within the heated tumour region without affecting systemic toxicity. In specific clinical settings regional hyperthermia (RHT) or hyperthermic perfusion has proved its value and deserve a greater focus and investigation in other malignancies. In Europe, more specialised centres should be created and maintained as network of excellence for hyperthermia in the field of oncology.
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Affiliation(s)
- Rolf D Issels
- University of Munich, Campus Grosshadern, Medical Clinic III, Munich, Germany.
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Soma D, Kitayama J, Ishigami H, Kaisaki S, Nagawa H. Different tissue distribution of paclitaxel with intravenous and intraperitoneal administration. J Surg Res 2008; 155:142-6. [PMID: 19328496 DOI: 10.1016/j.jss.2008.06.049] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2008] [Revised: 06/23/2008] [Accepted: 06/27/2008] [Indexed: 02/09/2023]
Abstract
PURPOSE Paclitaxel is considered to be suitable for disseminated cancer in the peritoneal cavity because of its high molecular weight and lipophilic characteristics. However, the difference in pharmacokinetics of paclitaxel after intraperitoneal (i.p.) and intravenous (i.v.) administration is not fully defined. Here, we investigated the tissue concentration of paclitaxel in various organs at various time points after i.p. or i.v. administration. METHODS Paclitaxel (5 mg/kg) was administrated in an ear vein or in the abdominal cavity of rabbits. At 0.5, 6, 24, and 48 h after administration, the rabbits were sacrificed, and organs as well as peripheral blood were harvested. The serum and tissue concentrations of paclitaxel were measured by HPLC procedure. RESULT The concentration of paclitaxel was high in the i.v. group at 0.5 h, whereas it was significantly higher in the i.p. group at 6 and 24 h. The AUC (area under the curve) was markedly higher in the omentum, mesenteric lymph nodes as well as ovary and stomach in the i.p. group. CONCLUSION Compared with i.v. administration, paclitaxel concentration was maintained at a high level in the whole body by i.p. administration. Repeated i.p. paclitaxel can produce more marked clinical effects than i.v. administration for metastatic lymph nodes and primary lesions as well as peritoneal dissemination.
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Affiliation(s)
- Daisuke Soma
- Department of Surgery, Division of Surgical Oncology, University of Tokyo, Japan.
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Reducing peritoneal vascular endothelial growth factor concentration and inhibiting cancer scattering in a mouse model of laparoscopy. Am J Obstet Gynecol 2008; 198:423.e1-7. [PMID: 18241828 DOI: 10.1016/j.ajog.2007.10.791] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2007] [Revised: 08/17/2007] [Accepted: 10/11/2007] [Indexed: 11/23/2022]
Abstract
OBJECTIVE The objective of the study was to investigate the efficacy of early intraperitoneal (i.p.) paclitaxel administration in reducing vascular endothelial growth factor (VEGF) concentration in peritoneal fluid and preventing intraoperative cancer scattering during laparoscopy. STUDY DESIGN Nude mice were given i.p. ovarian cancer SKOV-3 xenografts to simulate intraoperative cancer dissemination and were assigned into concurrent- (day 0) and salvage-giving (day 5) treatment groups and nontreatment and nonxenografted groups. RESULTS The xenografted nontreatment group showed markedly increased peritoneal VEGF concentrations, whereas the paclitaxel (no-tumor) control group showed significantly reduced concentrations. In mice with cancer xenografts, both concurrent- and salvage-giving treatment groups showed significantly decreased peritoneal VEGF concentrations (P < .05), and the concurrent-giving group had significantly fewer implanted cancer nodules (P < .05), whereas the salvage-giving group had decreased total tumor weights (P < .05) compared with nontreatment. Total tumor weights were found closely correlated to peritoneal VEGF concentrations in a positive exponential relationship (P = .003, R(2) = 0.581). CONCLUSION Early treatment with IP paclitaxel significantly decreased the VEGF concentration in peritoneal fluid, which was associated with reduced implantation and growth of disseminated cancer cells after laparoscopy. These encouraging results suggest a useful strategy for future clinical applications.
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Treatment of peritoneal carcinomatosis from ovarian cancer. Present, future directions and proposals. Clin Transl Oncol 2007; 9:652-62. [DOI: 10.1007/s12094-007-0118-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
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Auzenne E, Ghosh SC, Khodadadian M, Rivera B, Farquhar D, Price RE, Ravoori M, Kundra V, Freedman RS, Klostergaard J. Hyaluronic acid-paclitaxel: antitumor efficacy against CD44(+) human ovarian carcinoma xenografts. Neoplasia 2007; 9:479-86. [PMID: 17603630 PMCID: PMC1899257 DOI: 10.1593/neo.07229] [Citation(s) in RCA: 126] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2007] [Revised: 04/20/2007] [Accepted: 04/23/2007] [Indexed: 11/18/2022] Open
Abstract
Numerous human tumor types, including ovarian cancer, display a significant expression of the CD44 family of cell surface proteoglycans. To develop tumor-targeted drugs, we have initially evaluated whether the CD44 ligand hyaluronic acid (HA) could serve as a backbone for paclitaxel (TXL) prodrugs. HA-TXL was prepared by modification of previous techniques. The in vitro cytotoxicity of HA-TXL against the CD44(+) human ovarian carcinoma cell lines SKOV-3ip and NMP-1 could be significantly blocked by preincubation with a molar excess of free HA. Female nude mice bearing intraperitoneal implants of NMP-1 cells were treated intraperitoneally with a single sub-maximum tolerated dose dose of HA-TXL or with multiple-dose regimens of paclitaxel (Taxol; Mead Johnson, Princeton, NJ) to determine the effects of these regimens on host survival and intraperitoneal tumor burden, with the latter being assessed by magnetic resonance imaging. NMP-1 xenografts were highly resistant to Taxol regimens, as host survival was only nominally improved compared to controls (T//C approximately 120), whereas single-dose HA-TXL treatment significantly improved survival in this model (T//C approximately 140; P = .004). In both NMP-1 and SKOV-3ip models, MR images of abdomens of HA-TXL-treated mice obtained shortly before controls required humane sacrifice revealed markedly reduced tumor burdens compared to control mice. This study is among the first to demonstrate that HA-based prodrugs administered locoregionally have antitumor activity in vivo.
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Affiliation(s)
- Edmond Auzenne
- The University of Texas M. D. Anderson Cancer Center, Houston, TX 77339, USA
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de Bree E, Tsiftsis DD. Experimental and pharmacokinetic studies in intraperitoneal chemotherapy: from laboratory bench to bedside. RECENT RESULTS IN CANCER RESEARCH. FORTSCHRITTE DER KREBSFORSCHUNG. PROGRES DANS LES RECHERCHES SUR LE CANCER 2007; 169:53-73. [PMID: 17506249 DOI: 10.1007/978-3-540-30760-0_5] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Eelco de Bree
- Department of Surgical Oncology, Medical School of Crete University Hospital, Herakleion, Greece
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Michalakis J, Georgatos SD, de Bree E, Polioudaki H, Romanos J, Georgoulias V, Tsiftsis DD, Theodoropoulos PA. Short-term exposure of cancer cells to micromolar doses of paclitaxel, with or without hyperthermia, induces long-term inhibition of cell proliferation and cell death in vitro. Ann Surg Oncol 2007; 14:1220-8. [PMID: 17206477 DOI: 10.1245/s10434-006-9305-4] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2006] [Revised: 07/17/2006] [Accepted: 08/08/2006] [Indexed: 01/07/2023]
Abstract
BACKGROUND During intraoperative hyperthermic intraperitoneal chemotherapy for primary or secondary peritoneal malignancies, tumor cells are exposed to high drug concentrations for a relatively short period of time. We investigated in vitro the effect of paclitaxel and hyperthermia on cell proliferation, cell cycle kinetics and cell death under conditions resembling those during intraoperative hyperthermic intraperitoneal chemotherapy. METHODS Human breast MCF-7, ovarian SKOV-3 and hepatocarcinoma HEpG2 cells were exposed to 10 and 20 microM paclitaxel at 37, 41.5 or 43 degrees C for 2 h. Cell proliferation, cell cycle kinetics, necrosis and apoptosis were evaluated. RESULTS Hyperthermia exerted a cytostatic effect to all cell lines and at 43 degrees C a cytotoxic effect on MCF-7 cells. MCF-7 and SKOV-3 cells treated under normothermic conditions with paclitaxel were arrested at G2/M or M phase for at least 3 days. Most of MCF-7 cells and approximately half of SKOV-3 cells were in interphase and became multinucleated without properly completing cytokinesis. Hyperthermia at 41.5 degrees C altered cell cycle distribution and affected the paclitaxel-related effect on cell cycle kinetics of MCF-7 and SKOV-3 cells. Analysis of the mode of cell death showed that cell necrosis prevailed over apoptosis. Hyperthermia at 43 degrees C increased paclitaxel-mediated cytotoxicity in MCF-7 cells and to a lesser extent in SKOV-3 and HEpG2 cells. CONCLUSIONS Short-time treatment of carcinoma cells with high (micromolar) concentrations of paclitaxel in normothermic and hyperthermic conditions is highly efficient for cell growth arrest and could be of clinical relevance in locoregional chemotherapy.
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Affiliation(s)
- John Michalakis
- Department of Biochemistry, School of Medicine, University of Crete, P.O. Box 2208, 71003, Heraklion, Greece
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Jurczok A, Schneider A, Fornara P. Inhibition of tumor implantation after laparoscopy by specific oligopeptides: a novel approach to adjuvant intraperitoneal therapy to prevent tumor implantation in an animal model. Eur Urol 2006; 52:590-5. [PMID: 17097215 DOI: 10.1016/j.eururo.2006.10.057] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Accepted: 10/23/2006] [Indexed: 12/22/2022]
Abstract
OBJECTIVES The development of intra-abdominal tumor spread and port-site metastases in urothelial cancer are still questions regarding the safety of laparoscopic methods for the resection of malignancies. Currently, the actual incidence of intra-abdominal tumor spread and port-site metastasis remains unknown. Herein, we investigated the influence of antiadhesive oligopeptides and cytotoxic agents (administered intraperitoneally) on implantation of a tumor cell suspension after laparoscopic surgery in an experimental model. METHODS Forty C57 bl6 mice underwent laparoscopy with CO(2) insufflation and instillation of a MB 49 syngenic urothelial tumor cell suspension into the abdominal cavity. Mice were randomly allocated to one of the following groups (n=10 mice per group), and all agents were administrated intraperitoneally: (1) control (phosphate-buffered saline); (2) unspecific oligopeptides; (3) specific oligopeptides; (4) mitomycin. The mice were sacrificed 14 d after the procedure, and the peritoneal cavity and port sites examined for the presence of tumor. RESULTS A significant reduction in tumor implantation and port-site metastases was observed in all treatment groups (specific oligopeptides and mitomycin). The oligopeptide group showed the best performance regarding body weight. CONCLUSIONS This study suggests that tumor implantation after laparoscopic surgery and port-site metastases might be prevented by the intraperitoneal administration of specific oligopeptides or cytotoxic agents. Moreover, oligopeptides, in comparison with mitomycin, caused less weight loss of the mice.
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Affiliation(s)
- Andreas Jurczok
- Department of Urology, Medical Faculty, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
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