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Kazi M, Ajith A, Bhatt A. The Mitomycin versus Oxaliplatin debate on HIPEC in colorectal cancers - An updated systematic review and Meta-analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:110080. [PMID: 40286391 DOI: 10.1016/j.ejso.2025.110080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 03/29/2025] [Accepted: 04/18/2025] [Indexed: 04/29/2025]
Abstract
INTRODUCTION Following the PRODIGE-7 trial, surgeons have shifted to the use of Mitomycin-based HIPEC from Oxaliplatin for colorectal peritoneal metastasis. While preclinical studies have demonstrated the superiority of Mitomycin over oxaliplatin, clinical studies report variable results. The objective of the meta-analysis was to determine the most efficacious drug after cytoreduction for colorectal peritoneal metastasis. METHODS he databases searched were PubMed, Cochrane Library, Scopus, CINHAL (EBSCO), and Google Scholar based on the following concepts: colorectal, peritoneal, cytoreduction, Mitomycin, and Oxaliplatin. The risk of bias was assessed using the Newcastle-Ottawa scale and certainty of the evidence was assessed using the GRADE Pro tool. The analysis was carried out using the log hazard ratio as the outcome measure for survival data. All syntheses used the Random-effects model and were reported for Oxaliplatin-based HIPEC with MMC as the reference. RESULTS Thirteen studies with 3406 patients were included in the quantitative meta-analysis. The pooled hazard ratio for overall survival was 1.03 (95 % CI: 0.786-1.349) from ten studies. Six studies reported disease-free survival and the pooled hazard ratio was 0.941 (95 % CI: 0.683-1.297). Both survival estimates had moderate statistical heterogeneity. The evidence was of very low certainty for all the outcomes due to the non-randomized nature of studies, clinical and statistical heterogeneity, serious risk of bias due to uncontrolled measured confounding, selection bias, and unequal follow-up durations. CONCLUSION Our systematic review and meta-analysis found no significant difference in survival outcomes or postoperative morbidity between MMC and Oxaliplatin-based HIPEC.
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Affiliation(s)
- Mufaddal Kazi
- Division of Gastrointestinal Surgical Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, 400012, India; Department of Surgical Oncology, Advanced Centre for Treatment, Research, and Education in Cancer, Navi Mumbai, 410210, India; Homi Bhabha National Institute, Mumbai, India.
| | - Atul Ajith
- Division of Gastrointestinal Surgical Oncology, Department of Surgical Oncology, Tata Memorial Hospital, Mumbai, 400012, India; Homi Bhabha National Institute, Mumbai, India
| | - Aditi Bhatt
- Department of Surgical Oncology, Shalby Cancer and Research Institute, Ahmedabad, 382421, India
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Levine EA, Cos H, Votanopoulos KI, Shen P, Russell G, Mansfield P, Fournier K, Bartlett D, Stewart JH. Ten-Year Outcome of a Randomized Trial: Cytoreduction and HIPEC with Mitomycin C Versus Oxaliplatin for Appendiceal Neoplasm with Peritoneal Dissemination. Ann Surg Oncol 2025; 32:679-686. [PMID: 39531120 PMCID: PMC11698756 DOI: 10.1245/s10434-024-16441-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Appendiceal cancer is a rare disease that has proven difficult to study in prospectively. Our initial report of this trial showed minor hematologic toxicity with both mitomycin C and oxaliplatin and similar 3-year survival. We now report an update of the first prospective randomized trial for appendiceal cancer with 10-year follow up. PATIENTS AND METHODS Patients with mucinous appendiceal neoplasms and evidence of peritoneal dissemination were enrolled in the Multicenter Randomized Trial to evaluating HIPEC for 120 min with oxaliplatin (200 mg/M2) or mitomycin C (40 mg). Overall survival and disease-free survival were calculated at 10 years and compared between the groups. RESULTS A total of 121 patients were included in the study. The patients were 57% female, with a mean age of 55.3 years (range 22-82 years). The disease was low grade in 71% and high grade in 29%. The average peritoneal cancer index (PCI) score was 18 (SD 10) in the mitomycin C group and 17.9 (SD 9.4) in the oxaliplatin group (p = 0.94). The 10-year survival rate was 56.2% (SE 7.2) with mitomycin C and 47.5% (SE 8.4) with oxaliplatin, p = 0.83. The 10-year progression-free survival rate in the mitomycin C group was 45.2% (SE 8.4) compared with 50.4% (SE 6.7) in the oxaliplatin group, p = 0.95. Median survival was 9.1 years after HIPEC with oxaliplatin, and median not reached for the mitomycin C group (> 5.6 years). CONCLUSIONS Oxaliplatin and mitomycin C have similar long-term efficacy for hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal neoplasms and peritoneal dissemination. Long-term survival is experienced by most patients after cytoreduction surgery (CRS) and HIPEC for appendiceal neoplasms.
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Affiliation(s)
- Edward A Levine
- Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA.
| | - Heidy Cos
- Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA
| | - Konstantinos I Votanopoulos
- Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA
| | - Perry Shen
- Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA
| | - Greg Russell
- Department of Biostatistics and Data Science, Wake Forest Baptist Health, Winston-Salem, NC, USA
| | | | | | | | - John H Stewart
- Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston-Salem, NC, USA
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Kappen J, Abdel-Rahman O. Advances in pharmacotherapy for the treatment of peritoneal metastases from colorectal cancer. Expert Opin Pharmacother 2025; 26:17-30. [PMID: 39604139 DOI: 10.1080/14656566.2024.2435946] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 11/29/2024]
Abstract
INTRODUCTION Patients with peritoneal metastasis (PM) from colorectal cancer (CRC) typically have a poor prognosis with historically few treatment options. Cytoreductive surgery (CRS) is the mainstay of treatment to remove macrometastases into the peritoneum, but residual micrometastases are often left behind. Systemic chemotherapy remains a cornerstone of treatment for micrometastases, but intraperitoneal therapy offers advantages including higher local dose concentration with fewer systemic side effects from treatment. AREAS COVERED This review covers advancements in the routes and types of pharmacotherapies for PM in CRC. EXPERT OPINION More evidence is needed to justify HIPEC with CRS as the standard of care treatment modality for patients with resectable PM in CRC. New therapies such as oncolytic viruses, biologics, and small-molecule inhibitors may become additional treatment modalities for PM.
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Affiliation(s)
- Janson Kappen
- Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Omar Abdel-Rahman
- Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Alberta, Canada
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El Asmar A, Kamdem L, Khaled C, Liberale G. ASO Author Reflections: Histological Growth Patterns of Colorectal Peritoneal Metastases Significantly Affect Prognosis in Patients Presenting for Curative-Intent Cytoreductive Surgery. Ann Surg Oncol 2024; 31:4558-4559. [PMID: 38519784 DOI: 10.1245/s10434-024-15206-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 03/05/2024] [Indexed: 03/25/2024]
Affiliation(s)
- Antoine El Asmar
- Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Leonel Kamdem
- Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Charif Khaled
- Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - Gabriel Liberale
- Department of Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
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Ha YJ, Park SH, Tak KH, Lee JL, Kim CW, Kim JH, Kim SY, Kim SK, Yoon YS. CILP2 is a potential biomarker for the prediction and therapeutic target of peritoneal metastases in colorectal cancer. Sci Rep 2024; 14:12487. [PMID: 38816545 PMCID: PMC11139887 DOI: 10.1038/s41598-024-63366-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 05/28/2024] [Indexed: 06/01/2024] Open
Abstract
Peritoneal metastases (PM) in colorectal cancer (CRC) is associated with a dismal prognosis. Identifying and exploiting new biomarkers, signatures, and molecular targets for personalised interventions in the treatment of PM in CRC is imperative. We conducted transcriptomic profiling using RNA-seq data generated from the primary tissues of 19 CRC patients with PM. Using our dataset established in a previous study, we identified 1422 differentially expressed genes compared to non-metastatic CRC. The profiling demonstrated no differential expression in liver and lung metastatic CRC. We selected 12 genes based on stringent criteria and evaluated their expression patterns in a validation cohort of 32 PM patients and 84 without PM using real-time reverse transcription-polymerase chain reaction. We selected cartilage intermediate layer protein 2 (CILP2) because of high mRNA expression in PM patients in our validation cohort and its association with a poor prognosis in The Cancer Genome Atlas. Kaplan-Meier survival analysis in our validation cohort demonstrated that CRC patients with high CILP2 expression had significantly poor survival outcomes. Knockdown of CILP2 significantly reduced the proliferation, colony-forming ability, invasiveness, and migratory capacity and downregulated the expression of molecules related to epithelial-mesenchymal transition in HCT116 cells. In an in vivo peritoneal dissemination mouse knockdown of CILP2 also inhibited CRC growth. Therefore, CILP2 is a promising biomarker for the prediction and treatment of PM in CRC.
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Affiliation(s)
- Ye Jin Ha
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Seong-Hwan Park
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea
- Department of Bioscience, University of Science and Technology, Daejeon, 34113, Korea
| | - Ka Hee Tak
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jong Lyul Lee
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Chan Wook Kim
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea
| | - Jeong-Hwan Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea
- Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea
| | - Seon-Young Kim
- Department of Bioscience, University of Science and Technology, Daejeon, 34113, Korea
- Korea Bioinformation Center, KRIBB, Daejeon, 34141, Korea
| | - Seon-Kyu Kim
- Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, 34141, Korea.
- Department of Bioscience, University of Science and Technology, Daejeon, 34113, Korea.
- Personalized Genomic Medicine Research Center, KRIBB, Daejeon, 34141, Korea.
| | - Yong Sik Yoon
- Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
- Division of Colon and Rectal Surgery, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Korea.
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Quénet F, Carrère S, Sgarbura O. [Contribution of intraperitoneal chemotherapy in the treatment of colorectal peritoneal carcinoma. HIPEC, PIPAC, state of the art and future directions]. Bull Cancer 2024; 111:285-290. [PMID: 38331695 DOI: 10.1016/j.bulcan.2023.10.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/30/2023] [Accepted: 10/30/2023] [Indexed: 02/10/2024]
Abstract
After more than a decade of good results using the combination of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal carcinosis of colorectal origin, the PRODIGE7 study, which specifically evaluated the role of HIPEC, failed to show any superiority in terms of overall and disease-free survival for the CRS+HIPEC combination compared with CRS alone. This study constituted a radical change in the knowledge and therapeutic attitudes observed to date. After reviewing the literature and the consensus of national and international experts, a synthesis is provided, together with an outlook on the questions raised and the therapeutic trials and innovations of the near future. An analysis of recent advances due to the advent of a new technique, PIPAC, is also proposed, as well as a review of current therapeutic trials in this field.
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Affiliation(s)
- François Quénet
- Service de chirurgie oncologique, ICM Montpellier, 208, avenue des Apothicaires, 34000 Montpellier, France.
| | - Sébastien Carrère
- Service de chirurgie oncologique, ICM Montpellier, 208, avenue des Apothicaires, 34000 Montpellier, France
| | - Olivia Sgarbura
- Service de chirurgie oncologique, ICM Montpellier, 208, avenue des Apothicaires, 34000 Montpellier, France
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Radomski SN, Dunworth M, West JJ, Greer JB, Johnston FM, Ewald AJ. Intra- and Interpatient Drug Response Heterogeneity Exist in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Nongynecologic Cancers. Ann Surg Oncol 2024; 31:1996-2007. [PMID: 38175427 DOI: 10.1245/s10434-023-14696-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND Select patients with peritoneal metastases are treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC). We assayed for intra- and interpatient drug response heterogeneity through testing of patient-derived tumor organoids (PDTOs). METHODS PDTOs were generated from CRS/HIPEC patients from December 2021 to September 2022 and subjected to an in vitro HIPEC drug screen. Drug response was assessed with a cell viability assay and cleaved caspase-3 staining. RESULTS A total of 31 patients were consented for tissue collection. Viable tissue was harvested from 23, and PDTO generation was successful in 13 (56%). PDTOs were analyzed from six appendiceal, three colorectal, two small bowel, one gastric, and one adrenal tumor. Drug screen results were generated in as few as 7 days (62%), with an average time of 12 days. Most patients received mitomycin-C (MMC) intraoperatively (n = 9); however, in only three cases was this agent considered the optimal choice in vitro. Three sets of PDTOs were resistant (defined as > 50% PDTO viability) to all agents tested and two were pan-sensitive (defined as 3 or more agents with < 50% PDTO viability). In three patients, organoids were generated from multiple metastatic sites and intrapatient drug response heterogeneity was observed. CONCLUSIONS Both intra- and interpatient drug response heterogeneity exist in patients undergoing CRS/HIPEC for nongynecologic abdominal cancers. Caution must be used when interpreting patient response to chemotherapeutic agents based on a single site of testing in those with metastatic disease.
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Affiliation(s)
- Shannon N Radomski
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Matthew Dunworth
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Junior J West
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jonathan B Greer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Fabian M Johnston
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
| | - Andrew J Ewald
- Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA.
- Giovanis Institute for Translational Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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Hübner M, van Der Speeten K, Govaerts K, de Hingh I, Villeneuve L, Kusamura S, Glehen O. 2022 Peritoneal Surface Oncology Group International Consensus on HIPEC Regimens for Peritoneal Malignancies: Colorectal Cancer. Ann Surg Oncol 2024; 31:567-576. [PMID: 37940803 PMCID: PMC10695877 DOI: 10.1245/s10434-023-14368-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 09/13/2023] [Indexed: 11/10/2023]
Abstract
BACKGROUND Selected patients with peritoneal metastases of colorectal cancer (PM-CRC) can benefit from potentially curative cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC), with a median overall survival (OS) of more than 40 months. OBJECTIVE The aims of this evidence-based consensus were to define the indications for HIPEC, to select the preferred HIPEC regimens, and to define research priorities regarding the use of HIPEC for PM-CRC. METHODS The consensus steering committee elaborated and formulated pertinent clinical questions according to the PICO (patient, intervention, comparator, outcome) method and assessed the evidence according to the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Standardized evidence tables were presented to an international expert panel to reach a consensus (4-point, weak and strong positive/negative) on HIPEC regimens and research priorities through a two-round Delphi process. The consensus was defined as ≥ 50% agreement for the 4-point consensus grading or ≥ 70% for either of the two combinations. RESULTS Evidence was weak or very weak for 9/10 clinical questions. In total, 70/90 eligible panelists replied to both Delphi rounds (78%), with a consensus for 10/10 questions on HIPEC regimens. There was strong negative consensus concerning the short duration, high-dose oxaliplatin (OX) protocol (55.7%), and a weak positive vote (53.8-64.3%) in favor of mitomycin-C (MMC)-based HIPEC (preferred choice: Dutch protocol: 35 mg/m2, 90 min, three fractions), both for primary cytoreduction and recurrence. Determining the role of HIPEC after CRS was considered the most important research question, regarded as essential by 85.7% of the panelists. Furthermore, over 90% of experts suggest performing HIPEC after primary and secondary CRS for recurrence > 1 year after the index surgery. CONCLUSIONS Based on the available evidence, despite the negative results of PRODIGE 7, HIPEC could be conditionally recommended to patients with PM-CRC after CRS. While more preclinical and clinical data are eagerly awaited to harmonize the procedure further, the MMC-based Dutch protocol remains the preferred regimen after primary and secondary CRS.
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Affiliation(s)
- Martin Hübner
- Department of Visceral Surgery, Lausanne University Hospital (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland.
| | - Kurt van Der Speeten
- Department of Abdominal and Oncological Surgery, Ziekenhuis Oost Limburg (ZOL), Genk, Belgium
| | - Kim Govaerts
- Department of Abdominal and Oncological Surgery, Ziekenhuis Oost Limburg (ZOL), Genk, Belgium
| | - Ignace de Hingh
- Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
| | - Laurent Villeneuve
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands
| | | | - Olivier Glehen
- Department of Surgical Oncology, Centre Hospitalier Lyon-sud, Lyon, France
- CICLY: Center for Innovation in Cancer in Lyon, University Lyon 1, Lyon, France
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Hou Z, Qiu G, Xie Q, Jin Z, Mi S, Huang J. The prophylactic role of mitomycin C-based hyperthermic intraperitoneal chemotherapy (MMC-based HIPEC) on peritoneal metastasis of spontaneously ruptured hepatocellular carcinoma (srHCC): A pilot study. Glob Health Med 2023; 5:336-344. [PMID: 38162434 PMCID: PMC10730926 DOI: 10.35772/ghm.2023.01081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Revised: 09/29/2023] [Accepted: 10/07/2023] [Indexed: 01/03/2024]
Abstract
Hepatocellular carcinoma (HCC) was featured as spontaneous rupture hemorrhage under intratumoral overpressure. Spontaneous rupture hepatocellular carcinoma (srHCC) has a high propensity for peritoneal metastasis (PM). Although HIPEC has become standard treatment for malignancies with PM, it has been poorly described in srHCC. We conducted a single-arm, open-label, single-center, prospective study to explore the prophylactic role of MMC-based HIPEC on PM of srHCC. A total of 7 patients were collected from April 1, 2021 to April 30, 2022. HIPEC was conducted 3 times on the first, third and fifth postoperative days. 15 mg/m2 of MMC was used with 60 minutes perfusion at 43°C. The primary end-point was local peritoneum recurrence free survival (RFS), whereas the secondary end-point was systemic RFS and overall survival (OS). The mean hepatectomy operation time was 232 minutes (SD: 124.08 minutes). The median bleeding loss was 200 mL (range 50-400 mL). The mean hospital stay was 13 days (SD: 3.42 days). Only mild abdominal distension was reported in 4 patients (57%). There were no patients who suffered from life-threatening intra-abdominal and extra-abdominal complications (EAC). At the data cut-off (April 30, 2023), one patient (14%) had died due to cachexia. Local peritoneal recurrence occurred in three patients (43%). Median follow-up was 16.1 months (IQR: 12.8-16.6 months). Median local peritoneum RFS was 12.3 months (95% CI: 7.0- 17.5; 4 events) and median overall RFS was 7.5 months (95% CI: 4.2-10.8; 6 events). MMC-based HIPEC was safe and feasible in selected patients of srHCC. It showed a positive tendency in preventing PM, but large-scale research should be continued.
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Affiliation(s)
- Ziqi Hou
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Guoteng Qiu
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Qingyun Xie
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Zhaoxing Jin
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Shizheng Mi
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China
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10
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Mangieri CW, Valenzuela CD, Solsky IB, Erali RA, Votanopoulos KI, Shen P, Levine EA. Exposure to Neoadjuvant Oxaliplatin-Containing Chemotherapy, Does it Effect Intraperitoneal Hyperthermic Chemotherapy Perfusion? Ann Surg Oncol 2023; 30:2486-2493. [PMID: 36484904 DOI: 10.1245/s10434-022-12933-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 11/21/2022] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) are commonly exposed to oxaliplatin neoadjuvant chemotherapy (NAT) regimens. The impact of systemic exposure to oxaliplatin prior to HIPEC with oxaliplatin is unknown. METHODS We conducted a retrospective review of our institutional registry of CRS/HIPEC cases who received oxaliplatin-containing NAT, and compared patients who underwent HIPEC with oxaliplatin versus cases perfused with mitomycin C. The primary outcome was survival, defined by overall survival (OS) and disease-free survival (DFS). Subgroup analysis was performed based on primary tumor etiology and completeness of cytoreduction. RESULTS A total of 333 cases satisfied the selection criteria-159 appendiceal primaries (all high-grade disease) and 174 colorectal cases. Thirty-one cases (9.3%) underwent HIPEC with oxaliplatin, with the remaining 302 cases (90.7%) receiving mitomycin C. Both cohorts were identical in regard to baseline characteristics, and both groups were alike in regard to NAT regimens and oxaliplatin exposure. There was no difference in survival outcomes. OS times were 2.9 (± 2.8) and 2.8 ( ± 3.6) years for oxaliplatin and mitomycin C perfusions, respectively (p = 0.94), and the 5-year OS rates were also similar at 9.7 and 18.5% (odds ratio [OR] 0.49, 95% confidence interval [CI] 0.14-1.67, p = 0.24) for oxaliplatin and mitomycin cases, respectively. Likewise, DFS findings were similar, with survival of 2.5 (± 4.5) and 1.8 (± 2.4) years for oxaliplatin and mitomycin perfusions, respectively (p = 0.21). There was no difference in 5-year DFS rates, at 10.5 and 7.8% (OR 1.39, 95% CI 0.30-6.56, p = 0.68) for oxaliplatin and mitomycin C, respectively. Subgroup analysis found minimal discordant findings from the main results. CONCLUSION This analysis found no discernable association with NAT oxaliplatin exposure in regard to survival outcomes following CRS/HIPEC stratified out by perfusion agent.
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Affiliation(s)
- Christopher W Mangieri
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Cristian D Valenzuela
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Ian B Solsky
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Richard A Erali
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | | | - Perry Shen
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA
| | - Edward A Levine
- Division of Surgical Oncology, Wake Forest Baptist Health Medical Center, Winston-Salem, NC, USA.
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11
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Witmer HDD, Dhiman A, Turaga KK. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: Where do we stand? Cancer 2023; 129:495-502. [PMID: 36527271 PMCID: PMC10107206 DOI: 10.1002/cncr.34567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 09/18/2022] [Accepted: 10/03/2022] [Indexed: 12/23/2022]
Abstract
PLAIN LANGUAGE SUMMARY Patients with colorectal cancer that has spread to the lining of the abdomen (peritoneum) benefit from surgery to remove all the cancer. The addition of certain types of intra-abdominal chemotherapy during surgery improves survival for select patients.
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Affiliation(s)
- Hunter D D Witmer
- Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA
| | - Ankit Dhiman
- Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA
| | - Kiran K Turaga
- Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA
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Surgical Options for Peritoneal Surface Metastases from Digestive Malignancies-A Comprehensive Review. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:medicina59020255. [PMID: 36837456 PMCID: PMC9960111 DOI: 10.3390/medicina59020255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/25/2023] [Accepted: 01/25/2023] [Indexed: 01/31/2023]
Abstract
The peritoneum is a common site for the dissemination of digestive malignancies, particularly gastric, colorectal, appendix, or pancreatic cancer. Other tumors such as cholangiocarcinomas, digestive neuroendocrine tumors, or gastrointestinal stromal tumors (GIST) may also associate with peritoneal surface metastases (PSM). Peritoneal dissemination is proven to worsen the prognosis of these patients. Cytoreductive surgery (CRS), along with systemic chemotherapy, have been shown to constitute a survival benefit in selected patients with PSM. Furthermore, the association of CRS with hyperthermic intraperitoneal chemotherapy (HIPEC) seems to significantly improve the prognosis of patients with certain types of digestive malignancies associated with PSM. However, the benefit of CRS with HIPEC is still controversial, especially due to the significant morbidity associated with this procedure. According to the results of the PRODIGE 7 trial, CRS for PSM from colorectal cancer (CRC) achieved overall survival (OS) rates higher than 40 months, but the addition of oxaliplatin-based HIPEC failed to improve the long-term outcomes. Furthermore, the PROPHYLOCHIP and COLOPEC trials failed to demonstrate the effectiveness of oxaliplatin-based HIPEC for preventing peritoneal metastases development in high-risk patients operated for CRC. In this review, we discuss the limitations of these studies and the reasons why these results are not sufficient to refute this technique, until future well-designed trials evaluate the impact of different HIPEC regimens. In contrast, in pseudomyxoma peritonei, CRS plus HIPEC represents the gold standard therapy, which is able to achieve 10-year OS rates ranging between 70 and 80%. For patients with PSM from gastric carcinoma, CRS plus HIPEC achieved median OS rates higher than 40 months after complete cytoreduction in patients with a peritoneal cancer index (PCI) ≤6. However, the data have not yet been validated in randomized clinical trials. In this review, we discuss the controversies regarding the most efficient drugs that should be used for HIPEC and the duration of the procedure. We also discuss the current evidence and controversies related to the benefit of CRS (and HIPEC) in patients with PSM from other digestive malignancies. Although it is a palliative treatment, pressurized intraperitoneal aerosolized chemotherapy (PIPAC) significantly increases OS in patients with unresectable PSM from gastric cancer and represents a promising approach for patients with PSM from other digestive cancers.
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13
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Ammerata G, Filippo R, Laface C, Memeo R, Solaini L, Cavaliere D, Navarra G, Ranieri G, Currò G, Ammendola M. Hyperthermic intraperitoneal chemotherapy and colorectal cancer: From physiology to surgery. World J Clin Cases 2022; 10:10852-10861. [PMID: 36338235 PMCID: PMC9631165 DOI: 10.12998/wjcc.v10.i30.10852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 06/23/2022] [Accepted: 08/13/2022] [Indexed: 02/05/2023] Open
Abstract
The pursuit of this paper is to collect principal reviews and systematic reviews about hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) used in colorectal cancer (CRC). We focus on principal biological aspects of CRC, hyperthermia effects, and surgical procedures. We searched PubMed/MEDLINE for the principal reviews and systematic reviews published from 2010 to 2021 regarding the bimodal treatment (CRS + HIPEC) against local and advanced CRC. In the literature, from several studies, it seems that the efficacy of bimodal treatment with an accurate CRS can extend overall survival. Despite these studies, there are not still any straight guidelines more detailed and scheduled about the use of combined treatment in patients with CRC. Even if the concept is still not very clear and shared, after a careful evaluation of the published data, and after some technical and pathophysiological descriptions, we concluded that it is possible to improve the overall survival and quality of life and to reduce the tumor relapse in patients affected by locally advanced (pT4) CRC with peritoneal metastases.
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Affiliation(s)
- Giorgio Ammerata
- Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, Catanzaro 88100, Italy
| | - Rosalinda Filippo
- Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, Catanzaro 88100, Italy
| | - Carmelo Laface
- Interventional Oncology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre “Giovanni Paolo II”, Bari 70124, Italy
| | - Riccardo Memeo
- Hepato-Biliary and Pancreatic Surgical Unit, “F. Miulli” Hospital, Acquaviva delle Fonti, Bari 70124, Italy
| | - Leonardo Solaini
- Department of Medical and Surgical Sciences, University of Bologna, Forlì 40126, Italy
| | - Davide Cavaliere
- Department of General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
| | - Giuseppe Navarra
- Department of Human Pathology of Adult and Evolutive Age, Surgical Oncology Division, “G. Martino” Hospital, University of Messina, Messina 98122, Italy
| | - Girolamo Ranieri
- Interventional Oncology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre “Giovanni Paolo II”, Bari 70124, Italy
| | - Giuseppe Currò
- Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, Catanzaro 88100, Italy
| | - Michele Ammendola
- Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, Catanzaro 88100, Italy
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14
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Strach MC, Sutherland S, Horvath LG, Mahon K. The role of chemotherapy in the treatment of advanced appendiceal cancers: summary of the literature and future directions. Ther Adv Med Oncol 2022; 14:17588359221112478. [PMID: 35898968 PMCID: PMC9310237 DOI: 10.1177/17588359221112478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 06/20/2022] [Indexed: 11/16/2022] Open
Abstract
Appendiceal cancer is rare and encompasses a diverse group of tumours ranging from low-grade appendiceal mucinous neoplasms to high-grade adenocarcinomas. Appendiceal cancers often spread to the peritoneal cavity causing extensive mucinous dissemination and peritoneal metastases. Prognosis varies with histological subtype. Cytoreductive surgery and heated intraperitoneal chemotherapy is well-established as the most effective treatment achieving long-term survival in some patients. Chemotherapy regimens used to treat appendiceal cancer are extrapolated from the colorectal cancer setting, but disease biology differs and outcomes are inferior. The role of chemotherapy in the treatment of appendiceal cancer remains poorly defined. There is an urgent need to develop novel tailored treatment strategies in the perioperative and unresectable setting. This review aims to evaluate the literature for patients who received intraperitoneal and systemic chemotherapy for appendiceal cancers.
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Affiliation(s)
| | | | | | - Kate Mahon
- Chris O'Brien Lifehouse, 119-144 Missenden Road, Camperdown, NSW 2050, Australia
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15
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Delhorme JB, Sauvinet G, Séverac F, Diab S, Liu D, Rohr S, Romain B, Brigand C. Peritoneal Metastases of Colorectal Origin Treated with Complete Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy: The Efficiency of Mitomycin C. Ann Surg Oncol 2022; 29:7568-7576. [PMID: 35882692 DOI: 10.1245/s10434-022-12221-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/25/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Survival of patients affected by colorectal cancer peritoneal metastases (CRC-PM) can be improved with combined complete cytoreductive surgery (CCRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Two chemotherapeutic agents are mainly used: mitomycin C (MMC) and oxaliplatin. A recent prospective randomized clinical trial showed that oxaliplatin-based HIPEC does not improve survival compared with CCRS alone. The purpose of our study was to compare the survival effectiveness of MMC versus oxaliplatin-based HIPEC using a homogeneous surgical technique and drug protocol. METHODS This retrospective monocentric study included all patients prospectively registered for having undergone CCRS and HIPEC using MMC or oxaliplatin for CRC-PM in Strasbourg University Hospital, France, from December 2004 until December 2019. MMC-based HIPEC and oxaliplatin-based HIPEC groups were compared with an inverse probability of treatment weighting. RESULTS A total of 137 patients were included. Groups were comparable for all baseline characteristics except for peritoneal carcinomatosis index. In the weighted multivariate analysis, disease-free survival (DFS) and peritoneal disease-free survival (PDFS) were significantly higher in the MMC-based HIPEC group compared with the oxaliplatin-based HIPEC group with a hazard ratio of 0.74 (CI 95% 0.56-0.98), p = 0.035 and 0.59 (CI 95% 0.40-0.98), p = 0.0084, respectively. There was no difference in overall survival or postoperative morbidity between groups. CONCLUSIONS These results favor a superiority of MMC for DFS and PDFS in comparison with oxaliplatin in HIPEC after CCRS in treatment with curative intent for CRC-PM.
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Affiliation(s)
- Jean-Baptiste Delhorme
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France. .,INSERM UMR_S1113, Université de Strasbourg, FMTS, Strasbourg, France.
| | - Guillaume Sauvinet
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France
| | - François Séverac
- Department of Public Health, Strasbourg University Hospital, Strasbourg, France
| | - Samer Diab
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France
| | - David Liu
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France
| | - Serge Rohr
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,INSERM UMR_S1113, Université de Strasbourg, FMTS, Strasbourg, France
| | - Benoît Romain
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,INSERM UMR_S1113, Université de Strasbourg, FMTS, Strasbourg, France
| | - Cécile Brigand
- Department of General and Digestive Surgery, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,INSERM UMR_S1113, Université de Strasbourg, FMTS, Strasbourg, France
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16
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Turner KM, Morris MC, Sohal D, Sussman JJ, Wilson GC, Ahmad SA, Patel SH. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Summary of Key Clinical Trials. J Clin Med 2022; 11:jcm11123406. [PMID: 35743476 PMCID: PMC9225119 DOI: 10.3390/jcm11123406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Revised: 06/02/2022] [Accepted: 06/12/2022] [Indexed: 01/27/2023] Open
Abstract
The peritoneal cavity is a common site of metastatic spread from colorectal cancer (CRC). Patients with peritoneal metastases (PM) often have aggressive underlying tumor biology and poor survival. While only a minority of patients with CRC have potentially resectable disease, the high overall incidence of CRC makes management of PM a common clinical problem. In this population, cytoreductive surgery (CRS)-hyperthermic intraperitoneal chemotherapy (HIPEC) is the only effective therapy for appropriately selected patients. In this narrative review, we summarize the existing literature on CRS-HIPEC in colorectal PM. Recent prospective clinical trials have shown conflicting evidence regarding the benefit of HIPEC perfusion in addition to CRS. Current strategies to prevent PM in those at high-risk have been shown to be ineffective. Herein we will provide a framework for clinicians to understand and apply these data to treat this complex disease presentation.
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Affiliation(s)
- Kevin M. Turner
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA; (K.M.T.); (M.C.M.)
| | - Mackenzie C. Morris
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA; (K.M.T.); (M.C.M.)
| | - Davendra Sohal
- Department of Internal Medicine, Division of Hematology & Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0558, USA;
| | - Jeffrey J. Sussman
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way (ML 0558), Cincinnati, OH 45267-0558, USA; (J.J.S.); (G.C.W.); (S.A.A.)
| | - Gregory C. Wilson
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way (ML 0558), Cincinnati, OH 45267-0558, USA; (J.J.S.); (G.C.W.); (S.A.A.)
| | - Syed A. Ahmad
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way (ML 0558), Cincinnati, OH 45267-0558, USA; (J.J.S.); (G.C.W.); (S.A.A.)
| | - Sameer H. Patel
- Department of Surgery, Division of Surgical Oncology, University of Cincinnati College of Medicine, 231 Albert Sabin Way (ML 0558), Cincinnati, OH 45267-0558, USA; (J.J.S.); (G.C.W.); (S.A.A.)
- Correspondence: ; Tel.: +1-516-558-6018; Fax: +1-513-584-0459
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17
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Badran A, Azzam A, Noorelahi M, Alshamsan B, Alkhaldi S, Naguib R, Amin T. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with or without intraoperative radiotherapy for peritoneal carcinomatosis in elderly patients. SURGERY OPEN DIGESTIVE ADVANCE 2022; 6:100051. [DOI: 10.1016/j.soda.2022.100051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
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18
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Current Trends in Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for Peritoneal Disease from Appendiceal and Colorectal Malignancies. J Clin Med 2022; 11:jcm11102840. [PMID: 35628966 PMCID: PMC9143396 DOI: 10.3390/jcm11102840] [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: 04/13/2022] [Revised: 05/11/2022] [Accepted: 05/12/2022] [Indexed: 12/10/2022] Open
Abstract
Peritoneal carcinomatosis (PC) is a poor prognostic factor for all malignancies. This extent of metastatic disease progression remains difficult to treat with systemic therapies due to poor peritoneal vascularization resulting in limited drug delivery and penetration into tissues. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are surgical interventions that directly target peritoneal tumors and have improved outcomes for PC resulting from appendiceal and colorectal cancer (CRC). Despite these radical therapies, long-term survival remains infrequent, and recurrence is common. The reasons for these outcomes are multifactorial and signal the need for the continued development of novel therapeutics, techniques, and approaches to improve outcomes for these patients. Here, we review landmark historical studies that serve as the foundation for current recommendations, recent discoveries, clinical trials, active research, and areas of future interest in CRS/HIPEC to treat PC originating from appendiceal and colorectal malignancies.
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19
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Pereira F, Serrano A, Manzanedo I, Pérez-Viejo E, González-Moreno S, González-Bayón L, Arjona-Sánchez A, Torres J, Ramos I, Barrios ME, Cascales P, Morales R, Boldó E, García-Fadrique A, Arteaga X, Gutierrez-Calvo A, Sánchez-García S, Asensio E, Ramírez CP, Artiles M, Vaqué J, Parra PA, Villarejo P, Muñoz-Casares C, Turienzo E, Calero A, Torrejimeno IJ, Prieto I, Galindo J, Borrego V, Marcello ME, Rihuete C, Carrasco J, Gomez-Quiles L. GECOP-MMC: phase IV randomized clinical trial to evaluate the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) with mytomicin-C after complete surgical cytoreduction in patients with colon cancer peritoneal metastases. BMC Cancer 2022; 22:536. [PMID: 35549912 PMCID: PMC9097342 DOI: 10.1186/s12885-022-09572-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 04/19/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND The French PRODIGE 7 trial, published on January 2021, has raised doubts about the specific survival benefit provided by HIPEC with oxaliplatin 460 mg/m2 (30 minutes) for the treatment of peritoneal metastases from colorectal cancer. However, several methodological flaws have been identified in PRODIGE 7, specially the HIPEC protocol or the choice of overall survival as the main endpoint, so its results have not been assumed as definitive, emphasizing the need for further research on HIPEC. It seems that the HIPEC protocol with high-dose mytomicin-C (35 mg/m2) is the preferred regime to evaluate in future clinical studies. METHODS GECOP-MMC is a prospective, open-label, randomized, multicenter phase IV clinical trial that aims to evaluate the effectiveness of HIPEC with high-dose mytomicin-C in preventing the development of peritoneal recurrence in patients with limited peritoneal metastasis from colon cancer (not rectal), after complete surgical cytoreduction. This study will be performed in 31 Spanish HIPEC centres, starting in March 2022. Additional international recruiting centres are under consideration. Two hundred sixteen patients with PCI ≤ 20, in which complete cytoreduction (CCS 0) has been obtained, will be randomized intraoperatively to arm 1 (with HIPEC) or arm 2 (without HIPEC). We will stratified randomization by surgical PCI (1-10; 11-15; 16-20). Patients in both arms will be treated with personalized systemic chemotherapy. Primary endpoint is peritoneal recurrence-free survival at 3 years. An ancillary study will evaluate the correlation between surgical and pathological PCI, comparing their respective prognostic values. DISCUSSION HIPEC with high-dose mytomicin-C, in patients with limited (PCI ≤ 20) and completely resected (CCS 0) peritoneal metastases, is assumed to reduce the expected risk of peritoneal recurrence from 50 to 30% at 3 years. TRIAL REGISTRATION EudraCT number: 2019-004679-37; Clinicaltrials.gov: NCT05250648 (registration date 02/22/2022, ).
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Affiliation(s)
- Fernando Pereira
- Hospital Universitario de Fuenlabrada, Camino del Molino 2, Fuenlabrada, 28942, Madrid, Spain.
| | - Angel Serrano
- Hospital Universitario de Fuenlabrada, Camino del Molino 2, Fuenlabrada, 28942, Madrid, Spain
| | - Israel Manzanedo
- Hospital Universitario de Fuenlabrada, Camino del Molino 2, Fuenlabrada, 28942, Madrid, Spain
| | - Estibalitz Pérez-Viejo
- Hospital Universitario de Fuenlabrada, Camino del Molino 2, Fuenlabrada, 28942, Madrid, Spain
| | | | - Luis González-Bayón
- Hospital General Universitario Gregorio Marañón, C/ Doctor Esquerdo, 46 -, 28007, Madrid, Spain
| | | | - Juan Torres
- Hospital Universitario Torrecárdenas, Calle Hermandad de Donantes de Sangre s/n, 04009, Almería, Spain
| | - Isabel Ramos
- Hospital Sant Joan Despi Moises Broggi, Carrer de Jacint Verdaguer, 90, 08970 Sant Joan Despí, Barcelona, Spain
| | - Maria E Barrios
- Hospital Clinico Universitario de Valencia, Avenida de Blasco Ibañez, 17, 46010, Valencia, Spain
| | - Pedro Cascales
- Hospital Universitario Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120, El Palmar, Murcia, Spain
| | - Rafael Morales
- Hospital Universitario Son Espases, Carretera de Valldemossa, 79. 07210 Palma, Mallorca, Spain
| | - Enrique Boldó
- Consorcio Hospitalario Provincial De Castellón, Avenida del Doctor Clarà 19, 12006, Castellón de la Plana, Spain
| | | | - Xabier Arteaga
- Hospital Universitario Donostia, Begiristain Doktorea Pasealekua 109, 20014, Donostia, Gipuzkoa, Spain
| | - Alberto Gutierrez-Calvo
- Hospital Universitario Principe de Asturias, Carretera Alcalá-Meco, s/n - 28805 Alcalá de Henares, Madrid, Spain
| | - Susana Sánchez-García
- Hospital General Universitario de Ciudad Real, C/ Obispo Rafael Torija s/n - Pol. Larache, 13005, Ciudad Real, Spain
| | - Enrique Asensio
- Hospital Universitario Río Hortega, Calle Dulzaina, 2, 47012, Valladolid, Spain
| | - Cesar P Ramírez
- Hospital Quirónsalud Málaga, Avenida de Imperio Argentina, 1, 29004, Málaga, Spain
| | - Manuel Artiles
- Hospital Universitario de Gran Canaria Doctor Negrín, Barranco de la Ballena, 0, 35010, Las Palmas de Gran Canaria, Spain
| | - Javier Vaqué
- Hospital Universitario y Politécnico La Fe, Avenida Fernando Abril Martorell, 106, 46026, Valencia, Spain
| | - Pedro A Parra
- Hospital General Universitario Reina Sofía, Avda. Intendente Jorge Palacios, 1, 30003, Murcia, Spain
| | - Pedro Villarejo
- Fundación Jiménez Díaz, Avda. Reyes Católicos 2, 28040, Madrid, Spain
| | | | - Estrella Turienzo
- Hospital Universitario Central de Asturias, Avenida de Roma, 0, 33011, Oviedo, Spain
| | - Alicia Calero
- Hospital General Universitario de Elche, Camí de la Almazara, 11, 03203 Elche, Alicante, Spain
| | | | - Isabel Prieto
- Hospital Universitario La Paz, Paseo de la Castellana 261, 28046, Madrid, Spain
| | - Julio Galindo
- Hospital Universitario Ramón y Cajal, Ctra. de Colmenar Viejo km. 9,100, 28034, Madrid, Spain
| | - Vicente Borrego
- Hospital Clínico Universitario "Lozano Blesa", Avda. San Juan Bosco, 15, 50009, Zaragoza, Spain
| | - Manuel E Marcello
- Hospital Universitario Fundación Alcorcón, Calle de Budapest, 1, 28922 Alcorcón, Madrid, Spain
| | - Cristina Rihuete
- Hospital Universitario Infanta Elena, Avenida de los Reyes Católicos 21, 28340 Valdemoro, Madrid, Spain
| | - Joaquin Carrasco
- Hospital Regional Universitario de Málaga, Avda. Carlos Haya 82-88, 29010, Málaga, Spain
| | - Luis Gomez-Quiles
- Hospital General Universitario De Castellón, Avenida de Benicassim, 128, 12004, Castellón, Spain
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20
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Gangi A, Shah R. The Landmark Series: Appendiceal Primary Peritoneal Surface Malignancy. Ann Surg Oncol 2021; 29:2056-2068. [PMID: 34853944 DOI: 10.1245/s10434-021-10856-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/09/2021] [Indexed: 12/24/2022]
Abstract
Appendiceal primary peritoneal surface malignancies are rare and include a broad spectrum of pathologies ranging from indolent disease to aggressive disease. As such, the data that drive the management of appendiceal peritoneal surface malignancies is generally not based on prospective clinical trial data, but rather consists of level 1 data based on retrospective studies and high-volume institutional experiences. Complete surgical debulking typically offers the best chance for long-term survival. This review highlights the landmark articles on which management of primary appendiceal peritoneal surface malignancies are based.
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Affiliation(s)
- Alexandra Gangi
- Division of Surgical Oncology, Cedars Sinai Medical Center, Los Angeles, CA, USA.
| | - Rupen Shah
- Division of Surgical Oncology, Henry Ford Cancer Institute/Henry Ford Health System, Detroit, MI, USA
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21
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Alhumaid M, Sait S, Fallatah E, AlSayegh N, Farsi A, Nassif M, Farsi NJ, Akeel N, Samkari A, Shabkah AA, Trabulsi N. Outcomes of Cytoreduction and Oxaliplatin-Based Hyperthermic Intraperitoneal Chemotherapy in Patients With Peritoneal Carcinomatosis From Colorectal Cancer. Cureus 2021; 13:e18670. [PMID: 34786251 PMCID: PMC8579872 DOI: 10.7759/cureus.18670] [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] [Accepted: 10/11/2021] [Indexed: 12/04/2022] Open
Abstract
Among patients with metastatic colorectal cancer, 25% have isolated peritoneal carcinomatosis. We performed a systematic review and meta-analysis to assess the disease-free survival (DFS) and overall survival (OS) of patients undergoing hyperthermic intraperitoneal chemotherapy with oxaliplatin. Eleven studies were included in the final assessment. Pooled three- and five-year OS rates were 58.60% and 42.19%, respectively. The estimated pooled three- and five-year DFS rates were 23.47% and 14.26%, respectively.
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Affiliation(s)
- Moayad Alhumaid
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Salma Sait
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Emad Fallatah
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Nasser AlSayegh
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Ali Farsi
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Mohammed Nassif
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Nada J Farsi
- Department of Dental Public Health, King Abdulaziz University Faculty of Dentistry, Jeddah, SAU
| | - Nouf Akeel
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Ali Samkari
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
| | - Alaa A Shabkah
- Department of Surgery, International Medical Center, Jeddah, SAU
| | - Nora Trabulsi
- Department of Surgery, King Abdulaziz University Faculty of Medicine, Jeddah, SAU
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22
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Flood M, Narasimhan V, Wilson K, Lim WM, Ramsay R, Michael M, Heriot A. Organoids as a Robust Preclinical Model for Precision Medicine in Colorectal Cancer: A Systematic Review. Ann Surg Oncol 2021; 29:47-59. [PMID: 34596795 DOI: 10.1245/s10434-021-10829-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 07/24/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Patients with locally advanced or metastatic colorectal cancer (CRC) display heterogeneous responses to standard-of-care therapy. Robust preclinical models of malignancy in the form of patient-derived tumor organoids (PDTOs) have recently come to the fore in tailoring patient care to a personalized medicine level. This study aimed to review the literature systematically regarding PTDOs and gauge their impact on precision medicine in the management of CRC. METHODS A PRISMA-compliant systematic review of the MEDLINE, EMBASE, Web of Science, and Cochrane Library databases was performed. The results were categorized based on the primary objective of the individual studies as follows: organoid use in predicting effective hyperthermic intraperitoneal chemotherapy (HIPEC), systemic chemotherapy in CRC, or neoadjuvant chemoradiotherapy in rectal cancer. RESULTS The literature search found 200 publications, 16 of which met the inclusion criteria. Organoid models of primary and metastatic CRC have been increasingly used to assess clinical responses to standard therapy. Marked heterogeneity exists, matching the responses observed in clinical practice with ex vivo drug and radiation screening. Repeated correlation between organoid and patient sensitivity to forms of HIPEC, systemic chemotherapy, and chemoradiotherapy has been observed. CONCLUSION Patient-derived tumor organoids are the latest tool in predictive translational research. Current organoid-based studies in precision medicine have shown their great potential for predicting the clinical response of patients to CRC therapy. Larger-scale, prospective data are required to fully support this exciting avenue in cancer care.
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Affiliation(s)
- Michael Flood
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia. .,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.
| | - Vignesh Narasimhan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Kasmira Wilson
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Wei Mou Lim
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Robert Ramsay
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Michael Michael
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia.,Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Alexander Heriot
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
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Davis CH, Alexander HR. What is the Current Role of Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer? Adv Surg 2021; 55:159-174. [PMID: 34389090 DOI: 10.1016/j.yasu.2021.05.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Affiliation(s)
- Catherine H Davis
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA. https://twitter.com/CDavisMD
| | - H Richard Alexander
- Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08901, USA.
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Verwaal VJ, Funder JA, Sørensen MM, Iversen LH. The impact of postoperative complications following cytoreductive surgery combined with oxaliplatin based heated intraperitoneal chemotherapy. Eur J Surg Oncol 2021; 48:183-187. [PMID: 34474946 DOI: 10.1016/j.ejso.2021.08.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 07/15/2021] [Accepted: 08/20/2021] [Indexed: 11/16/2022] Open
Abstract
INTRODUCTION Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) has become the mainstream treatment for peritoneal metastases of colorectal origin. This extensive treatment is known for its increased morbidity rate. In this study, the impact of postoperative complications on survival was evaluated in a high-volume centre. PATIENTS AND METHOD Between November 2016 through October 2018, all 106 patients with peritoneal metastases of colorectal origin treated with CRS + HIPEC with oxaliplatin were evaluated. Data on patient characteristics, Peritoneal Carcinomatosis Index (PCI), operative procedure, post-operative complications (Clavien-Dindo classification grade III or higher) and survival were collected. In-hospital postoperative complications were analysed for their association with patient characteristics, tumour load (PCI), and operative procedure with logistic regression analyses. Survival was analysed with the Cox regression analysis. RESULTS Of 106 patients, 78% had an un-eventful in-hospital recovery. Of those patients who experienced complications, 52% patients had one complication and 48% had more than one. The median follow-up time was 33.8 months. Median survival was 22.4 months (95% CI 12.2-NR) for patients who experienced complications and not reached for those who did not. Survival was significantly associated with complications (HR 2.2, 95% CI 1.2-4.0) as well as with PCI (HR 1.1, 95% CI 1.1-1.2) in univariate analyses. A stepwise Cox regression analysis showed both PCI and complications had an independent negative impact on survival. CONCLUSION Postoperative complications, independently of tumour load, led to reduced survival in patients with peritoneal metastases of colorectal origin when treated with CRS + HIPEC with oxaliplatin.
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Affiliation(s)
- Victor Jilbert Verwaal
- Department of Surgery, Aarhus University Hospital, Denmark; Hospital of Southwestern Jutland, University of Southern Denmark, Esbjerg, Denmark
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25
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van Stein RM, Aalbers AGJ, Sonke GS, van Driel WJ. Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer: A Review. JAMA Oncol 2021; 7:1231-1238. [PMID: 33956063 DOI: 10.1001/jamaoncol.2021.0580] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Importance The peritoneal surface is a common site of disease in ovarian and colorectal cancer. Peritoneal metastases carry a poor prognosis, despite maximal therapeutic efforts, including surgical removal of tumor deposits and intravenous chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative procedure that delivers chemotherapy directly into the abdominal cavity, leading to high intracellular drug concentration at the peritoneal surface. This review describes the current knowledge regarding the mechanism of action, safety, and efficacy of HIPEC in the treatment of peritoneal metastases from epithelial ovarian and colorectal cancers and explores current knowledge gaps. Observations Toxic effects of HIPEC are limited. Evidence from a randomized trial shows improved recurrence-free and overall survival after HIPEC in patients with ovarian cancer who are ineligible for primary cytoreductive surgery (CRS). The effect of HIPEC for patients with ovarian cancer undergoing primary CRS or CRS for recurrent disease has not yet been determined, and results of ongoing trials must be awaited. A recent study in patients with peritoneal metastases from colorectal cancer did not show a benefit of HIPEC when added to perioperative chemotherapy. Conclusions and Relevance Based on available evidence, various international guidelines include the option to add HIPEC to interval CRS for patients with stage III ovarian cancer. The role of HIPEC in colorectal cancer is less well defined. Future studies will need to tailor patient selection, timing, and optimal regimens of HIPEC to improve the effectiveness of this specialized treatment in ovarian, colorectal, and other tumor types.
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Affiliation(s)
- Ruby M van Stein
- Department of Gynecologic Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Arend G J Aalbers
- Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Gabe S Sonke
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Willemien J van Driel
- Center for Gynecologic Oncology Amsterdam, The Netherlands Cancer Institute, Amsterdam
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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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Synchronous Liver Resection, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Liver and Peritoneal Metastases: A Systematic Review and Meta-analysis. Dis Colon Rectum 2021; 64:754-764. [PMID: 33742615 DOI: 10.1097/dcr.0000000000002027] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Synchronous liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy for colorectal liver and peritoneal metastases have traditionally been contraindicated. More recent clinical practice has begun to promote this aggressive treatment in select patients. OBJECTIVE This study aimed to investigate the perioperative and oncological outcomes of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy, with and without liver resection, in the management of metastatic colorectal cancer. DATA SOURCES Medline, Embase, and Cochrane Library databases were searched up to July 2020. STUDY SELECTION Cohort studies comparing outcomes following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with and without liver resection for metastatic colorectal cancer were reviewed. No randomized controlled trials were available. INTERVENTION Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with or without synchronous liver resection were compared. MAIN OUTCOME MEASURES The primary outcome measures were perioperative mortality and major morbidity. Secondary outcomes included 3- and 5-year overall survival and 1- and 3-year disease-free survival. RESULTS Fourteen studies fitted the inclusion criteria, with 8 studies included in the meta-analysis. On pooled analysis, there was no significant difference in perioperative morbidity and mortality between the two groups. Patients that underwent concomitant liver resection had worse 1- and 3-year disease-free survival and 3- and 5-year overall survival. LIMITATIONS Only a limited number of studies were available, with a moderate degree of heterogeneity. CONCLUSIONS The addition of synchronous liver resection to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the treatment of resectable metastatic colorectal cancer was not associated with increased perioperative major morbidity and mortality in comparison with cytoreduction and hyperthermic intraperitoneal chemotherapy alone. However, the presence of liver metastases was associated with inferior disease-free and overall survival. These data support the continued practice of liver resection, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy in the management of select patients with such stage IV disease.
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Ray MD, Dhall K. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in the management of peritoneal surface malignancies - An evidence-based review. Curr Probl Cancer 2021; 45:100737. [PMID: 34116836 DOI: 10.1016/j.currproblcancer.2021.100737] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 02/27/2021] [Accepted: 03/15/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Traditionally, peritoneal surface malignancies (PSM) were considered terminal diseases because of their advanced nature, therefore, systemic chemotherapy was given with palliative intent only. As a result, very poor survival outcomes were observed. But with the introduction of complete Cytoreductive surgery (CRS) and Hyperthermic intraperitoneal chemotherapy (HIPEC), the scenario has changed dramatically. METHODOLOGY An objective electronic database search was performed in Pubmed, NLM Catalog, Google scholar, Bookshelf, and Pubmed Central published in the time period from 2000 till 2020. All the randomized studies were included. In the absence of randomized studies, both prospective and retrospective studies were included. The outcomes of HIPEC were measured in terms of median survival, disease-free survival, overall survival, complications and drug toxicities. RESULTS CRS and HIPEC are considered the standard of care for PMP and MPM even in the absence of level 1 evidence due to lack of an effective alternative treatment. In colorectal and gastric cancer, several phase-three trials are showing overall survival benefit in selected cases while there is a prophylactic and palliative role of HIPEC in gastric cancer. Three reported phase 3 trials showed positive results in ovarian cancer. In peritoneal sarcomatosis, the role of HIPEC is yet to be proven. CONCLUSION The patient selection is the key to the successful outcomes after HIPEC. HIPEC should be performed by the experienced surgeons in specialized centres with a strong critical care and intensive care support to reduce the morbidity and mortality. Ongoing trials and future directions will prove to be an indispensable arm in the oncological armamentarium.
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Affiliation(s)
- Mukur Dipi Ray
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India
| | - Kunal Dhall
- Department of Surgical Oncology, All India Institute of Medical Sciences, New Delhi, India.
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Cytoreductive surgery and mitomycin C hyperthermic intraperitoneal chemotherapy with CO 2 recirculation (HIPEC-CO 2) for colorectal cancer peritoneal metastases: analysis of short-term outcomes. Updates Surg 2021; 73:1443-1448. [PMID: 33782856 DOI: 10.1007/s13304-021-01034-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 03/16/2021] [Indexed: 12/27/2022]
Abstract
Peritoneal dissemination from colorectal cancer (CRC) has long been associated with unfavorable prognosis. However, in the last decades, the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was able to obtain up to 30% 5-year survival rate in selected centers. Despite the wide diffusion of CRS and HIPEC, until now, there are no clear recommendations on the drug of choice for HIPEC nor its technique, and safety and efficacy data of HIPEC regimens and techniques are lacking. We performed a retrospective analysis of a prospectively maintained database of 26 CRS and mitomycin C HIPEC with CO2 recirculation (HIPEC-CO2) for CRC peritoneal metastasis (PM) performed at our center. The main endpoints were morbidity, mortality, the temperature of perfusate during HIPEC and metabolic changes throughout the procedure. Morbidity was assessed by analysis of postoperative adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE version 4.0). Continuous variables of Arterial Blood Gas (ABG) analysis at three time-points were compared by the Student t test. There were no postoperative deaths. The overall grade 3-4 CTCAE complications rate at 30 days was 38.4%, with ten severe adverse events occurring to six (23.0%) patients. The temperature within HIPEC perfusion maintained between 41 and 42 °C in all cases and we experienced no HIPEC-related intraoperative complications. We observed a significant difference between all baseline and pre-HIPEC ABG parameters evaluated but no statistically significant differences between pre- and post-HIPEC ABG outcomes. This study shows that mitomycin C HIPEC-CO2 is feasible and has a safety profile comparable to that of other HIPEC techniques reported in the literature. Further research is needed to validate prospectively the safety and efficacy of this technique.
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30
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Benzaquen E, Wang Y, Wiseman S, Rosenfeld V, Sideris L, Dubé P, Pelletier JS, Vanounou T. Morbidity associated with the use of oxaliplatin versus mitomycin C in hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal carcinomatosis of colorectal or appendiceal origin: a multi-institutional comparative study. Can J Surg 2021; 64:E111-E118. [PMID: 33651573 PMCID: PMC8064255 DOI: 10.1503/cjs.001619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Background The raw costs of mitomycin C (MMC) and oxaliplatin for hyperthermic intraperitoneal chemotherapy (HIPEC) differ substantially. We sought to compare the morbidity and toxicity profiles associated with the use of oxaliplatin and MMC in patients undergoing cytoreductive surgery (CRS) and HIPEC for peritoneal carcinomatosis (PC) of colorectal or appendiceal origin, to evaluate whether the cost-effectiveness of these 2 agents should dictate drug choice. Methods We conducted a retrospective multi-institutional study of all patients with PC of colorectal or appendiceal origin treated with CRS-HIPEC using MMC or oxaliplatin from 2010 to 2015. Demographic, perioperative, morbidity, toxicity and cost data were compared between the 2 treatment groups and between cancer-origin subgroups. Results Forty-two patients treated with MMC and 76 treated with oxaliplatin were included in the study. Baseline demographic and tumour characteristics were comparable in the 2 groups, except that the patients treated with MMC had higher Charlson Comorbidity Index scores. The MMC group had a higher rate of cancer of colorectal origin (76.2% v. 57.9%, p = 0.047) and longer operative times (553 v. 320 min, p < 0.001). In the subgroup of patients whose cancer was of colorectal origin, patients treated with MMC had a higher transfusion rate (50.0% v. 28.6%, p = 0.023) and lower postoperative baseline hemoglobin level (100 v. 119 g/L, p = 0.002) than those treated with oxaliplatin. There was no difference in hematologic toxicity scores after controlling for postoperative anemia. There was no difference in the rates of major complications and 90-day mortality. However, MMC was less costly than oxaliplatin ($724 v. $8928). Conclusion MMC and oxaliplatin are both suitable agents for HIPEC and are associated with comparable morbidity and toxicity profiles, regardless of cancer origin. Thus, we propose that cost-effectiveness should ultimately dictate drug selection.
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Affiliation(s)
- Ella Benzaquen
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Yifan Wang
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Stephanie Wiseman
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Velka Rosenfeld
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Lucas Sideris
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Pierre Dubé
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Jean-Sebastien Pelletier
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
| | - Tsafrir Vanounou
- From the Division of General Surgery, Jewish General Hospital, Montréal, Que. (Benzaquen, Wang, Wiseman, Rosenfeld, Pelletier, Vanounou); and the Division of Surgical Oncology, Hôpital Maisonneuve-Rosemont, Montréal, Que. (Sideris, Dubé)
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31
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Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22:256-266. [PMID: 33476595 DOI: 10.1016/s1470-2045(20)30599-4] [Citation(s) in RCA: 501] [Impact Index Per Article: 125.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/30/2020] [Accepted: 09/25/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.
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Ray MD, Dhall K. Where Does HIPEC Stand: An Evidence Based Review. MULTIDISCIPLINARY APPROACH TO SURGICAL ONCOLOGY PATIENTS 2021:349-358. [DOI: 10.1007/978-981-15-7699-7_44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Brind'Amour A, Dubé P, Tremblay JF, Soucisse ML, Mack L, Bouchard-Fortier A, McCart JA, Govindarajan A, Bischof D, Haase E, Giacomantonio C, Hebbard P, Younan R, MacNeill A, Boulanger-Gobeil C, Sidéris L. Canadian guidelines on the management of colorectal peritoneal metastases. Curr Oncol 2020; 27:e621-e631. [PMID: 33380878 PMCID: PMC7755452 DOI: 10.3747/co.27.6919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Modern management of colorectal cancer (crc) with peritoneal metastasis (pm) is based on a combination of cytoreductive surgery (crs), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (hipec). Although the role of hipec has recently been questioned with respect to results from the prodige 7 trial, the role and benefit of a complete crs were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, crc with pm is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with pm from crc should be referred to, or discussed with, a pm surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of pm from crc and to reflect on the new practice standards set by recent publications on the topic.
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Affiliation(s)
- A Brind'Amour
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, chu de Québec-Université Laval, Quebec City
| | - P Dubé
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - J F Tremblay
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - M L Soucisse
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - L Mack
- Department of Surgery, University of Calgary, Calgary, AB
| | | | - J A McCart
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - A Govindarajan
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - D Bischof
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - E Haase
- Department of Surgery, University of Alberta, Edmonton, AB
| | | | - P Hebbard
- Department of Surgery, University of Manitoba, Winnipeg, MB
| | - R Younan
- Department of Surgery, University of Montreal, Montreal, QC
- Department of Surgery, Centre Hospitalier de l'Université de Montréal, Montreal, QC
| | - A MacNeill
- Department of Surgery, University of British Columbia, Vancouver, BC
| | | | - L Sidéris
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
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Narasimhan V, Tan S, Kong J, Pham T, Michael M, Ramsay R, Warrier S, Heriot A. Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis. Colorectal Dis 2020; 22:1482-1495. [PMID: 32027455 DOI: 10.1111/codi.15003] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/15/2019] [Indexed: 12/13/2022]
Abstract
AIM Peritoneal metastases from colorectal cancer confer the worst survival among all metastatic sites. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with isolated colorectal peritoneal metastases (CRPM) a favourable long-term survival. There are numerous factors postulated to influence survival in patients undergoing CRS and HIPEC. The aim of this study was to identify the key perioperative prognostic factors that influence survival in patients undergoing CRS and HIPEC for isolated CRPM. METHOD A systematic review and meta-analysis were conducted to evaluate prognostic factors influencing survival in patients undergoing CRS and HIPEC for isolated CRPM. RESULTS Thirty-three studies fitted the inclusion criteria for the systematic review, with 25 studies included in the meta-analysis. On pooled analysis, incomplete cytoreduction, increasing peritoneal carcinoma index (PCI) and lymph node involvement were significantly associated with a worse survival. Additionally, a rectal primary [hazard ratio (HR) 1.93, 95% CI 1.10-3.37], adjuvant chemotherapy (HR 0.71, 95% CI 0.54-0.93) and perioperative grade III/IV morbidity (HR 1.59, 95% CI 1.17-2.16) were also found to significantly influence survival. Notably, tumour differentiation and signet ring cell histology did not influence survival on pooled analysis. CONCLUSION This meta-analysis confirms that in patients undergoing CRS and HIPEC for isolated CRPM, incomplete cytoreduction, high PCI and lymph node involvement have a negative influence on survival. In addition, a rectal primary, adjuvant chemotherapy use and grade III/IV morbidity are important factors that also significantly influence survival.
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Affiliation(s)
- V Narasimhan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - S Tan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - J Kong
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - T Pham
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - M Michael
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - R Ramsay
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - S Warrier
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A Heriot
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
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Zhang X, Wu Q, Wei M, Deng X, Gu C, Wang Z. Oxaliplatin versus mitomycin C in HIPEC for peritoneal metastasis from colorectal cancer: a systematic review and meta-analysis of comparative studies. Int J Colorectal Dis 2020; 35:1831-1839. [PMID: 32725345 DOI: 10.1007/s00384-020-03702-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/14/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) following cytoreductive surgery (CRS) has been applied for peritoneal metastasis (PM) from colorectal cancer (CRC). This study aimed to compare oxaliplatin (OX) with mitomycin C (MMC) in HIPEC for PM from CRC in surgical and survival outcomes. METHODS A systematic literature search was performed in PubMed and Ovid databases for studies comparing OX with MMC in HIPEC for PM from CRC. The last search was performed on June 21, 2020. RESULTS Eleven articles published between 2006 and 2020 with 2091 patients were included. When compared with MMC group, the OX group showed significantly higher rate of major complications (P = 0.006, OR = 1.57, 95% CI [1.14, 2.16], I2 = 0%). Besides, no significant difference was observed between the two groups for survival outcomes, regardless of 3-year overall survival (P = 0.98, OR = 1.00, 95% CI [0.83, 1.22], I2 = 0%), 3-year disease-free survival (P = 0.98, OR = 1.00, 95% CI [0.83, 1.22], I2 = 0%), or 5-year overall survival (P = 0.91, OR = 1.01, 95% CI [0.81, 1.26], I2 = 0%). CONCLUSION OX and MMC could achieve comparable survival in HIPEC for PM from CRC. However, in consideration of the high incidence of major complication in OX group, MMC might be the safer one in clinical routines.
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Affiliation(s)
- Xubing Zhang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China
| | - Qingbin Wu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China
| | - Mingtian Wei
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China
| | - Xiangbing Deng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China
| | - Chaoyang Gu
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China
| | - Ziqiang Wang
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Guo Xue Xiang No. 37, Chengdu, 610041, China.
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Narasimhan V, Warrier S, Michael M, Ramsay R, Heriot A. Oxaliplatin versus Mitomycin C following complete cytoreduction for colorectal peritoneal metastases: a comparative study. J Gastrointest Surg 2020; 24:2104-2112. [PMID: 31745907 DOI: 10.1007/s11605-019-04447-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 10/24/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND AND OBJECTIVES Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases (CRPM) a favorable long-term survival. While cytoreductive techniques are standardized, there remains great variability in HIPEC drugs with mitomycin C or oxaliplatin use based largely on institute preference. In this study, we compared outcomes based on mitomycin C or oxaliplatin use after complete cytoreduction. METHODS This is a retrospective analysis over a 7-year period of all patients undergoing complete cytoreduction with HIPEC. RESULTS Seventy-eight patients underwent complete cytoreduction with HIPEC during this time. Forty-six patients received oxaliplatin as HIPEC, and 32 received mitomycin C. There was no difference in patient characteristics, resections, or major morbidity between the two groups. Superficial wound infections were higher in the mitomycin C group (37.5% v 15.2%, p = 0.02). Median overall and disease-free survival for the entire cohort was 40 and 14 months, respectively. There was no difference in overall survival or disease-free survival between the two HIPEC groups (HR 0.50, 95% CI 0.11-2.28). CONCLUSION Complete cytoreduction and HIPEC can offer selected patients a favorable survival. The choice of mitomycin C or oxaliplatin for HIPEC had no influence on survival. Prospective studies are needed to explore this important issue.
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Affiliation(s)
- Vignesh Narasimhan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia.
- Sir Peter MacCallum Dept. of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia.
| | - Satish Warrier
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Dept. of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Michael Michael
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
| | - Robert Ramsay
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Dept. of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Alexander Heriot
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Dept. of Oncology, University of Melbourne, Parkville, VIC, 3010, Australia
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Guidelines for Perioperative Care in Cytoreductive Surgery (CRS) with or without hyperthermic IntraPEritoneal chemotherapy (HIPEC): Enhanced Recovery After Surgery (ERAS®) Society Recommendations - Part II: Postoperative management and special considerations. Eur J Surg Oncol 2020; 46:2311-2323. [PMID: 32826114 DOI: 10.1016/j.ejso.2020.08.006] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Enhanced recovery after surgery (ERAS) pathways have been shown to considerably reduce complications, length of stay and costs after most of surgical procedures by standardised application of best evidence-based perioperative care. The aim was to elaborate dedicated recommendations for cytoreductive surgery (CRS) ± hyperthermic intraperitoneal chemotherapy (HIPEC) in a two-part series of guidelines based on expert consensus. The present part II of the guidelines highlights postoperative management and special considerations. METHODS The core group assembled a multidisciplinary panel of 24 experts involved in peritoneal surface malignancy surgery representing the fields of general surgery (n = 12), gynaecological surgery (n = 6), and anaesthesia (n = 6). Experts systematically reviewed and summarized the available evidence on 72 identified perioperative care items, following the GRADE (grading of recommendations, assessment, development, evaluation) system. Final consensus (defined as ≥50%, or ≥70% of weak/strong recommendations combined) was reached by a standardised 2-round Delphi process, regarding the strength of recommendations. RESULTS Response rates were 100% for both Delphi rounds. Quality of evidence was evaluated high, moderate low and very low, for 15 (21%), 26 (36%), 29 (40%) and 2 items, respectively. Consensus was reached for 71/72(98.6%) items. Strong recommendations were defined for 37 items. No consensus could be reached regarding the preemptive use of fresh frozen plasma. CONCLUSION The present ERAS recommendations for CRS ± HIPEC are based on a standardised expert consensus process providing clinicians with valuable guidance. There is an urgent need to produce high quality studies for CRS ± HIPEC and to prospectively evaluate recommendations in clinical practice.
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The Temperature-Dependent Effectiveness of Platinum-Based Drugs Mitomycin-C and 5-FU during Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer Cell Lines. Cells 2020; 9:cells9081775. [PMID: 32722384 PMCID: PMC7464333 DOI: 10.3390/cells9081775] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2020] [Revised: 07/23/2020] [Accepted: 07/23/2020] [Indexed: 12/24/2022] Open
Abstract
Cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment with curative intent for peritoneal metastasis of colorectal cancer (CRC). Currently, there is no standardized HIPEC protocol: choice of drug, perfusate temperature, and duration of treatment vary per institute. We investigated the temperature-dependent effectiveness of drugs often used in HIPEC. METHODS The effect of temperature on drug uptake, DNA damage, apoptosis, cell cycle distribution, and cell growth were assessed using the temperature-dependent IC50 and Thermal Enhancement Ratio (TER) values of the chemotherapeutic drugs cisplatin, oxaliplatin, carboplatin, mitomycin-C (MMC), and 5-fluorouracil (5-FU) on 2D and 3D CRC cell cultures at clinically relevant hyperthermic conditions (38-43 °C/60 min). RESULTS Hyperthermia alone decreased cell viability and clonogenicity of all cell lines. Treatment with platinum-based drugs and MMC resulted in G2-arrest. Platinum-based drugs display a temperature-dependent synergy with heat, with increased drug uptake, DNA damage, and apoptosis at elevated temperatures. Apoptotic levels increased after treatment with MMC or 5-FU, without a synergy with heat. CONCLUSION Our in vitro results demonstrate that a 60-min exposure of platinum-based drugs and MMC are effective in treating 2D and 3D CRC cell cultures, where platinum-based drugs require hyperthermia (>41 °C) to augment effectivity, suggesting that they are, in principle, suitable for HIPEC.
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Forsythe SD, Sasikumar S, Moaven O, Sivakumar H, Shen P, Levine EA, Soker S, Skardal A, Votanopoulos KI. Personalized Identification of Optimal HIPEC Perfusion Protocol in Patient-Derived Tumor Organoid Platform. Ann Surg Oncol 2020; 27:4950-4960. [PMID: 32632882 DOI: 10.1245/s10434-020-08790-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/18/2020] [Indexed: 11/18/2022]
Abstract
BACKGROUND Chemotherapy dosing duration and perfusion temperature vary significantly in HIPEC protocols. This study investigates patient-derived tumor organoids as a platform to identify the most efficacious perfusion protocol in a personalized approach. PATIENTS AND METHODS Peritoneal tumor tissue from 15 appendiceal and 8 colon cancer patients who underwent CRS/HIPEC were used for personalized organoid development. Organoids were perfused in parallel at 37 and 42 °C with low- and high-dose oxaliplatin (200 mg/m2 over 2 h vs. 460 mg/m2 over 30 min) and MMC (40 mg/3L over 2 h). Viability assays were performed and pooled for statistical analysis. RESULTS An adequate organoid number was generated for 75% (6/8) of colon and 73% (11/15) of appendiceal patients. All 42 °C treatments displayed lower viability than 37 °C treatments. On pooled analysis, MMC and 200 mg/m2 oxaliplatin displayed no treatment difference for either appendiceal or colon organoids (19% vs. 25%, p = 0.22 and 27% vs. 31%, p = 0.55, respectively), whereas heated MMC was superior to 460 mg/m2 oxaliplatin in both primaries (19% vs. 54%, p < 0.001 and 27% vs. 53%, p = 0.002, respectively). In both appendiceal and colon tumor organoids, heated 200 mg/m2 oxaliplatin displayed increased cytotoxicity as compared with 460 mg/m2 oxaliplatin (25% vs. 54%, p < 0.001 and 31% vs. 53%, p = 0.008, respectively). CONCLUSIONS Organoids treated with MMC or 200 mg/m2 heated oxaliplatin for 2 h displayed increased susceptibility in comparison with 30-min 460 mg/m2 oxaliplatin. Optimal perfusion protocol varies among patients, and organoid technology may offer a platform for tailoring HIPEC conditions to the individual patient level.
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Affiliation(s)
- Steven D Forsythe
- Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Shyama Sasikumar
- Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Omeed Moaven
- Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA.,Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA
| | - Hemamylammal Sivakumar
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.,The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Perry Shen
- Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA.,Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA
| | - Edward A Levine
- Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA.,Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA
| | - Shay Soker
- Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA.,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.,Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Aleksander Skardal
- Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA.,The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
| | - Konstantinos I Votanopoulos
- Wake Forest Organoid Research Center (WFORCE), Wake Forest School of Medicine, Winston-Salem, NC, USA. .,Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA. .,Comprehensive Cancer Center at Wake Forest Baptist Medical, Winston-Salem, NC, USA. .,Department of Surgery - Surgical Oncology, Wake Forest Baptist Medical Center, Winston-Salem, NC, 27157, USA.
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Chicago Consensus Working Group. The Chicago Consensus on peritoneal surface malignancies: Management of colorectal metastases. Cancer 2020; 126:2534-2540. [PMID: 32282070 DOI: 10.1002/cncr.32874] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Accepted: 08/14/2019] [Indexed: 01/05/2023]
Abstract
The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of colorectal cancer specifically as it relates to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts, including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.
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Chicago Consensus Working Group. The Chicago Consensus on Peritoneal Surface Malignancies: Management of Colorectal Metastases. Ann Surg Oncol 2020; 27:1761-1767. [PMID: 32285270 DOI: 10.1245/s10434-020-08315-x] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Indexed: 12/11/2022]
Abstract
The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of colorectal cancer specifically as it relates to the management of peritoneal surface malignancy. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.
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Bakkers C, van Erning FN, Rovers KP, Nienhuijs SW, Burger JW, Lemmens VE, Aalbers AG, Kok NF, Boerma D, Brandt AR, Hemmer PH, van Grevenstein WM, de Reuver PR, Tanis PJ, Tuynman JB, de Hingh IH. Long-term survival after hyperthermic intraperitoneal chemotherapy using mitomycin C or oxaliplatin in colorectal cancer patients with synchronous peritoneal metastases: A nationwide comparative study. Eur J Surg Oncol 2020; 46:1902-1907. [PMID: 32340819 DOI: 10.1016/j.ejso.2020.04.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/03/2020] [Accepted: 04/12/2020] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES In the Netherlands, limited variability exists in performance of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) among centers treating colorectal peritoneal metastases (PM), except for the intraperitoneal drug administration. This offers a unique opportunity to investigate any disparities in survival between the two most frequently used HIPEC regimens worldwide: mitomycin C (MMC) and oxaliplatin. METHODS This was a comparative, population-based cohort study of all Dutch patients diagnosed with synchronous colorectal PM who underwent CRS-HIPEC between 2014 and 2017. They were retrieved from the Netherlands Cancer Registry. Main outcome was overall survival (OS). The effect of the intraperitoneal drug on OS was investigated using multivariable Cox regression analysis. RESULTS In total, 297 patients treated between 2014 and 2017 were included. Among them, 177 (59.6%) received MMC and 120 (40.4%) received oxaliplatin. Only primary tumor location was different between the two groups: more left-sided colon in the Oxaliplatin group (47.5% vs. 33.3%, respectively, p=0.048). The 1-, 2- and 3-year OS were 84.6% vs. 85.8%, 61.6% vs. 63.9% and 44.7% vs. 53.5% in patients treated with MMC and oxaliplatin, respectively. Median OS was 30.7 months in the MMC group vs. 46.6 months in the oxaliplatin group (p=0.181). In multivariable analysis, no influence of intraperitoneal drug on survival was observed (adjusted HR 0.77 [0.53-1.13]). CONCLUSIONS Long-term survival between patients treated with either MMC or oxaliplatin during CRS-HIPEC was not significantly different.
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Affiliation(s)
- C Bakkers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands.
| | - F N van Erning
- Department of Research, Netherlands Comprehensive Cancer Organization, Utrecht, the Netherlands
| | - K P Rovers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - S W Nienhuijs
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - J W Burger
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands
| | - V E Lemmens
- Department of Research, Netherlands Comprehensive Cancer Organization, Utrecht, the Netherlands
| | - A G Aalbers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - N F Kok
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - D Boerma
- Department of Surgery, St. Antonius Hospital, Nieuwegein, the Netherlands
| | - A R Brandt
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, the Netherlands
| | - P H Hemmer
- Department of Surgery, University Medical Center Groningen, Groningen, the Netherlands
| | - W M van Grevenstein
- Department of Surgery, University Medical Center Utrecht, Utrecht, the Netherlands
| | - P R de Reuver
- Department of Surgery, Radboud University Medical Center, Nijmegen, the Netherlands
| | - P J Tanis
- Department of Surgery, Amsterdam University Medical Centers, University of Amsterdam, Cancer Centre Amsterdam, Amsterdam, the Netherlands
| | - J B Tuynman
- Department of Surgery, Amsterdam University Medical Centers, VU Medical Center, Amsterdam, the Netherlands
| | - I H de Hingh
- Department of Surgery, Catharina Cancer Institute, Eindhoven, the Netherlands; GROW - School for Oncology and Development Biology, Maastricht University, Maastricht, the Netherlands
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Woeste MR, Philips P, Egger ME, Scoggins CR, McMasters KM, Martin RCG. Optimal perfusion chemotherapy: A prospective comparison of mitomycin C and oxaliplatin for hyperthermic intraperitoneal chemotherapy in metastatic colon cancer. J Surg Oncol 2020; 121:1298-1305. [PMID: 32239529 DOI: 10.1002/jso.25920] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 02/05/2020] [Accepted: 03/20/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Peritoneal carcinomatosis of colorectal adenocarcinoma (CRC) origin is common and is the second-most frequent cause of death in colorectal cancer. There is survival benefit to surgical resection plus hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with metastatic CRC. However, there remains controversy between oxaliplatin (Oxali) and mitomycin C (MMC), as the agent of choice. METHODS A review of our 285 patients prospective HIPEC database from July 2007 to May 2018 identified 48 patients who underwent cytoreductive surgery plus HIPEC with MMC or Oxali. Patients were stratified based on preoperative and postoperative peritoneal cancer indices (PCI). The primary outcomes of survival and progression-free survival were compared. RESULTS Type of HIPEC chemotherapy was not found to be predictive of overall survival. Preoperative PCI (P = .04), preoperative response to chemotherapy (P = .0001), and postoperative PCI (P = .05) were predictive for overall survival. CONCLUSIONS MMC or Oxali based HIPEC chemotherapy are both safe and effective for the management of peritoneal only metastatic CRC. Both perfusion therapies should be considered with all patients receiving modern induction chemotherapy.
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Affiliation(s)
- Matthew R Woeste
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Prejesh Philips
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Michael E Egger
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Charles R Scoggins
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Kelly M McMasters
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
| | - Robert C G Martin
- Division of Surgical Oncology, Department of Surgery, University of Louisville, Louisville, Kentucky
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Auer RC, Sivajohanathan D, Biagi J, Conner J, Kennedy E, May T. Indications for hyperthermic intraperitoneal chemotherapy with cytoreductive surgery: a systematic review. Eur J Cancer 2020; 127:76-95. [PMID: 31986452 DOI: 10.1016/j.ejca.2019.10.034] [Citation(s) in RCA: 61] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/25/2019] [Accepted: 10/30/2019] [Indexed: 12/27/2022]
Abstract
The purpose of the present review was to describe evidence-based indications for hyperthermic intraperitoneal chemotherapy (HIPEC), with cytoreductive surgery (CRS), in patients with a diagnosis of mesothelioma, appendiceal (including appendiceal mucinous neoplasm), colorectal, gastric, ovarian or primary peritoneal carcinoma. Relevant studies were identified from a systematic MEDLINE and EMBASE search of studies published from 1985 to 2019. Studies were included if they were RCTs. If no RCTs were identified, prospective and retrospecctive comparative studies (where confounders are controlled for studies with greater than 30 patients) were included. Overall survival, progression-free survival, recurrence-free survival, adverse events and quality of life data were extracted. For patients with newly diagnosed, primary stage III epithelial ovarian, fallopian tube or primary peritoneal carcinoma, HIPEC with CRS should be considered for those with at least stable disease following neoadjuvant chemotherapy at the time of interval CRS if complete or optimal cytoreduction is achieved. There is insufficient evidence to recommend the addition of HIPEC when primary CRS is performed for patients with newly diagnosed, primary advanced epithelial ovarian, fallopian tube or primary peritoneal carcinoma or in those with recurrent ovarian cancer outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS for the prevention of or for the treatment of peritoneal colorectal carcinomatosis outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS for the prevention of or for the treatment of gastric peritoneal carcinomatosis outside of a clinical trial. There is insufficient evidence to recommend HIPEC with CRS in patients with malignant peritoneal mesothelioma or in those with disseminated mucinous neoplasm in the appendix as a standard of care; however, these patients should be referred to HIPEC specialty centres for assessment for treatment as part of an ongoing research protocol.
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Affiliation(s)
- Rebecca C Auer
- Department of Surgery, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.
| | - Duvaraga Sivajohanathan
- Department of Oncology, McMaster University & Program in Evidence-Based Care, Cancer Care Ontario, 1280 Main Street West, Hamilton, ON, L8S 4L8, Canada
| | - Jim Biagi
- Department of Medical Oncology, Cancer Centre of Southeastern Ontario, 25 King Street West, Kingston, ON, K7L 5P9, Canada
| | - James Conner
- Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Erin Kennedy
- Department of Surgery, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, M5G 1X5, Canada
| | - Taymaa May
- Department of Oncology, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2C1, Canada
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Yang SY, Kang JH, Kim HS, Han YD, Min BS, Lee KY. Status of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer. J Gastrointest Oncol 2019; 10:1251-1265. [PMID: 31949946 PMCID: PMC6955007 DOI: 10.21037/jgo.2019.01.36] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Accepted: 01/27/2019] [Indexed: 12/19/2022] Open
Abstract
Peritoneal carcinomatosis (PC) was previously considered an incurable disease with a poor survival outcome. As our understanding of its biology evolved, the paradigm of the management of PC from colorectal cancer (CRC) has changed, including the combination of macroscopic disease control, cytoreductive surgery (CRS), maximal regional chemotherapy to treat residual microscopic disease, and hyperthermic intraperitoneal chemotherapy (HIPEC). As with many surgical innovations, CRS with HIPEC has evolved faster than data to support it, leaving many skeptics and critics. This review highlights the recent evidence of current practice and outcome of CRS with HIPEC. Furthermore, it also summarizes the ongoing clinical trials and potential future progress of this treatment modality.
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Affiliation(s)
- Seung Yoon Yang
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hyun Kang
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Ho Seung Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Yoon Dae Han
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Byung Soh Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Kang Young Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
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Moaven O, Votanopoulos KI, Shen P, Mansfield P, Bartlett DL, Russell G, McQuellon R, Stewart JH, Levine EA. Health-Related Quality of Life After Cytoreductive Surgery/HIPEC for Mucinous Appendiceal Cancer: Results of a Multicenter Randomized Trial Comparing Oxaliplatin and Mitomycin. Ann Surg Oncol 2019; 27:772-780. [PMID: 31720933 DOI: 10.1245/s10434-019-08064-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Indexed: 01/01/2023]
Abstract
BACKGROUND This study evaluated health-related quality of life (HRQOL) using patient-reported outcomes in subjects with mucinous appendiceal neoplasms who underwent cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) as part of a randomized trial comparing mitomycin with oxaliplatin. METHODS In this prospective multicenter study, 121 mucinous appendiceal cancer patients, with evidence of peritoneal dissemination who underwent CRS, were randomized to receive mitomycin (divided 40 mg) or oxaliplatin (200 mg/m2) for HIPEC. The Functional Assessment of Cancer Therapy Neurotoxicity (FACT-G/NTX) questionnaire was utilized to assess HRQOL. The Trial Outcome Index (TOI) is a summary index responsive to changes in physical/functional outcomes. Repeated measures mixed models with an unstructured variance matrix were applied to assess changes in HRQOL longitudinally. RESULTS Baseline questionnaire compliance was 95.9%. Baseline physical well-being (PWB) was independently associated with overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.96; p = 0.017). The TOI was significantly lower in the mitomycin group compared with the oxaliplatin arm at 12 weeks (p = 0.044; score difference 6.35) and 24 weeks after surgery (p = 0.049; score difference 5.61). At 12 weeks after surgery, declines from baseline were significant in the TOI (p = 0.004; score decline 8.99), PWB (p < 0.001; score decline 2.83), and FWB (p < 0.001; score decline 3.42) in the mitomycin group but not the oxaliplatin group. CONCLUSIONS Compared with mitomycin, HIPEC perfusion with oxaliplatin results in significantly better physical and functional outcomes. With similar survival outcomes and complication rates, oxaliplatin should be considered as the chemoperfusion agent of choice in mucinous appendiceal cancer patients undergoing CRS/HIPEC.
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Affiliation(s)
- Omeed Moaven
- Department of Surgery, Wake Forest University, Winston Salem, NC, USA
| | | | - Perry Shen
- Department of Surgery, Wake Forest University, Winston Salem, NC, USA
| | - Paul Mansfield
- Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - David L Bartlett
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Greg Russell
- Department of Surgery, Wake Forest University, Winston Salem, NC, USA
| | - Richard McQuellon
- Department of Surgery, Wake Forest University, Winston Salem, NC, USA
| | - John H Stewart
- Department of Surgery, University of Illinois, Chicago, IL, USA
| | - Edward A Levine
- Department of Surgery, Wake Forest University, Winston Salem, NC, USA. .,Section of Surgical Oncology, Department of General Surgery, Wake Forest Baptist Health, Winston Salem, NC, USA.
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Baratti D, Kusamura S, Azmi N, Guaglio M, Montenovo M, Deraco M. Colorectal Peritoneal Metastases Treated by Perioperative Systemic Chemotherapy and Cytoreductive Surgery With or Without Mitomycin C-Based HIPEC: A Comparative Study Using the Peritoneal Surface Disease Severity Score (PSDSS). Ann Surg Oncol 2019; 27:98-106. [PMID: 31691116 DOI: 10.1245/s10434-019-07935-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND The Prodige-7 trial has questioned the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal metastases from colorectal cancer (CRC-PM). PATIENTS AND METHODS We compared a prospectively collected group of 48 patients undergoing oxaliplatin/irinotecan-based perioperative systemic chemotherapy (s-CT) with targeted agents, and cytoreductive surgery (CRS) (no-HIPEC group) with 48 controls undergoing the same perioperative s-CT and CRS/HIPEC (HIPEC group). Patients were matched (1:1) according to the Peritoneal Surface Disease Severity Score, completeness of cytoreduction, history of extraperitoneal disease (EPD), and Peritoneal Cancer Index. RESULTS The groups were comparable, except for a higher number of patients in the HIPEC group with World Health Organization performance status 0, pN2 stage primary tumor, and treated with preoperative s-CT. Forty-one patients in the no-HIPEC group and 43 patients in the HIPEC group had optimal comprehensive treatment (P = 0.759), defined as complete cytoreduction of PM and margin-negative EPD resection. Median follow-up was 31.6 months in the no-HIPEC group and 39.9 months in the HIPEC group. Median overall survival was 39.3 months in the no-HIPEC group and 34.8 months in the HIPEC group (P = 0.702). In the two groups, severe morbidity occurred in 14 (29.2%) and 13 (27.1%) patients, respectively (P = 1.000), with no operative deaths. On multivariate analysis, left-sided primary and curative treatment independently correlated with better survival while HIPEC did not (hazard ratio 0.73; 95% confidence interval 0.47-1.15; P = 0.178). CONCLUSIONS Our results confirmed that, in selected patients, perioperative s-CT and surgical treatment of CRC-PM resulted in unexpectedly high survival rates. Mitomycin C-based HIPEC did not increase morbidity but did not impact prognosis.
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Affiliation(s)
- Dario Baratti
- Peritoneal Malignancy Program, Department of Surgery, National Cancer Institute, Milan, Italy.
| | - Shigeki Kusamura
- Peritoneal Malignancy Program, Department of Surgery, National Cancer Institute, Milan, Italy
| | - Norfarizan Azmi
- Department of General Surgery, Hospital Tuanku Ja'afar, Seremban, Negeri Sembilan, Malaysia
| | - Marcello Guaglio
- Peritoneal Malignancy Program, Department of Surgery, National Cancer Institute, Milan, Italy
| | - Matteo Montenovo
- Peritoneal Malignancy Program, Department of Surgery, National Cancer Institute, Milan, Italy
| | - Marcello Deraco
- Peritoneal Malignancy Program, Department of Surgery, National Cancer Institute, Milan, Italy
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Wisselink DD, Braakhuis LLF, Gallo G, van Grevenstein WMU, van Dieren S, Kok NFM, de Reuver PR, Tanis PJ, de Hingh IHJT. Systematic review of published literature on oxaliplatin and mitomycin C as chemotherapeutic agents for hyperthermic intraperitoneal chemotherapy in patients with peritoneal metastases from colorectal cancer. Crit Rev Oncol Hematol 2019; 142:119-129. [PMID: 31400583 DOI: 10.1016/j.critrevonc.2019.06.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 06/28/2019] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND The role of hyperthermic intraperitoneal chemotherapy (HIPEC) with oxaliplatin in addition to cytoreductive surgery (CRS) has recently been questioned in peritoneal metastases of colorectal cancer. Whether this applies to all published CRS/HIPEC regimens is unclear. METHODS A systematic literature search identified 46 studies on CRS/HIPEC using either oxaliplatin of mitomycin C with at least one oncological outcome parameter RESULTS: Oxaliplatin and mitomycin C studies were comparable regarding extent of disease, but differed substantially regarding synchronous versus metachronous presentation, application of neo-adjuvant systemic chemotherapy, duration of HIPEC, and completeness of cytoreduction for at least one of the oncological endpoints. Severe postoperative complication rate seemed significantly higher after oxaliplatin-based CRS/HIPEC. CONCLUSION Published cohorts on oxaliplatin-based CRS/HIPEC differed essentially from MMC-based procedures, especially considering the application of oxaliplatin-containing neo-adjuvant systemic therapy and shorter exposure time to intraperitoneal chemotherapy in oxaliplatin studies. No meaningful comparison could be made regarding DFS and OS.
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Affiliation(s)
- Daan D Wisselink
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
| | - Linde L F Braakhuis
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
| | - Gaetano Gallo
- Department of Medical and Surgical Sciences, Università Magna Graecia di Catanzaro, Viale Europa, 88100 Catanzaro, CZ, Italy.
| | | | - Susan van Dieren
- Clinical Research Unit, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
| | - Niels F M Kok
- Department of surgery, Antoni van Leeuwenhoek hospital, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, the Netherlands.
| | - Philip R de Reuver
- Department of surgery, Radboud University Medical Centre, Geert Grooteplein-Zuid 22, 6525 GA Nijmegen, the Netherlands.
| | - Pieter J Tanis
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105AZ Amsterdam, the Netherlands.
| | - Ignace H J T de Hingh
- Department of surgery, Catharina hospital, Michelangelolaan 2, 5623 EJ Eindhoven, the Netherlands.
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Analysis of Bacterial and Fungal Infections after Cytoreduction Surgery and Hyperthermic Intraperitoneal Chemotherapy: An Observational Single-Centre Study. Int J Microbiol 2019; 2019:6351874. [PMID: 31467552 PMCID: PMC6701354 DOI: 10.1155/2019/6351874] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Accepted: 06/19/2019] [Indexed: 12/18/2022] Open
Abstract
Introduction While hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreduction surgery (CRS) has been shown to improve patient survival and disease-free progression in peritoneal carcinoma (PC) patients, the procedure relates to a high postoperative infection rate. Herein, we report the bacterial and fungal infections after CRS and HIPEC from a single institution in Saudi Arabia. Patients and Methods A prospective observational study was conducted on 38 patients with PC selected for CRS/HIPEC procedure between 2012 and 2015 in our centre. Results Postoperative bacterial and fungal infection within 100 days was 42.2%, bacterial infection was reported always, and fungal infection was reported in 5 (13.2%) cases. Infections from the surgical site were considered the most common infection site. Multidrug-resistant extended-spectrum beta-lactamase (ESBL) Escherichia coli was the most frequent isolate, followed by multidrug-resistant Acinetobacter baumannii and Pseudomonas aeruginosa. Lower preoperative albumin and a prolonged preoperative activated partial thromboplastin time (APTT) are associated with postoperative infections, while a prolonged preoperative hospital stay (hazard ratio (HR) = 1.064; confidence interval (CI) = 1.002–1.112; P=0.042) and more intraoperative blood loss (>10%) (HR = 3.919; 95% CI = 1.024–14.995; P=0.046) were independent risk factors for postoperative infections. Three cases died during the follow-up period; all were due to infection. Discussion The infection rate in our centre compared to previous studies of comparable patients was matching. Effective management of postoperative infections should be considered, and identified risk factors in this study can help to focus on effective prevention and treatment strategies.
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50
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Jong LA, Erp NP. Reply to ‘Hyperthermic intraperitoneal chemotherapy with oxaliplatin—Still not standard of care for patients with colorectal peritoneal metastases’ by Julianov and Saroglu. Br J Clin Pharmacol 2019; 85:1848-1849. [DOI: 10.1111/bcp.13983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2019] [Revised: 04/23/2019] [Accepted: 05/05/2019] [Indexed: 11/30/2022] Open
Affiliation(s)
- Loek A.W. Jong
- Department of Pharmacy, Radboud Institute for Health SciencesRadboudumc Nijmegen The Netherlands
| | - Nielka P. Erp
- Department of Pharmacy, Radboud Institute for Health SciencesRadboudumc Nijmegen The Netherlands
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