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Dai W, Chen Y, Xue Y, Wan M, Mao C, Zhang K. Progress in the Treatment of Peritoneal Metastatic Cancer and the Application of Therapeutic Nanoagents. ACS APPLIED BIO MATERIALS 2023; 6:4518-4548. [PMID: 37916787 DOI: 10.1021/acsabm.3c00662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023]
Abstract
Peritoneal metastatic cancer is a cancer caused by the direct growth of cancer cells from the primary site through the bloodstream, lymph, or peritoneum, which is a difficult part of current clinical treatment. In the abdominal cavity of patients with metastatic peritoneal cancer, there are usually nodules of various sizes and malignant ascites. Among them, nodules of different sizes can obstruct intestinal movement and form intestinal obstruction, while malignant ascites can cause abdominal distension and discomfort, and even cause patients to have difficulty in breathing. The pathology and physiology of peritoneal metastatic cancer are complex and not fully understood. The main hypothesis is "seed" and "soil"; i.e., cells from the primary tumor are shed and implanted in the peritoneal cavity (peritoneal metastasis). In the last two decades, the main treatment modalities used clinically are cytoreductive surgery (CRS), systemic chemotherapy, intraperitoneal chemotherapy, and combined treatment, all of which help to improve patient survival and quality of life (QOL). However, the small-molecule chemotherapeutic drugs used clinically still have problems such as rapid drug metabolism and systemic toxicity. With the rapid development of nanotechnology in recent years, therapeutic nanoagents for the treatment of peritoneal metastatic cancer have been gradually developed, which has improved the therapeutic effect and reduced the systemic toxicity of small-molecule chemotherapeutic drugs to a certain extent. In addition, nanomaterials have been developed not only as therapeutic agents but also as imaging agents to guide peritoneal tumor CRS. In this review, we describe the etiology and pathological features of peritoneal metastatic cancer, discuss in detail the clinical treatments that have been used for peritoneal metastatic cancer, and analyze the advantages and disadvantages of the different clinical treatments and the QOL of the treated patients, followed by a discussion focusing on the progress, obstacles, and challenges in the use of therapeutic nanoagents in peritoneal metastatic cancer. Finally, therapeutic nanoagents and therapeutic tools that may be used in the future for the treatment of peritoneal metastatic cancer are prospected.
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Affiliation(s)
- Wenjun Dai
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Yidan Chen
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yunxin Xue
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Mimi Wan
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Chun Mao
- National and Local Joint Engineering Research Center of Biomedical Functional Materials, School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210023, China
| | - Ke Zhang
- Department of Radiation Oncology, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
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Ornella MSC, Badrinath N, Kim KA, Kim JH, Cho E, Hwang TH, Kim JJ. Immunotherapy for Peritoneal Carcinomatosis: Challenges and Prospective Outcomes. Cancers (Basel) 2023; 15:cancers15082383. [PMID: 37190310 DOI: 10.3390/cancers15082383] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/13/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Peritoneal metastasis, also known as peritoneal carcinomatosis (PC), is a refractory cancer that is typically resistant to conventional therapies. The typical treatment for PC is a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Recently, research in this area has seen significant advances, particularly in immunotherapy as an alternative therapy for PC, which is very encouraging. Catumaxomab is a trifunctional antibody intraperitoneal (IP) immunotherapy authorized in Europe that can be used to diminish malignant ascites by targeting EpCAM. Intraperitoneal (IP) immunotherapy breaks immunological tolerance to treat peritoneal illness. Increasing T-cell responses and vaccination against tumor-associated antigens are two methods of treatment. CAR-T cells, vaccine-based therapeutics, dendritic cells (DCs) in combination with pro-inflammatory cytokines and NKs, adoptive cell transfer, and immune checkpoint inhibitors are promising treatments for PC. Carcinoembryonic antigen-expressing tumors are suppressed by IP administration of CAR-T cells. This reaction was strengthened by anti-PD-L1 or anti-Gr1. When paired with CD137 co-stimulatory signaling, CAR-T cells for folate receptor cancers made it easier for T-cell tumors to find their way to and stay alive in the body.
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Affiliation(s)
- Mefotse Saha Cyrelle Ornella
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Narayanasamy Badrinath
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Kyeong-Ae Kim
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Jung Hee Kim
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Euna Cho
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Tae-Ho Hwang
- Department of Pharmacology, School of Medicine, Pusan National University, Yangsan 50612, Republic of Korea
- Bionoxx Inc., Parkview Tower #1905, 248 Jeongjail-ro, Bundang-gu, Seongnam 13554, Republic of Korea
| | - Jae-Joon Kim
- Division of Hematology & Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
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Larsen SG, Graf W, Mariathasan AB, Sørensen O, Spasojevic M, Goscinski MA, Selboe S, Lundstrøm N, Holtermann A, Revheim ME, Bruland ØS. First experience with 224Radium-labeled microparticles (Radspherin®) after CRS-HIPEC for peritoneal metastasis in colorectal cancer (a phase 1 study). Front Med (Lausanne) 2023; 10:1070362. [PMID: 36936230 PMCID: PMC10016379 DOI: 10.3389/fmed.2023.1070362] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 01/23/2023] [Indexed: 03/05/2023] Open
Abstract
Background Peritoneal metastasis (PM) from colorectal cancer carries a dismal prognosis despite extensive cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). With a median time to recurrence of 11-12 months, there is a need for novel therapies. Radspherin® consists of the α-emitting radionuclide radium-224 (224Ra), which has a half-life of 3.6 days and is adsorbed to a suspension of biodegradable calcium carbonate microparticles that are designed to give short-range radiation to the serosal peritoneal surface linings, killing free-floating and/or tumor cell clusters that remain after CRS-HIPEC. Methods A first-in-human phase 1 study (EudraCT 2018-002803-33) was conducted at two specialized CRS-HIPEC centers. Radspherin® was administered intraperitoneally 2 days after CRS-HIPEC. Dose escalation at increasing activity dose levels of 1-2-4-7-MBq, a split-dose repeated injection, and expansion cohorts were used to evaluate the safety and tolerability of Radspherin®. The aim was to explore the recommended dose and biodistribution using gamma-camera imaging. The results from the planned safety interim analysis after the completion of the dose-limiting toxicity (DLT) period of 30 days are presented. Results Twenty-three patients were enrolled: 14 in the dose escalation cohort, three in the repeated cohort, and six in the expansion cohort. Of the 23 enrolled patients, seven were men and 16 were women with a median age of 64 years (28-78). Twelve patients had synchronous PM stage IV and 11 patients had metachronous PM [primary stage II; (6) and stage III; (5)], with a disease-free interval of 15 months (3-30). The peritoneal cancer index was median 7 (3-19), operation time was 395 min (194-515), and hospital stay was 12 days (7-37). A total of 68 grade 2 adverse events were reported for 17 patients during the first 30 days; most were considered related to CRS and/or HIPEC. Only six of the TEAEs were evaluated as related to Radspherin®. One TEAE, anastomotic leakage, was reported as grade 3. Accordion ≥3 grade events occurred in a total of four of the 23 patients: reoperation due to anastomotic leaks (two) and drained abscesses (two). No DLT was documented at the 7 MBq dose level that was then defined as the recommended dose. The biodistribution of Radspherin® showed a relatively even peritoneal distribution. Conclusion All dose levels of Radspherin® were well tolerated, and DLT was not reached. No deaths occurred, and no serious adverse events were considered related to Radspherin®.Clinical Trial Registration: Clinicaltrials.gov, NCT03732781.
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Affiliation(s)
- Stein Gunnar Larsen
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- *Correspondence: Stein Gunnar Larsen,
| | - Wilhelm Graf
- Department of Surgical Sciences, Uppsala University, Uppsala, Sweden
- Uppsala Academic Hospital, Uppsala, Sweden
| | - Anthony Burton Mariathasan
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Olaf Sørensen
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Milan Spasojevic
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Mariusz Adam Goscinski
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Silje Selboe
- Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
| | - Nadja Lundstrøm
- Uppsala Academic Hospital, Uppsala, Sweden
- Department of Nuclear Medicine, Uppsala, Sweden
| | - Anne Holtermann
- Department of Gastroenterological Surgery, Section for Surgical Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Mona-Elisabeth Revheim
- Division of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Øyvind Sverre Bruland
- Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Department of Oncology, Oslo University Hospital, Oslo, Norway
- Oncoinvent AS, Oslo, Norway
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Larsen SG, Goscinski MA, Dueland S, Steigen SE, Hofsli E, Torgunrud A, Lund-Iversen M, Dagenborg VJ, Flatmark K, Sorbye H. Impact of KRAS, BRAF and microsatellite instability status after cytoreductive surgery and HIPEC in a national cohort of colorectal peritoneal metastasis patients. Br J Cancer 2022; 126:726-735. [PMID: 34887523 PMCID: PMC8888568 DOI: 10.1038/s41416-021-01620-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 10/18/2021] [Accepted: 10/29/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Patients with metastatic colorectal cancer (mCRC) carrying BRAF (mutBRAF) or KRAS mutation (mutKRAS) have an inferior prognosis after liver or lung surgery, whereas the prognostic role in the context of peritoneal metastasis (PM) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been less investigated. METHODS In total, 257 patients with non-appendiceal PM-CRC were included from the Norwegian National Unit for CRS-HIPEC. RESULTS In total, 180 patients received CRS-HIPEC with Mitomycin C, 77 patients received palliative surgery only. In the CRS-HIPEC group, mutBRAF was found in 24.7%, mutKRAS 33.9% and double wild-type 41.4% without differences in survival. MSI was found in 29.3% of mutBRAF cases. Patients with mutBRAF/MSI had superior 5-year survival compared to mutBRAF with MSS (58.3% vs 25.2%, P = 0.022), and better 3-year disease-free survival (DFS) compared to mutKRAS (48.6% vs 17.2%, P = 0.049). Peritoneal Cancer Index and the number of lymph node metastasis were prognostic for OS, and the same two, location and gender prognostic for DFS in multivariate analysis. CONCLUSIONS PM-CRC with CRS-HIPEC patients has a surprisingly high proportion of mutBRAF (24.7%). Survival was similar comparing mutBRAF, mutKRAS and double wild-type cases, whereas a small subgroup with mutBRAF and MSI had better survival. Patients with mutBRAF tumours and limited PM should be considered for CRS-HIPEC.
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Affiliation(s)
- S. G. Larsen
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - M. A. Goscinski
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - S. Dueland
- grid.55325.340000 0004 0389 8485Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - S. E. Steigen
- grid.412244.50000 0004 4689 5540Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - E. Hofsli
- grid.52522.320000 0004 0627 3560The Cancer Clinic, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway ,grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - A. Torgunrud
- grid.5947.f0000 0001 1516 2393Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - M. Lund-Iversen
- grid.5510.10000 0004 1936 8921Department of Clinical Pathology, University of Oslo, Oslo, Norway
| | - V. J. Dagenborg
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
| | - K. Flatmark
- grid.55325.340000 0004 0389 8485Section for Surgical Oncology, Norwegian Radium Hospital, Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway ,grid.55325.340000 0004 0389 8485Department of Tumor Biology, Institute for Cancer Research, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - H. Sorbye
- grid.7914.b0000 0004 1936 7443Department of Oncology, Haukeland University Hospital and Department of Clinical Science, University of Bergen, Bergen, Norway
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Kim YJ, Kim CH. Treatment for Peritoneal Metastasis of Patients With Colorectal Cancer. Ann Coloproctol 2021; 37:425-433. [PMID: 34961304 PMCID: PMC8717073 DOI: 10.3393/ac.2021.00920.0131] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
From the perspective of survival outcomes, the cancer survival of colorectal cancer (CRC) in the whole stage has improved. Peritoneal metastasis (PM) is found in approximately 8% to 15% of patients with CRC, with a poorer prognosis than that associated with other sites of metastases. Randomized controlled trials and up-to-date meta-analyses provide firm evidence that cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) could significantly improve overall survival compared with systemic chemotherapy alone in selected patients with CRC-PM. Practical guidelines recommend that the management of CRC-PM should be led by a multidisciplinary team carried out in experienced centers and consider CRS plus HIPEC for selected patients. In this review, we aim to provide the latest results of land mark studies and an overview of recent insights with regard to the management of CRC-PM.
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Affiliation(s)
- Young Jin Kim
- Department of Surgery, Seokjeong Wellpark Hospital, Gochang, Korea
| | - Chang Hyun Kim
- Division of Colorectal Surgery, Department of Surgery, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
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Ravn S, Thaysen HV, Verwaal VJ, Seibæk L, Iversen LH. Cancer follow-up supported by patient-reported outcomes in patients undergoing intended curative complex surgery for advanced cancer. J Patient Rep Outcomes 2021; 5:120. [PMID: 34748095 PMCID: PMC8575728 DOI: 10.1186/s41687-021-00391-1] [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: 09/19/2020] [Accepted: 10/17/2021] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND AIM Patient activation (PA) and Patient Involvement (PI) are considered elements in good survivorship. We aimed to evaluate the effect of a follow-up supported by electronic patient-reported outcomes (ePRO) on PA and PI. METHOD From February 2017 to January 2019, we conducted an explorative interventional study. We included 187 patients followed after intended curative complex surgery for advanced cancer at two different Departments at a University Hospital. Prior to each follow-up consultation, patients used the ePRO to screen themselves for clinical important symptoms, function and needs. The ePRO was graphically presented to the clinician during the follow-up, aiming to facilitate patient activation and involvement in each follow-up. PA was measured by the Patient Activation Measurement (PAM), while PI was measured by five indicator questions. PAM and PI data compared between (- ePRO) and interventional (+ ePRO) consultations. PAM data were analysed using a linear mixed effect regression model with intervention (yes/no) and time along with the interaction between them as categorical fixed effects. The analyses were further adjusted for time (days) since surgery. RESULTS According to our data, ePRO supported consultations did not improve PA. The average mean difference in PAM score between + ePRO and - ePRO consultations were - 0.2 (95% confidence interval - 2.6; 2.2, p = 0.9). There was no statistically significant improvement in PAM scores over time in neither + ePRO nor - ePRO group (p = 0.5). Based on the five PI-indicator questions, the majority of all consultations were evaluated as "some, much or very much" involved in consultation; providing a wider scope of dialogue, encouraged patients to ask questions and share their experiences and concerns. Nevertheless, another few patients reported not to be involved at all in the consultations. CONCLUSION We did not demonstrate evidence for ePRO supported consultations to improve patient activation, and patient activation did not improve over time. Our results generate the hypotheses that factors related to ePRO supported consultation had the potential to support PI by offering a wider scope of dialogue, and encourage patients to ask questions and share their experiences and concerns during follow-up.
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Affiliation(s)
- Sissel Ravn
- Department of Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark.
| | - Henriette Vind Thaysen
- Department of Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | - Victor Jilbert Verwaal
- Department of Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
| | | | - Lene Seibæk
- Department of Gynaecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark
| | - Lene Hjerrild Iversen
- Department of Surgery, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, 8200, Aarhus N, Denmark
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Cashin PH, Graf W. Sequential postoperative intraperitoneal chemotherapy for colorectal cancer with peritoneal metastases: a narrative review. J Gastrointest Oncol 2021; 12:S131-S135. [PMID: 33968433 DOI: 10.21037/jgo-20-137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Sequential postoperative intraperitoneal chemotherapy (SPIC) is a chemotherapy abdominal infusion given as a postoperative adjuvant treatment for 6 months after cytoreductive surgery (CRS) for peritoneal surface malignancies. It has most commonly been used in conjunction with ovarian cancer where the SPIC treatment has been integrated with adjuvant systemic chemotherapy. This review investigates the role of SPIC in the setting of colorectal cancer with peritoneal metastases. The focus is on the CRS+SPIC combination treatment with no systemic chemotherapy component. Several cohort studies, several comparative studies, and one randomized trial have been reported with several important endpoints. The following aspects will be covered in this review: overall survival, disease-free survival, morbidity, quality-of-life, and cost-effectiveness. In comparison to systemic chemotherapy alone for isolated resectable colorectal peritoneal metastases, CRS+SPIC is superior concerning overall survival, has no difference in morbidity, is similar in quality-of-life, and SPIC is cost-effective. In comparison to HIPEC, results are conflicting in multivariate analysis; but in a univariate analysis HIPEC (most often combined with systemic adjuvant therapy) appears superior to SPIC alone (no systemic component). The future of SPIC is uncertain. However, a combination of HIPEC and SPIC ± a systemic chemotherapy component is a possible direction to explore further.
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Affiliation(s)
- Peter H Cashin
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| | - Wilhelm Graf
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
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Leimkühler M, Hentzen JEKR, Hemmer PHJ, Been LB, van Ginkel RJ, Kruijff S, van Leeuwen BL, de Bock GH. Systematic Review of Factors Affecting Quality of Life After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy. Ann Surg Oncol 2020; 27:3973-3983. [PMID: 32335752 PMCID: PMC7471142 DOI: 10.1245/s10434-020-08379-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous studies have shown that, overall, quality of life (QoL) decreases within the first 3-6 months after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC), returning to baseline levels by 6-12 months. This systematic review aims to evaluate the factors affecting QoL after CRS + HIPEC within 12 months of surgery. METHODS Electronic databases were investigated searching for articles reporting QoL with validated questionnaires up to September 2019. Risk of bias was assessed with the methodological index for non-randomized studies tool. The primary outcomes were short-term (< 6 months after surgery) and medium-term (6-12 months after surgery) determinants of QoL after CRS + HIPEC. Secondary outcomes were QoL and reported symptoms over time. RESULTS We included 14 studies that used 12 different questionnaires. The reported data were collected prospectively or retrospectively for 1556 patients (dropout < 50% in four studies). Overall, studies showed diminished QoL within 3 months after surgery and a recovery to baseline or greater by 12 months. QoL was negatively influenced by higher age, female sex, prolonged operation time, extensive disease, residual disease, adjuvant chemotherapy, complications, stoma placement, and recurrent disease. QoL results were comparable between studies, with dropout rates above and below 50%. CONCLUSIONS QoL returns to baseline levels within 12 months after CRS + HIPEC provided the disease does not recur, and this recovery process is influenced by several factors.
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Affiliation(s)
- Maleen Leimkühler
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Judith E K R Hentzen
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Patrick H J Hemmer
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Lukas B Been
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Robert J van Ginkel
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Schelto Kruijff
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Barbara L van Leeuwen
- Division of Surgical Oncology, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Geertruida H de Bock
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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Evrard S, Desolneux G, Bellera C, Esnaud T, Bécouarn Y, Collet D, Chafai N, Marchal F, Cany L, Lermite E, Rivoire M, Mathoulin-Pélissier S. Systemic chemotherapy plus cetuximab after complete surgery in the treatment of isolated colorectal peritoneal carcinoma: COCHISE phase II clinical trial. BMC Res Notes 2019; 12:450. [PMID: 31331370 PMCID: PMC6647143 DOI: 10.1186/s13104-019-4476-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/12/2019] [Indexed: 11/16/2022] Open
Abstract
Objective The primary objective of this non-randomised phase II study was to evaluate the combination of systemic chemotherapy plus cetuximab after complete cytoreductive surgery (CCS) for treatment of isolated colorectal peritoneal carcinoma (CRPC). This multicentre, prospective phase II clinical trial was conducted in seven national cancer referral centres, however research published during study recruitment indicated cetuximab treatment as ineffective in patients with mutated KRAS genes, leading to an additional exclusion criterion to the current protocol, excluding patients with mutated KRAS genes. This significantly impacted recruitment and the study did not achieve the necessary recruitment of 46 patients. Results Fourteen patients underwent CCS and were included in the study, however one did not provide informed consent and another received only one cycle of chemotherapy leading to 12 patients in the per protocol population for analysis. Adjuvant Folfox Cetuximab was administered when CCS was achieved for patients > 18 years with histologically proven CRPC and no other metastatic disease (liver, lungs, lymphadenopathy, etc.). CRPC median index was 5.00 (range: 1–17). Median PFS was 12.3 months [95% CI (3.7–28.2)] with 8.3% [95% CI (0.5–31.1)] and 0% PFS at 3 and 5 years respectively. Median OS was 43.4 months [95% CI (16.8–60)]. Trial registration Clinical Trials NCT00766142, October 3, 2008. Retrospectively registered
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Affiliation(s)
- Serge Evrard
- Digestive Tumours Unit, Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France. .,Univ. Bordeaux, 146 rue Léo Saignat, 33000, Bordeaux, France.
| | - Grégoire Desolneux
- Digestive Tumours Unit, Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France
| | - Carine Bellera
- Clinical Research and Clinical Epidemiology Unit (ISO 9001 Certified), Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France.,INSERM CIC-EC 14.01 (Clinical Epidemiology), Bordeaux, France
| | - Thomas Esnaud
- Clinical Research and Clinical Epidemiology Unit (ISO 9001 Certified), Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France
| | - Yves Bécouarn
- Digestive Tumours Unit, Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France
| | - Denis Collet
- Department of Visceral Surgery, CHU Bordeaux, Haut Levêque, 33000, Pessac, France
| | - Najim Chafai
- Department of Visceral Surgery, Hôpital Saint Antoine, 184 Rue du Faubourg Saint-Antoine, 75012, Paris, France
| | - Francois Marchal
- Department of Visceral Surgery, CHU Nancy, Rue du Morvan, 54500, Vandœuvre-lès-Nancy, France
| | - Laurent Cany
- Clinique Francheville, 34 Boulevard de Vesone, 24000, Périgueux, France
| | - Emilie Lermite
- Department of Visceral Surgery, CHU Angers, 4 Rue Larrey, 49100, Angers, France
| | - Michel Rivoire
- Department of Surgical Oncology, Centre Léon Bérard, Comprehensive Cancer Centre, 28 Promenade Léa et Napoléon Bullukian, 69008, Lyon, France.,Université de Lyon, 92 Rue Pasteur, 69007, Lyon, France
| | - Simone Mathoulin-Pélissier
- Clinical Research and Clinical Epidemiology Unit (ISO 9001 Certified), Institut Bergonié, Comprehensive Cancer Centre, 229 Cours de l'Argonne, 33076, Bordeaux, France.,Univ. Bordeaux, 146 rue Léo Saignat, 33000, Bordeaux, France
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10
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Survival outcomes in patients aged 75 years and over with peritoneal colorectal carcinomatosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC): multicenter study of the Spanish Group of Peritoneal Cancer Surgery (GECOP). Clin Transl Oncol 2019; 22:130-136. [PMID: 31049819 DOI: 10.1007/s12094-019-02124-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 04/19/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND The attitude toward cytoreductive surgery with HIPEC in peritoneal carcinomatosis from colorectal cancer is unclear. The aim of this study is to report the perioperative outcomes after cytoreductive surgery with HIPEC in patients ≥ 75 years. METHODS This retrospective multicenter study collected the data the Spanish Group of Peritoneal Cancer Surgery. Thirty-six patients with peritoneal carcinomatosis from colorectal cancer met the selection criteria for the study. Morbidity, mortality, disease-free and overall survival were analyzed. RESULTS Morbidity (grade III-IV) was 17% and 2 patients died of complications related to the procedure (5.4%). Median disease-free survival (DFS) was 16 months. DFS at 1 and 3 years was 81% and 42%, respectively. Overall survival at 1 and 3 years was 96% and 75%. In the univariate analysis, preoperative comorbidities (p = 0.01), liver metastases (p = 0.02), blood transfusion (p = 0.001) and postoperative complications (p = 0.001); and in the multivariate analysis, perioperative blood transfusion (OR 2.56, 95% CI 1.95-6.24, p = 0.03) and postoperative complications (OR 3.25, 95% CI 2.35-7.56, p = 0.02) were associated with a lower overall survival. CONCLUSIONS Age is not an absolute contraindication to perform cytoreduction surgery with HIPEC in highly selected elderly patients with colorectal peritoneal carcinomatosis.
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11
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Frøysnes IS, Andersson Y, Larsen SG, Davidson B, Øien JMT, Julsrud L, Fodstad Ø, Dueland S, Flatmark K. ImmunoPeCa trial: Long-term outcome following intraperitoneal MOC31PE immunotoxin treatment in colorectal peritoneal metastasis. Eur J Surg Oncol 2019; 47:134-138. [PMID: 31036394 DOI: 10.1016/j.ejso.2019.04.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 04/09/2019] [Accepted: 04/19/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The ImmunoPeCa trial investigated the use of intraperitoneal MOC31PE immunotoxin as a novel therapeutic principle for the treatment of peritoneal metastasis from colorectal cancer (PM-CRC). We here report long-term outcome from the trial. METHODS This was a dose-finding trial aiming to evaluate safety and toxicity (primary endpoint) upon a single dose of intraperitoneal MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with mitomycin C. Overall survival (OS) and disease-free survival (DFS) were secondary endpoints. Twenty-one patients received the study drug at four dose levels on the first postoperative day, including six patients constituting an expansion cohort. RESULTS With a 34-month follow-up, the median OS was not reached and the estimated 3-year OS was 78%. Median DFS for all patients was 21 months and the 3-year DFS was 33%, with a median follow-up of 31 months. When excluding patients with potential favorable characteristics from the analysis (n = 4), the median DFS was 13 months and the 3-year OS 72%. CONCLUSIONS The promising long-term outcome combined with low systemic absorbance, high drug concentration and cytotoxic activity in peritoneal fluid support further investigations of clinical efficacy.
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Affiliation(s)
- Ida S Frøysnes
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Yvonne Andersson
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Stein G Larsen
- Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ben Davidson
- Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | | | - Lars Julsrud
- Department of Radiology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Svein Dueland
- Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway.
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12
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Leimkühler M, Hemmer PHJ, Reyners AKL, de Groot DJA, van Ginkel RJ, Been LB, de Bock GH, van Leeuwen BL. Neoadjuvant chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer: a feasibility and safety study. World J Surg Oncol 2019; 17:14. [PMID: 30635070 PMCID: PMC6330449 DOI: 10.1186/s12957-018-1554-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 12/27/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Standard treatment for colorectal peritoneal carcinomatosis typically involves cytoreductive surgery, hyperthermic intraperitoneal chemotherapy (HIPEC), and if possible, postoperative adjuvant chemotherapy. However, a substantial percentage of patients never receive adjuvant chemotherapy because of postoperative complications. Neoadjuvant chemotherapy could be beneficial in this setting, so we assessed its feasibility and safety when used before cytoreductive surgery and HIPEC. METHODS In this non-randomized, single-center, observational feasibility study, patients were scheduled to receive six cycles of capecitabine and oxaliplatin before cytoreductive surgery and HIPEC. Computed tomography was performed after the third and sixth chemotherapy cycles to evaluate tumor response, and patients underwent cytoreductive surgery and HIPEC if there were no pulmonary and/or hepatic metastases. Postoperative complications, graded according to the Clavien-Dindo classification, were compared with those of a historic control group that received postoperative adjuvant chemotherapy. RESULTS Of the 14 patients included in the study, 4 and 3 had to terminate neoadjuvant chemotherapy early because of toxicity and tumor progression, respectively. Cytoreductive surgery and HIPEC were performed in eight patients, and the timing and severity of complications were comparable to those of patients in the historic control group treated without neoadjuvant chemotherapy. CONCLUSION Patients with peritoneal metastases due to colorectal carcinoma can be treated safely with neoadjuvant chemotherapy before definitive therapy with cytoreductive surgery and HIPEC. TRIAL REGISTRATION NUMBER NTR 3905, registered on 20th march, 2013, http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3905.
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Affiliation(s)
- M Leimkühler
- Department of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - P H J Hemmer
- Department of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands.
| | - A K L Reyners
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - D J A de Groot
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - R J van Ginkel
- Department of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - L B Been
- Department of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - G H de Bock
- Department of Epidemiology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands
| | - B L van Leeuwen
- Department of Surgery, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713GZ, Groningen, The Netherlands.
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13
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Alzahrani NA, Valle SJ, Fisher OM, Sugarbaker PH, Yonemura Y, Glehen O, Goere D, Honore C, Brigand C, de Hingh I, Verwaal VJ, Deraco M, Baratti D, Kusamura S, Pocard M, Piso P, Maerz L, Marchal F, Moran B, Levine EA, Dumont F, Pezet D, Abboud K, Kozman MA, Liauw W, Morris DL. Iterative cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A multi-institutional experience. J Surg Oncol 2018; 119:336-346. [PMID: 30554404 DOI: 10.1002/jso.25277] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Accepted: 09/24/2018] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND OBJECTIVES The aims of this multi-institutional study were to assess the feasibility of iterative cytoreductive surgery (iCRS)/hyperthermic intraperitoneal chemotherapy, iCRS in colorectal peritoneal carcinomatosis (CRPC), evaluate survival, recurrence, morbidity and mortality outcomes, and identify prognostic factors for overall survival. METHODS Patients with CRPC that underwent an iCRS, with or without intraperitoneal chemotherapy, from June 1993 to July 2016 at 13 institutions were retrospectively analyzed from prospectively maintained databases. RESULTS The study comprised of 231 patients, including 126 females (54.5%) with a mean age at iCRS of 51.3 years. The iterative high-grade (3/4) morbidity and mortality rates were 23.4% and 1.7%, respectively. The median recurrence-free survival was 15.0 and 10.1 months after initial and iCRS, respectively. The median and 5-year survivals were 49.1 months and 43% and 26.4 months and 26% from the initial and iCRS, respectively. Independent negative predictors of survival from the initial CRS included peritoneal carcinomatosis index (PCI) > 20 ( P = 0.02) and lymph node positivity ( P = 0.04), and from iCRS, PCI > 10 ( P = 0.03 for PCI 11-20; P < 0.001 for PCI > 20), high-grade complications ( P = 0.012), and incomplete cytoreduction ( P < 0.001). CONCLUSION iCRS can provide long-term survival benefits to highly selected colorectal peritoneal carcinomatosis patients with comparable mortality and morbidity rates to the initial CRS procedure. Careful patient selection is necessary to improve overall outcomes.
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Affiliation(s)
- Nayef A Alzahrani
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia.,College of Medicine, Al-Imam Mohammad Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Sarah J Valle
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia
| | - Oliver M Fisher
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia
| | - Paul H Sugarbaker
- MedStar Washington Hospital Center, Peritoneal Surface Oncology Unit, Washington, DC
| | - Yutaka Yonemura
- Peritoneal Metastasis Center, Kishiwada Tokushukai Hospital, Osaka, Japan
| | - Olivier Glehen
- Surgical Oncology Department, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France
| | - Dianne Goere
- Institute Gustave Roussy Cancer Campus, Department of Digestive and Oncology Surgery, Paris, France
| | - Charles Honore
- Institute Gustave Roussy Cancer Campus, Department of Digestive and Oncology Surgery, Paris, France
| | - Cecile Brigand
- General & Digestive Surgery, CHRU Hautepierre, Strasbourg, France
| | - Ignace de Hingh
- Catharina Hospital, Department of Surgery, Eindhoven, Netherlands
| | - Vic J Verwaal
- Catharina Hospital, Department of Surgery, Eindhoven, Netherlands.,Department of Surgical Oncology, Aarhus University Hospital, Denmark
| | - Marcello Deraco
- Fondazione IRCCS Istituto Nazionale dei Tumori, Peritoneal Surface Malignancies Program, Milan, Italy
| | - Dario Baratti
- Fondazione IRCCS Istituto Nazionale dei Tumori, Peritoneal Surface Malignancies Program, Milan, Italy
| | - Shigeki Kusamura
- Fondazione IRCCS Istituto Nazionale dei Tumori, Peritoneal Surface Malignancies Program, Milan, Italy
| | - Mark Pocard
- Surgical Oncology Department, St. Louis Hospital Lariboisiere, Paris, France
| | - Pompiliu Piso
- Department of Surgical Oncology, Hospital Barmherzige Brueder Regensburg, Germany
| | - Loreen Maerz
- Department of Surgical Oncology, Hospital Barmherzige Brueder Regensburg, Germany
| | - Frederic Marchal
- Department of Surgical Oncology, Institute of Cancer, Vandoeeuvre Les Nancy, France
| | - Brendan Moran
- Peritoneal Malignancy Department, Basingstoke North Hampshire Hospital, Basingstoke, UK
| | - Edward A Levine
- Wake Forest Baptist Health, Surgical Oncology, Winston-Salem, North Carolina
| | - Frédéric Dumont
- Surgical Oncology, René Gauducheau Cancer Center, Nantes, France
| | - Denis Pezet
- Department of Digestive Surgery, CHU Estaing, Clermont Ferrand, France
| | - Karine Abboud
- Department of General Surgery, CHU Nord, Saint Etienne, France
| | - Mathew A Kozman
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia
| | - Winston Liauw
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia.,Cancer Care Centre, St. George Hospital, Sydney, NSW, Australia
| | - David L Morris
- St. George Hospital & University of New South Wales, Department of Surgery, Sydney, NSW, Australia
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14
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Metastatic Colorectal Cancer to the Peritoneum: Current Treatment Options. Curr Treat Options Oncol 2018; 19:49. [DOI: 10.1007/s11864-018-0563-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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15
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Glockzin G, Zeman F, Croner RS, Königsrainer A, Pelz J, Ströhlein MA, Rau B, Arnold D, Koller M, Schlitt HJ, Piso P. Perioperative Systemic Chemotherapy, Cytoreductive Surgery, and Hyperthermic Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: Results of the Prospective Multicenter Phase 2 COMBATAC Trial. Clin Colorectal Cancer 2018; 17:285-296. [PMID: 30131226 DOI: 10.1016/j.clcc.2018.07.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/21/2018] [Accepted: 07/24/2018] [Indexed: 01/29/2023]
Abstract
BACKGROUND Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as parts of an interdisciplinary treatment concept including systemic chemotherapy can improve survival of selected patients with peritoneal metastatic colorectal cancer (pmCRC). Nevertheless, the sequence of the therapeutic options is still a matter of debate. Thus, the COMBATAC (COMBined Anticancer Treatment of Advanced Colorectal cancer) trial was conducted to evaluate a combined treatment regimen consisting of preoperative systemic polychemotherapy + cetuximab followed by CRS + HIPEC and postoperative systemic polychemotherapy + cetuximab. PATIENTS AND METHODS The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase 2 trial. Twenty-six patients with synchronous or metachronous colorectal or appendiceal peritoneal carcinomatosis were included. Enrollment was terminated prematurely by the sponsor because of slow recruitment. Progression-free survival as primary end point and overall survival were estimated by the Kaplan-Meier method. Also evaluated were morbidity according to Common Terminology Criteria for Adverse Events v4.0 and feasibility of the combined treatment concept. RESULTS Median progression-free survival for the intention-to-treat population (n = 25) was 14.9 months. Median overall survival was not reached during the study duration. Ninety-two adverse events were documented in 16 patients, including 14 serious adverse events in 9 patients. The overall morbidity rate was 64%, and the grade 3/4 morbidity rate was 44%. Of all grade 3/4 morbidity events, 36.4% were related to systemic chemotherapy and 22.7% to surgery, whereas 40.9% were not directly related. There was no treatment-related mortality. CONCLUSION The results of the COMBATAC trial show that the multimodal treatment concept consisting of perioperative systemic chemotherapy and CRS + HIPEC is safe and feasible. Progression-free survival in selected patients with colorectal or appendiceal peritoneal metastasis might be improved.
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Affiliation(s)
- Gabriel Glockzin
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany; Department of Surgery, Klinikum Bogenhausen, Munich, Germany.
| | - Florian Zeman
- Center for Clinical Studies, University Medical Center Regensburg, Regensburg, Germany
| | - Roland S Croner
- Department of Surgery, University of Erlangen-Nuremberg, Erlangen, Germany; Department of Surgery, University Hospital Magdeburg, Magdeburg, Germany
| | - Alfred Königsrainer
- Department of Surgery, University of Tübingen, Comprehensive Cancer Center, Tübingen, Germany
| | - Jörg Pelz
- Department of Surgery, University Hospital Würzburg, Würzburg, Germany; Department of Surgery, St Bernward Hospital, Hildesheim, Germany
| | - Michael A Ströhlein
- Department of Abdominal, Vascular and Transplant Surgery, Cologne-Merheim Medical Center, Witten/Herdecke University, Cologne, Germany
| | - Beate Rau
- Department of Surgery, Campus Virchow and Mitte, Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Dirk Arnold
- Asklepios Tumor Center Hamburg, AK Altona, Department of Oncology, Hamburg, Germany
| | - Michael Koller
- Center for Clinical Studies, University Medical Center Regensburg, Regensburg, Germany
| | - Hans J Schlitt
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany
| | - Pompiliu Piso
- Department of Surgery, University Medical Center Regensburg, Regensburg, Germany; Department of Surgery, Krankenhaus Barmherzige Brüder Regensburg, Regensburg, Germany
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16
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Cashin PH, Mahteme H, Syk I, Frödin JE, Glimelius B, Graf W. Quality of life and cost effectiveness in a randomized trial of patients with colorectal cancer and peritoneal metastases. Eur J Surg Oncol 2018. [PMID: 29530346 DOI: 10.1016/j.ejso.2018.02.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The aim was to compare health-related quality-of-life (HRQOL) and cost-effectiveness between cytoreductive surgery with intraperitoneal chemotherapy (CRS + IPC) and systemic chemotherapy for patients with colorectal peritoneal metastases. METHODS Patients included in the Swedish Peritoneal Trial comparing CRS + IPC and systemic chemotherapy completed the EORTC QLQ-C30 and SF-36 questionnaires at baseline, 2, 4, 6, 12, 18, and 24 months. HRQOL at 24 months was the primary endpoint. EORTC sum score, SF-36 physical and mental component scores at 24 months were calculated and compared for each arm and then referenced against general population values. Two quality-adjusted life-year (QALY) indices were applied (EORTC-8D and SF-6D) and an incremental cost-effectiveness ratio (ICER) per QALY gained was calculated. A projected life-time ICER per QALY gained was calculated using predicted survival according to Swedish population statistics. RESULTS No statistical differences in HRQOL between the arms were noted at 24 months. Descriptively, survivors in the surgery arm had higher summary scores than the general population at 24 months, whereas survivors in the chemotherapy arm had lower scores. The projected life-time QALY benefit was 3.8 QALYs in favor of the surgery arm (p=0.06) with an ICER per QALY gained at 310,000 SEK (EORTC-8D) or 362,000 SEK (SF-6D) corresponding to 26,700-31,200 GBP. CONCLUSION The HRQOL in patients with colorectal peritoneal metastases undergoing CRS + IPC appear similar to those receiving systemic chemotherapy. Two-year survivors in the CRS + IPC arm have comparable HRQOL to a general population reference. The treatment is cost-effective according to NICE guidelines.
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Affiliation(s)
- P H Cashin
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, 75185 Uppsala, Sweden.
| | - H Mahteme
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, 75185 Uppsala, Sweden; Uppsala Cancer Clinic, Uppsala, Sweden
| | - I Syk
- Department of Clinical Sciences, Section for Surgery, Lund University, Malmö, Sweden
| | - J E Frödin
- Department of Oncology and Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden
| | - B Glimelius
- Department of Oncology and Pathology, Karolinska Institutet, 171 76, Stockholm, Sweden; Department of Immunology, Genetics and Pathology, Uppsala University, 75105, Uppsala, Sweden
| | - W Graf
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, 75185 Uppsala, Sweden
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17
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Virzì S, Iusco D, Baratti D, Bonomi S, Grassi A, Kusamura S, Deraco M. Pilot study of adjuvant hyperthermic intraperitoneal chemotherapy in patients with colorectal cancer at high risk for the development of peritoneal metastases. TUMORI JOURNAL 2018; 99:589-95. [DOI: 10.1177/030089161309900505] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Aims and background The prognosis of peritoneal metastases from colorectal cancer has recently improved with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Although outcomes are further improved when early stage peritoneal metastases are treated, adjuvant hyperthermic intraperitoneal chemotherapy has never been thoroughly addressed. This prospective pilot study assessed feasibility, safety and efficacy of hyperthermic intraperitoneal chemotherapy combined with primary curative surgery in colorectal cancer at high risk for peritoneal metastases. Methods Twelve patients were prospectively selected according to predetermined risk factors for the development of peritoneal metastases. Patients underwent conventional colon surgery, closed-abdomen mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy, and cytoreductive surgical procedures, as needed. Results Preoperative tumor-related risk factors were confirmed by intraoperative findings and pathological examination in all patients: minimal synchronous peritoneal metastases (n = 2), synchronous ovarian metastases (n = 1), positive peritoneal washing cytology (n = 2), primary tumor directly invading other organs (n = 6), or penetrating visceral peritoneum (n = 1). Major morbidity occurred in 2 patients and operative death in none. Median follow-up was 49 months (range, 22–72). Peritoneal metastases occurred in 1 patient and distant metastases in 2. Five-year overall survival was 83.3%. Conclusions Preoperative/early intraoperative assessment can reliably identify colorectal cancer patients at high risk for peritoneal metastases. Adjuvant hyperthermic intraperitoneal chemotherapy is well tolerated and safe. These preliminary results would support the design of future phase-III trials of adjuvant hyperthermic intraperitoneal chemotherapy.
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Affiliation(s)
- Salvatore Virzì
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio (BO)
| | - Domenico Iusco
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio (BO)
| | - Dario Baratti
- Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Serena Bonomi
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio (BO)
| | - Antonio Grassi
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio (BO)
| | - Shigeki Kusamura
- Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Marcello Deraco
- Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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18
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Abstract
Częstość przerzutów do otrzewnej w raku jelita grubego wynosi 5%-15% w przypadku przerzutów synchronicznych i aż 40% w przypadku wystąpienia wznowy miejscowej. Najlepsze wyniki leczenia uzyskuje się poprzez skojarzone wykonanie zabiegu cytoredukcyjnego w połączeniu z dootrzewnową chemioterapią perfuzyjną w hipertermii (HIPEC). Wyniki takiego leczenia są zdecydowanie lepsze i pozwalają na osiągnięcie przeżyć 5-letnich na poziomie 30%-50%. Zabiegi te wymagają dużego doświadczenia w chirurgii jamy brzusznej, są czasochłonne (średni czas procedury chirurgicznej wynosi 6-8 godzin) i obarczone powikłaniami związanymi nie tylko z zabiegiem operacyjnym, ale także podaniem cytostatyku do jamy otrzewnej w podwyższonej temperaturze (41,5 st. C). Chorzy po zabiegu wymagają pobytu na oddziale intensywnej terapii, co jest związane z wystąpieniem potencjalnych powikłań spowodowanych rozległością zabiegu, długością procedury chirurgicznej, zastosowaniu chemioterapii w połączeniu z hipertermią. Prowadzenie pooperacyjne tych chorych wymaga doświadczenia całego zespołu lekarskiego i pielęgniarskiego. Zabiegi cytoredukcyjne w połączeniu z HIPEC jako wysoce specjalistyczne procedury medyczne powinny być merytorycznie ocenione pod kątem korzyści długoterminowych dla chorych i odpowiednio skalkulowane pod względem realnej wysokości refundacji. Jako procedura zalecana w wytycznych Kionsultanta Krajowego d.s. Chirurgii Onkologicznej oraz wytycznych ESMO, niezbędna jest jej realna wycena i refundacja pokrywająca jej całkowite średnie koszty.
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Affiliation(s)
| | - Wojciech Zegarski
- Clinic of Oncological Surgery, Ludwik Rydygier Collegium Medicum UMK in Toruń, Center of Oncology in Bydgoszcz
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19
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Wu W, Yan S, Liao X, Xiao H, Fu Z, Chen L, Mou J, Yu H, Zhao L, Liu X. Curative versus palliative treatments for colorectal cancer with peritoneal carcinomatosis: a systematic review and meta-analysis. Oncotarget 2017; 8:113202-113212. [PMID: 29348899 PMCID: PMC5762584 DOI: 10.18632/oncotarget.21912] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/05/2017] [Indexed: 12/12/2022] Open
Abstract
The objective of this study was to provide an up-to-date summary of the current evidence that may be useful for updating guidelines. We comprehensively searched the published literatures and conferences for studies that compared curative with palliative treatments in colorectal cancer patients with peritoneal metastasis. The primary outcomes considered in this study were three- and five-year overall survival rates. We pooled data across studies and estimated summary effect sizes. Overall, patients who received curative treatments had improved three-year survival (hazard ratio (HR), 2.19 [95% CI, 1.83 to 2.62]) and five-year survival (HR, 2.22 [95% CI, 1.83 to 2.69]) compared with those who received palliative treatments. Patients who received curative treatments had an increased risk of treatment-related morbidity (odds ratio (OR), 2.90 [95% CI, 2.02 to 4.17]), but there was no significant difference in treatment-related mortality between patients who received curative treatments and those who received palliative treatments (OR, 1.46 [CI, 0.62 to 3.47]). Curative treatments improved overall survival in colorectal cancer patients with peritoneal metastasis and did not increase the risk of treatment-related mortality. Curative treatments were associated with a higher risk of treatment-related morbidity. These data highlight the importance for further investigation aimed at prevention of treatment-associated morbidity.
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Affiliation(s)
- Wenqiong Wu
- Department of Radiation Oncology, Hunan Cancer Hospital-The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Shipeng Yan
- Department of Cancer Prevention and Control, Hunan Cancer Hospital-The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Xianzhen Liao
- Department of Cancer Prevention and Control, Hunan Cancer Hospital-The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Haifang Xiao
- Department of Cancer Prevention and Control, Hunan Cancer Hospital-The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
| | - Zhongxi Fu
- Department of Chronic Diseases Prevention and Control, Centers for Disease Control and Prevention of Hunan, Changsha, Hunan Province, China
| | - Lizhang Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Central South University, Changsha, Hunan Province, China
| | - Jinsong Mou
- Department of Epidemiology and Health Statistics, Changsha Medical University, Changsha, Hunan Province, China
| | - Haibo Yu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Lian Zhao
- Department of Gastroenterology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China.,Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan Province, China
| | - Xiangguo Liu
- Department of Cancer Prevention and Control, Hunan Cancer Hospital-The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan Province, China
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20
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Yu HH, Yonemura Y, Hsieh MC, Mizumoto A, Wakama S, Lu CY. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal goblet cell carcinomas with peritoneal carcinomatosis: results from a single specialized center. Cancer Manag Res 2017; 9:513-523. [PMID: 29089784 PMCID: PMC5655158 DOI: 10.2147/cmar.s147227] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Background Goblet cell carcinomas (GCCs) of the appendix are rare and aggressive malignancies with early peritoneal dissemination. The aim of the present article is to describe our experience in the management of GCCs with peritoneal carcinomatosis (PC) through cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) and to determine the impact of multiple clinical characteristics on the prognosis. Methods From a prospectively maintained database of patients receiving CRS and HIPEC for peritoneal surface malignancy, the data of 15 patients with GCC and PC were collected. Neo-adjuvant laparoscopic HIPEC was performed if indicated. CRS and HIPEC with mitomycin-C or 5-fluorouracil plus oxaliplatin were performed. Adjuvant chemotherapy was also arranged if suitable for the patient’s condition. Results Nine males and six females with a mean age of 52.4 years were enrolled. The estimated median survival after the diagnosis of GCC with PC and after definitive CRS–HIPEC was 28 and 17 months, respectively. The 1-, 2-, 3-, 4-year survival rates were 86%, 69%, 57%, and 24%, respectively. Log-rank test revealed that the significant independent risk factors for more favorable outcomes were age >50 years, peritoneal cancer index (PCI) <27, postoperative PCI <20, administration of HIPEC, and adjuvant chemotherapy. Multivariate analyses confirmed that administration of HIPEC played a crucial role in providing prognostic benefit. Conclusion The management of GCC with PC remains challenging. We recommend CRS and HIPEC, followed by adjuvant systemic chemotherapy, as a promising strategy to improve survival, especially in selected patients with low PCI and possibility to achieve complete cytoreduction.
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Affiliation(s)
- Hsin-Hsien Yu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yutaka Yonemura
- Peritoneal Dissemination Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka, Japan.,Department of Surgery, Kusatsu General Hospital, Kusatsu, Shiga, Japan.,Nonprofit Organization to Support Peritoneal Surface Malignancy Treatment, Kyoto, Osaka, Japan
| | - Mao-Chih Hsieh
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Akiyoshi Mizumoto
- Department of Surgery, Kusatsu General Hospital, Kusatsu, Shiga, Japan
| | - Satoshi Wakama
- Peritoneal Dissemination Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka, Japan
| | - Chang-Yun Lu
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Division of General Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
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21
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Frøysnes IS, Andersson Y, Larsen SG, Davidson B, Øien JMT, Olsen KH, Giercksky KE, Julsrud L, Fodstad Ø, Dueland S, Flatmark K. Novel Treatment with Intraperitoneal MOC31PE Immunotoxin in Colorectal Peritoneal Metastasis: Results From the ImmunoPeCa Phase 1 Trial. Ann Surg Oncol 2017; 24:1916-1922. [PMID: 28224367 DOI: 10.1245/s10434-017-5814-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND MOC31PE immunotoxin was developed to rapidly kill cells expressing the tumor-associated epithelial cell adhesion molecule, which is highly expressed in colorectal cancer. Although cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may offer long-term survival to patients with peritoneal metastasis from colorectal cancer (PM-CRC), most patients experience disease relapse and novel therapeutic options are needed. On this basis, MOC31PE is being developed as a novel therapeutic principle to target PM-CRC. METHODS This was a dose-escalating phase I trial to evaluate the safety and toxicity (primary endpoint), pharmacokinetic profile, and neutralizing antibody response (secondary endpoints) upon intraperitoneal administration of MOC31PE in patients with PM-CRC undergoing CRS-HIPEC with Mitomycin C. Fifteen patients received the study drug at four dose levels (3+3+3+6), administered intraperitoneally as a single dose the day after CRS-HIPEC. RESULTS No dose-limiting toxicity was observed, and the maximum tolerated dose was not reached. There was negligible systemic absorption of the study drug. Drug concentrations in peritoneal fluid samples were in the cytotoxic range and increased in a dose-dependent manner. MOC31PE recovered from peritoneal cavity retained its cytotoxic activity in cell-based assays. All patients developed neutralizing antibodies. CONCLUSIONS Intraperitoneal administration of MOC31PE was safe and well tolerated, and combined with low systemic uptake, MOC31PE seems ideal for local intraperitoneal treatment. The drug will be further evaluated in an ongoing phase II expansion cohort.
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Affiliation(s)
- Ida S Frøysnes
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Yvonne Andersson
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Stein G Larsen
- Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Ben Davidson
- Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | | | - Kari Hauge Olsen
- Department of Medical Biochemistry, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Karl-Erik Giercksky
- Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Lars Julsrud
- Department of Radiology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Øystein Fodstad
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Svein Dueland
- Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. .,Faculty of Medicine, University of Oslo, Oslo, Norway. .,Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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22
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Foster J, Shienbaum AJ, Poretta T, Kaiser-Smith J. A Rare Case of Metastatic Colorectal Carcinoma in the Testicle. J Gastrointest Cancer 2016; 49:337-339. [PMID: 27975179 DOI: 10.1007/s12029-016-9900-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Jonathan Foster
- Department of Internal Medicine, Rowan University - School of Osteopathic Medicine, Stratford, NJ, USA
| | - Alan J Shienbaum
- Department of Pathology, Kennedy University Hospital - Cherry Hill, 2201 Chapel Avenue West, Cherry Hill, NJ, 08002, USA. .,Department of Pathology, Rowan University - School of Osteopathic Medicine, Stratford, NJ, USA.
| | - Trina Poretta
- Department of Internal Medicine, Kennedy University Hospital, Stratford, NJ, USA
| | - Joanne Kaiser-Smith
- Department of Internal Medicine, Rowan University - School of Osteopathic Medicine, Stratford, NJ, USA
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23
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Lin EK, Hsieh MC, Chen CH, Lu YJ, Wu SY. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer with peritoneal metastasis. Medicine (Baltimore) 2016; 95:e5522. [PMID: 28033247 PMCID: PMC5207543 DOI: 10.1097/md.0000000000005522] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
In Taiwan, colorectal cancer with peritoneal carcinomatosis is considered a terminal condition. We examined the clinical outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) treatment for colorectal cancer with peritoneal carcinomatosis in Taiwan.We enrolled patients with colorectal cancer and peritoneal metastasis from Taipei Medical University, Wanfang Hospital between January 1999 and December 2014. Of the enrolled patients, 3 had mucinous-type tumors. In total, we enrolled 31 patients who underwent a total of 33 procedures. Of the 31 patients, 2 received the HIPEC procedure twice. Cytoreductive surgery was performed followed by HIPEC. The hazard ratios of death following cytoreductive surgery and HIPEC were calculated using the Cox proportional hazards model.The 2- and 5-year overall survival rates of these patients following cytoreductive surgery and HIPEC were 57% and 38%, respectively. The completeness of cytoreduction (CC) scores were CC-0, CC-1, CC-2, and CC-3 in 18 (54.5%), 3 (9%), 7 (21.2%), and 5 (15.2%) patients, respectively. The mean peritoneal cancer index (PCI) was 16.20, and the mean postoperative PCI (PPCI) was 4.6. The major risk factors for death in these patients were a total PCI score > 20, total PPCI score > 0, and CC score ≥ 2 (P = 0.022, 0.031, and 0.0001, respectively; log-rank test). Multivariate analysis revealed that the total PPCI score was the strongest predictor of death following cytoreductive surgery and HIPEC in these patients.In Taiwan, performing cytoreductive surgery and administering HIPEC for treating colorectal cancer with peritoneal metastasis are feasible and resulted in long-term survival. In addition, the total PPCI score was related to poor prognosis following cytoreductive surgery and HIPEC in patients with colorectal cancer and peritoneal metastasis.
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Affiliation(s)
| | - Mao-Chih Hsieh
- Department of General Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | | | | | - Szu-Yuan Wu
- Institute of Toxicology, College of Medicine, National Taiwan University
- Department of Radiation Oncology, Wan Fang Hospital
- Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei
- Department of Biotechnology, Hungkuang University, Taichung
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24
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Baratti D, Kusamura S, Iusco D, Gimondi S, Pietrantonio F, Milione M, Guaglio M, Bonomi S, Grassi A, Virzì S, Leo E, Deraco M. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the Time of Primary Curative Surgery in Patients with Colorectal Cancer at High Risk for Metachronous Peritoneal Metastases. Ann Surg Oncol 2016; 24:167-175. [PMID: 27519353 DOI: 10.1245/s10434-016-5488-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Indexed: 01/09/2023]
Abstract
BACKGROUND Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are maximally effective in early-stage colorectal cancer peritoneal metastases (CRC-PM); however, the use of HIPEC to treat subclinical-stage PM remains controversial. This prospective two-center study assessed adjuvant HIPEC in CRC patients at high risk for metachronous PM ( www.clinicaltrials.gov NCT02575859). METHODS During 2006-2012, a total of 22 patients without systemic metastases were prospectively enrolled to receive HIPEC simultaneously with curative surgery, plus adjuvant systemic chemotherapy (oxaliplatin/irinotecan-containing ± biologics), based on primary tumor-associated criteria: resected synchronous ovarian (n = 2) or minimal peritoneal (n = 6) metastases, primaries directly invading other organs (n = 4) or penetrating the visceral peritoneum (n = 10). A control group retrospectively included 44 matched (1:2) patients undergoing standard treatments and no HIPEC during the same period. The cumulative PM incidence was calculated in a competing-risks framework. RESULTS Patient characteristics were comparable for all groups. Median follow-up was 65.2 months [95 % confidence interval (CI) 50.9-79.5] in the HIPEC group and 34.5 months (95 % CI 21.1-47.9) in the control group. The 5-year cumulative PM incidence was 9.3 % in the HIPEC group and 42.5 % in the control group (p = 0.004). Kaplan-Meier estimated 5-year overall survival (OS) was 81.3 % in the HIPEC group versus 70.0 % in the control group (p = 0.047). No operative death occurred. Grade 3-4 [National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4] morbidity rates were 18.2 % in the HIPEC group and 25 % in controls (p = 0.75). At multivariate analysis, HIPEC correlated to lower PM cumulative incidence [hazard ratio (HR) 0.04, 95 % CI 0.01-0.31; p = 0.002], and better OS (HR 0.25, 95 % CI 0.07-0.89; p = 0.039) and progression-free survival (HR 0.31, 95 % CI 0.11-0.85; p = 0.028). CONCLUSION Adjuvant HIPEC may benefit CRC patients at high-risk for peritoneal failure. These results warrant confirmation in phase III trials.
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Affiliation(s)
- Dario Baratti
- Peritoneal Malignancy Program, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
| | - Shigeki Kusamura
- Peritoneal Malignancy Program, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Domenico Iusco
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio, Bologna, Italy
| | - Silvia Gimondi
- Department of Haematology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Massimo Milione
- Department of Pathology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Marcello Guaglio
- Colorectal Cancer Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Serena Bonomi
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio, Bologna, Italy
| | - Antonio Grassi
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio, Bologna, Italy
| | - Salvatore Virzì
- General Surgery Unit, Bentivoglio Hospital, AUSL Bologna, Bentivoglio, Bologna, Italy
| | - Ermanno Leo
- Colorectal Cancer Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - Marcello Deraco
- Peritoneal Malignancy Program, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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25
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Rentsch M, Schiergens T, Khandoga A, Werner J. Surgery for Colorectal Cancer - Trends, Developments, and Future Perspectives. Visc Med 2016; 32:184-91. [PMID: 27493946 DOI: 10.1159/000446490] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Although colorectal surgery is long established as the mainstay treatment for colon cancer, certain topics regarding technical fine-tuning to increase postsurgical recurrence-free survival have remained a matter of debate throughout the past years. These include complete mesocolic excision (CME), treatment strategies for metastatic disease, significance of hyperthermic intraperitoneal chemotherapy (HIPEC), and surgical techniques for the treatment of colorectal cancer recurrence. In addition, new surgical techniques have been introduced in oncologic colorectal surgery, and their potential to provide sufficiently radical resection has yet to be proven. METHODS A structured review of the literature was performed to identify the current state of the art with regard to the mentioned key issues in colorectal surgery. RESULTS This article provides a comprehensive review of the current literature addressing the above-mentioned current challenges in colorectal surgery. The focus lies on the impact of CME and, in relation to this, on lymph node dissection, as well as on treatment of metastatic disease including peritoneal spread, and finally on the treatment of recurrent disease. CONCLUSION Uniformly, the current literature reveals that surgery aiming at complete malignancy elimination within multimodal treatment approaches represents the fundamental quantum leap for the achievement of long-term tumor-free survival.
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Affiliation(s)
- Markus Rentsch
- Department of General, Visceral, Transplantation Surgery, University of Munich, Campus Großhadern, Munich, Germany
| | - Tobias Schiergens
- Department of General, Visceral, Transplantation Surgery, University of Munich, Campus Großhadern, Munich, Germany
| | - Andrej Khandoga
- Department of General, Visceral, Transplantation Surgery, University of Munich, Campus Großhadern, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, Transplantation Surgery, University of Munich, Campus Großhadern, Munich, Germany
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26
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Dervenis C, Xynos E, Sotiropoulos G, Gouvas N, Boukovinas I, Agalianos C, Androulakis N, Athanasiadis A, Christodoulou C, Chrysou E, Emmanouilidis C, Georgiou P, Karachaliou N, Katopodi O, Kountourakis P, Kyriazanos I, Makatsoris T, Papakostas P, Papamichael D, Pechlivanides G, Pentheroudakis G, Pilpilidis I, Sgouros J, Tekkis P, Triantopoulou C, Tzardi M, Vassiliou V, Vini L, Xynogalos S, Ziras N, Souglakos J. Clinical practice guidelines for the management of metastatic colorectal cancer: a consensus statement of the Hellenic Society of Medical Oncologists (HeSMO). Ann Gastroenterol 2016; 29:390-416. [PMID: 27708505 PMCID: PMC5049546 DOI: 10.20524/aog.2016.0050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 03/10/2016] [Indexed: 12/12/2022] Open
Abstract
There is discrepancy and failure to adhere to current international guidelines for the management of metastatic colorectal cancer (CRC) in hospitals in Greece and Cyprus. The aim of the present document is to provide a consensus on the multidisciplinary management of metastastic CRC, considering both special characteristics of our Healthcare System and international guidelines. Following discussion and online communication among the members of an executive team chosen by the Hellenic Society of Medical Oncology (HeSMO), a consensus for metastastic CRC disease was developed. Statements were subjected to the Delphi methodology on two voting rounds by invited multidisciplinary international experts on CRC. Statements reaching level of agreement by ≥80% were considered as having achieved large consensus, whereas statements reaching 60-80% moderate consensus. One hundred and nine statements were developed. Ninety experts voted for those statements. The median rate of abstain per statement was 18.5% (range: 0-54%). In the end of the process, all statements achieved a large consensus. The importance of centralization, care by a multidisciplinary team, adherence to guidelines, and personalization is emphasized. R0 resection is the only intervention that may offer substantial improvement in the oncological outcomes.
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Affiliation(s)
- Christos Dervenis
- General Surgery, "Konstantopouleio" Hospital of Athens, Greece (Christos Dervenis)
| | - Evaghelos Xynos
- General Surgery, "InterClinic" Hospital of Heraklion, Greece (Evangelos Xynos)
| | | | - Nikolaos Gouvas
- General Surgery, "METROPOLITAN" Hospital of Piraeus, Greece (Nikolaos Gouvas)
| | - Ioannis Boukovinas
- Medical Oncology, "Bioclinic" of Thessaloniki, Greece (Ioannis Boukovinas)
| | - Christos Agalianos
- General Surgery, Athens Naval & Veterans Hospital, Greece (Christos Agalianos, Ioannis Kyriazanos, George Pechlivanides)
| | - Nikolaos Androulakis
- Medical Oncology, "Venizeleion" Hospital of Heraklion, Greece (Nikolaos Androulakis)
| | | | | | - Evangelia Chrysou
- Radiology, University Hospital of Heraklion, Greece (Evangelia Chrysou)
| | - Christos Emmanouilidis
- Medical Oncology, "Interbalkan" Medical Center, Thessaloniki, Greece (Christos Emmanoulidis)
| | - Panagiotis Georgiou
- Colorectal Surgery, Chelsea and Westminster NHS Foundation Trust, London, UK (Panagiotis Georgiou, Paris Tekkis)
| | - Niki Karachaliou
- Medical Oncology, Dexeus University Institut, Barcelona, Spain (Niki Carachaliou)
| | - Ourania Katopodi
- Medical Oncology, "Iaso" General Hospital, Athens, Greece (Ourania Katopoidi)
| | - Panteleimon Kountourakis
- Medical Oncology, Oncology Center of Bank of Cyprus, Nicosia, Cyprus (Pandelis Kountourakis, Demetris Papamichael)
| | - Ioannis Kyriazanos
- General Surgery, Athens Naval & Veterans Hospital, Greece (Christos Agalianos, Ioannis Kyriazanos, George Pechlivanides)
| | - Thomas Makatsoris
- Medical Oncology, University Hospital of Patras, Greece (Thomas Makatsoris)
| | - Pavlos Papakostas
- Medical Oncology, "Ippokrateion" Hospital of Athens, Greece (Pavlos Papakostas)
| | - Demetris Papamichael
- Medical Oncology, Oncology Center of Bank of Cyprus, Nicosia, Cyprus (Pandelis Kountourakis, Demetris Papamichael)
| | - George Pechlivanides
- General Surgery, Athens Naval & Veterans Hospital, Greece (Christos Agalianos, Ioannis Kyriazanos, George Pechlivanides)
| | | | - Ioannis Pilpilidis
- Gastroenterology, "Theageneion" Cancer Hospital, Thessaloniki, Greece (Ioannis Pilpilidis)
| | - Joseph Sgouros
- Medical Oncology, "Agioi Anargyroi" Hospital of Athens, Greece (Joseph Sgouros)
| | - Paris Tekkis
- Colorectal Surgery, Chelsea and Westminster NHS Foundation Trust, London, UK (Panagiotis Georgiou, Paris Tekkis)
| | | | - Maria Tzardi
- Pathology, University Hospital of Heraklion, Greece (Maria Tzardi)
| | - Vassilis Vassiliou
- Radiation Oncology, Oncology Center of Bank of Cyprus, Nicosia, Cyprus (Vassilis Vassiliou)
| | - Louiza Vini
- Radiation Oncology, "Iatriko" Center of Athens, Greece (Lousa Vini)
| | - Spyridon Xynogalos
- Medical Oncology, "George Gennimatas" General Hospital, Athens, Greece (Spyridon Xynogalos)
| | - Nikolaos Ziras
- Medical Oncology, "Metaxas" Cancer Hospital, Piraeus, Greece (Nikolaos Ziras)
| | - John Souglakos
- Medical Oncology, University Hospital of Heraklion, Greece (John Souglakos)
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27
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Frøysnes IS, Larsen SG, Spasojevic M, Dueland S, Flatmark K. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis in Norway: Prognostic factors and oncologic outcome in a national patient cohort. J Surg Oncol 2016; 114:222-7. [PMID: 27173150 DOI: 10.1002/jso.24290] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Accepted: 04/29/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND AND OBJECTIVES Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) can offer long-term survival to patients with resectable peritoneal metastasis (PM) from colorectal cancer (CRC), a condition with otherwise dismal prognosis. This study describes short- and long-term outcome in a national patient cohort and aims to identify prognostic factors. METHODS All patients treated with CRS-HIPEC for non-appendiceal PM-CRC in Norway 2004-2013 were included (n = 119), and outcome and potential prognostic factors were examined using survival- and ROC-curve analysis. RESULTS Five-year overall survival (OS) and disease-free survival (DFS) were 36% and 14%, respectively, with 45 months median follow-up. The only factor associated with OS in multivariable analysis was peritoneal cancer index (PCI), with HR 1.05 (1.01-1.09) for every increase in PCI-score (P = 0.015). Peritoneal relapse was associated with shorter OS than distant metastasis (P = 0.002). ROC-curves identified PCI > 12 as a marker with 100% specificity for prediction of disease relapse. Severe postoperative complications (Clavien-Dindo ≥ 3) occurred in 15% of patients and there was no 100-day mortality. CONCLUSIONS Long-term outcome was in line with published results, morbidity was acceptable and there was no 100-day mortality. The results reemphasize CRS-HIPEC as an important treatment option in PM-CRC, with particularly good results in patients with PCI < 12. J. Surg. Oncol. 2016;114:222-227. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ida S Frøysnes
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Stein G Larsen
- Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Milan Spasojevic
- Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Svein Dueland
- Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Kjersti Flatmark
- Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Gastroenterological Surgery, Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
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28
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Gou H, Gu LY, Shang BZ, Xiong Y, Wang C. Protective effect of Bu-Zhong-Yi-Qi decoction, the water extract of Chinese traditional herbal medicine, on 5-fluorouracil-induced intestinal mucositis in mice. Hum Exp Toxicol 2016; 35:1243-1251. [PMID: 26801985 DOI: 10.1177/0960327115627686] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Intestinal mucositis is a serious toxic side effect of 5-fluorouracil (5-FU) treatment. Bu-Zhong-Yi-Qi decoction (BZYQD), a water extract of Chinese traditional herbal medicine, is widely used in chemotherapy in Asia as an alternative treatment to reduce the side effects of chemotherapy. However, the mechanism is unknown. To evaluate its mechanism, we investigated the effect of BZYQD on 5-FU-induced intestinal mucositis in mice, especially with regard to apoptosis in the intestinal mucosal epithelia. In the present study, mice were divided into three groups: control, 5-FU, and 5-FU + BZYQD. Mice in the 5-FU and 5-FU + BZYQD groups were administered 5-FU (100 mg/kg/day, intraperitoneally) for 6 days, and the mice in the latter group were given BZYQD (8 g/kg/day, intragastrically) beginning 4 days before 5-FU and continuing until the termination of the experiment. Loss in body weight and diarrhea during the 5-FU treatment were significantly attenuated by administration of BZYQD. The morphological signs of intestinal damage, including shortened villi height, crypt destruction, apoptosis, and necrosis, in intestinal mucosal epithelia were also reversed, accompanied by reduced neutrophil infiltration, nitrite levels, and inflammatory factors (tumor necrosis factor α and interleukin 1β) and increased levels of reduced glutathione. These results suggest that BZYQD inhibits 5-FU-induced intestinal mucositis, and this effect may be due to the reduction in apoptosis and necrosis in intestinal mucosal epithelia via the suppression of inflammatory cytokine upregulation. In conclusion, inhibiting cytokine-mediated apoptosis or necrosis can be the molecular mechanism by which BZYQD reduces the gastrointestinal side effects of cancer chemotherapy.
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Affiliation(s)
- H Gou
- Department of Cell Biology, Basic Medical College, Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China (Province-Ministry Co-construct), Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - L Y Gu
- Department of Cell Biology, Basic Medical College, Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China (Province-Ministry Co-construct), Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - B Z Shang
- Northeastern Yucai Foreign Language School, Shenyang, China
| | - Y Xiong
- Department of Cell Biology, Basic Medical College, Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China (Province-Ministry Co-construct), Liaoning University of Traditional Chinese Medicine, Shenyang, China
| | - C Wang
- Department of Cell Biology, Basic Medical College, Key Laboratory of Ministry of Education for TCM Viscera-State Theory and Applications, Ministry of Education of China (Province-Ministry Co-construct), Liaoning University of Traditional Chinese Medicine, Shenyang, China
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Cytoreductive surgery and intraperitoneal chemotherapy versus systemic chemotherapy for colorectal peritoneal metastases: A randomised trial. Eur J Cancer 2016; 53:155-62. [PMID: 26751236 DOI: 10.1016/j.ejca.2015.09.017] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Revised: 09/04/2015] [Accepted: 09/19/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND First-line treatment of isolated resectable colorectal peritoneal metastases remains unclear. This study (the Swedish peritoneal study) compares cytoreductive surgery and intraperitoneal chemotherapy (surgery arm) with systemic chemotherapy (chemotherapy arm). METHODS Patients deemed resectable preoperatively were randomised to surgery and intraperitoneal 5-fluorouracil 550 mg/m(2)/d for 6 d with repeated courses every month or to systemic oxaliplatin and 5-fluorouracil regimen every second week. Both treatments continued for 6 months. Primary end-point was overall survival (OS) and secondary end-points were progression-free survival (PFS), and morbidity. RESULTS The study terminated prematurely when 48 eligible patients (24/arm) were included due to recruitment difficulties. Two-year OS was 54% in the surgery arm and 38% in the chemotherapy arm (p = 0.04). After 5 years, 8 versus 1 patient were alive, respectively (p = 0.02). Median OS was 25 months versus 18 months, respectively, hazard ratio 0.51 (95% confidence interval: 0.27-0.96, p = 0.04). PFS in the surgery arm was 12 months versus 11 months in the chemotherapy arm (p = 0.16) with 17% versus 0% 5-year PFS. Grade III-IV morbidity was seen in 42% and 50% of the patients, respectively. No mortalities. CONCLUSIONS Cytoreductive surgery with intraperitoneal chemotherapy may be superior to systemic oxaliplatin-based treatment of colorectal cancer with resectable isolated peritoneal metastases.(ClinicalTrials.gov nr:NCT01524094).
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Heaney RM, Shields C, Mulsow J. Outcome following incomplete surgical cytoreduction combined with intraperitoneal chemotherapy for colorectal peritoneal metastases. World J Gastrointest Oncol 2015; 7:445-454. [PMID: 26688707 PMCID: PMC4678391 DOI: 10.4251/wjgo.v7.i12.445] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Revised: 06/20/2015] [Accepted: 10/09/2015] [Indexed: 02/05/2023] Open
Abstract
Cytoreductive surgery combined with intraperitoneal chemotherapy can improve survival in appropriately selected patients with colorectal peritoneal metastases. Outcomes are best in those patients in whom a complete cytoreduction can be achieved. Unresectable disease is however encountered in approximately one-quarter of patients at laparotomy. The merits, or otherwise, of proceeding with an incomplete cytoreduction in this setting are unclear. We performed a review of published outcomes following incomplete cytoreduction for colorectal peritoneal metastases. Using the electronic databases, PubMed and MEDLINE, a systematic search of available literature published during the period January 1997 to September 2014 was conducted. Following application of exclusion criteria, 19 papers were identified and included in this review. These comprised fifteen case series, 3 case control studies and one randomised control trial. In the nineteen studies included in this review, 2790 patients underwent cytoreductive surgery with or without intraperitoneal chemotherapy for peritoneal metastases of colorectal origin. Of these, 1732 (62%) underwent a complete cytoreduction while 986 (35%) patients underwent an incomplete cytoreduction. Median survival in the complete cytoreduction group ranged from 11 to 62 mo while survival in the latter group ranged from 2.4 to 32 mo. Of the 986 patients with an incomplete cytoreduction, 331 patients received intraperitoneal chemotherapy and survival in this cohort ranged from 4.5 to 32 mo. An incomplete cytoreduction, with or without intraperitoneal chemotherapy, does not appear to confer a survival benefit. The limited available data points to a palliative benefit in a subset of patients. In the absence of high quality data, the decision as to whether or not to proceed with surgery should be made on an individual patient basis.
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Liu JY, Yuan JP, Geng XF, Qu AP, Li Y. Morphological study and comprehensive cellular constituents of milky spots in the human omentum. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:12877-12884. [PMID: 26722479 PMCID: PMC4680424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Accepted: 09/25/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE To analyze morphological features of omental milky spots (MS). METHOD Hematoxylin-eosin staining and immunohistochemistry technique were used to study the omental MS of gastric cancer (GC) patients and rectal cancer (RC) patients. We focused on morphological features of MS and conducted quantitative analysis on the cells number and cellular constituents. Differences in MS parameters between GC and RC were also analyzed. RESULTS Various shapes of MS were mainly round, oval, irregular form in the adipose and perivascular annular. The median MS perimeter was 2752 (range 817~7753) computer-based pixels. The median value of immune cells in one MS was 141 (43~650), comprising T lymphocytes (46.1%), B lymphocytes (28.4%), macrophages (12.4%) and other immune cells (13.1%). Relatively high density of vessels in MS could be calculated by micro-vessel density (MVD) as 4 (0~13). The median value of mesothelial cells loosely arranged in the surface layer was 5 (0~51). There were no significant differences in MS perimeter, MVD, the number of mesothelial cells, total immune cells, T lymphocytes and macrophages between GC and RC (P>0.05), while the number of MS B lymphocytes in RC was significantly higher than that in GC (P<0.001). CONCLUSION MS are primary immune tissues in the omentum and structural bases for development and progression of peritoneal dissemination of GC and RC. Analyzing the morphology and cellular constituents could help understanding the mechanism of peritoneal metastasis.
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Affiliation(s)
- Jiu-Yang Liu
- Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study CenterWuhan 430071, Hubei Province, China
| | - Jing-Ping Yuan
- Department of Pathology, Renmin Hospital of Wuhan UniversityWuhan, Hubei Province, China
| | - Xia-Fei Geng
- Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study CenterWuhan 430071, Hubei Province, China
| | - Ai-Ping Qu
- School of Computer, Wuhan UniversityWuhan 430071, Hubei Province, China
| | - Yan Li
- Department of Oncology, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors and Hubei Cancer Clinical Study CenterWuhan 430071, Hubei Province, China
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Gene therapy using therapeutic and diagnostic recombinant oncolytic vaccinia virus GLV-1h153 for management of colorectal peritoneal carcinomatosis. Surgery 2015; 157:331-7. [PMID: 25616946 DOI: 10.1016/j.surg.2014.09.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 09/08/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND Peritoneal carcinomatosis (PC) is a terminal progression of colorectal cancer (CRC). Poor response to cytoreductive operation and chemotherapy coupled with the inability to reliably track disease progression by the use of established diagnostic methods, make this a deadly disease. We examined the effectiveness of the oncolytic vaccinia virus GLV-1h153 as a therapeutic and diagnostic vehicle. We believe that viral expression of the human sodium iodide transporter (hNIS) provides both real-time monitoring of viral therapy and effective treatment of colorectal peritoneal carcinomatosis (CRPC). METHODS Infectivity and cytotoxic effect of GLV-1h153 on CRC cell lines was assayed in vitro. Viral replication was examined by standard viral plaque assays. Orthotopic CRPC xenografts were generated in athymic nude mice and subsequently administered GLV-1h153 intraperitoneally. A decrease in tumor burden was assessed by mass. Orthotopic tumors were visualized by single-photon emission computed tomography/computed tomography after Iodine ((131)I) administration and by fluorescence optical imaging. RESULTS GLV-1h153 infected and killed CRC cells in a time- and concentration-dependent manner. Viral replication demonstrated greater than a 2.35 log increase in titer over 4 days. Intraperitoneal treatment of orthotopic CRPC xenografts resulted in a substantial decrease in tumor burden. Infection of orthotopic xenografts was therapeutic and facilitated monitoring by (131)I-single-photon emission computed tomography/computed tomography via expression of hNIS in infected tissue. CONCLUSION GLV-1h153 kills CRC in vitro effectively and decreases tumor burden in vivo. We demonstrate that GLV-1h153 can be used as an agent to provide accurate delineation of tumor burden in vivo. These findings indicate that GLV-1h153 has potential for use as a therapeutic and diagnostic agent in the treatment of CRPC.
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Désolneux G, Mazière C, Vara J, Brouste V, Fonck M, Béchade D, Bécouarn Y, Evrard S. Cytoreductive surgery of colorectal peritoneal metastases: outcomes after complete cytoreductive surgery and systemic chemotherapy only. PLoS One 2015; 10:e0122816. [PMID: 25825874 PMCID: PMC4380351 DOI: 10.1371/journal.pone.0122816] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Accepted: 02/25/2015] [Indexed: 12/24/2022] Open
Abstract
Background Cytoreductive peritoneal surgery (CRS) associated with hyperthermic peritoneal chemotherapy (HIPEC) has long been considered the standard treatment for colorectal peritoneal metastases (CPM). However, although efficacy of surgery has been demonstrated, evidence supporting HIPEC’s role is less certain. Method Overall survival (OS), progression-free survival (PFS) and morbidity were analysed retrospectively for fifty consecutively included patients treated for colorectal CPM with complete CRS and systemic chemotherapy only. Results Median peritoneal cancer index (PCI) was 8 (range 1-24). 23 patients had liver or lung metastases (LLM). 22 patients had synchronous CPM. 27 complications occurred (12 Grade 1/2, 14 Grade 3, 1 Grade 4a, 0 Grade 5). Median follow-up was 62.5 months (95 %CI 45.4-81.3), median survival 32.4 months (21.5-41.7). Three- and 5-year OS were 45.5% (0.31-0.59) and 29.64% (0.17-0.44) respectively. Presence of LLMs associated with peritoneal carcinomatosis was significantly associated with poorer prognosis, with survival at 5 years of 13.95% (95 %CI 2.9-33.6) vs. 43.87% (22.2-63.7) when no metastases were present (P= 0.018). Median PFS was 9.5 months (95 %CI 6.2-11.1). Conclusion With an equivalent PCI range and despite one of the highest rates of LLM in the literature, our survival data of CRS + systemic chemotherapy only compare well with results reported after additional HIPEC. Tolerance was better with acceptable morbidity without any mortality. Extra-hepatic metastasis (LLM) is a strong factor of poor prognosis. Awaiting the results of the randomized PRODIGE trial, these results indicate that CRS + systemic chemotherapy only is a robust hypothesis to treat colorectal CPM.
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Affiliation(s)
| | | | - Jérémy Vara
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France
| | - Véronique Brouste
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | - Marianne Fonck
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | - Dominique Béchade
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | - Yves Bécouarn
- Clinical and Epidemiological Research Unit, Institut Bergonié, Bordeaux, France
| | - Serge Evrard
- Digestive Tumours Unit, Institut Bergonié, Bordeaux, France; Univ. Bordeaux, Bordeaux, France
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Mirnezami R, Moran BJ, Harvey K, Cecil T, Chandrakumaran K, Carr N, Mohamed F, Mirnezami AH. Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases. World J Gastroenterol 2014; 20:14018-14032. [PMID: 25320542 PMCID: PMC4194588 DOI: 10.3748/wjg.v20.i38.14018] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/16/2013] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To systematically review the available evidence regarding cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for colorectal peritoneal metastases (CPM).
METHODS: An electronic literature search was carried out to identify publications reporting oncological outcome data (overall survival and/or disease free survival and/or recurrence rates) following CRS and IPC for treatment of CPM. Studies reporting outcomes following CRS and IPC for cancer subtypes other than colorectal were only included if data were reported independently for colorectal cancer-associated cases; in addition studies reporting outcomes for peritoneal carcinomatosis of appendiceal origin were excluded.
RESULTS: Twenty seven studies, published between 1999 and 2013 with a combined population of 2838 patients met the predefined inclusion criteria. Included studies comprised 21 case series, 5 case-control studies and 1 randomised controlled trial. Four studies provided comparative oncological outcome data for patients undergoing CRS in combination with IPC vs systemic chemotherapy alone. The primary indication for treatment was CPM in 96% of cases (2714/2838) and recurrent CPM (rCPM) in the remaining 4% (124/2838). In the majority of included studies (20/27) CRS was combined with hyperthermic intraperitoneal chemotherapy (HIPEC). In 3 studies HIPEC was used in combination with early post-operative intraperitoneal chemotherapy (EPIC), and 2 studies used EPIC only, following CRS. Two studies evaluated comparative outcomes with CRS + HIPEC vs CRS + EPIC for treatment of CPM. The delivery of IPC was performed using an “open” or “closed” abdomen approach in the included studies.
CONCLUSION: The available evidence presented in this review indicates that enhanced survival times can be achieved for CPM after combined treatment with CRS and IPC.
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Aoyagi T, Terracina KP, Raza A, Takabe K. Current treatment options for colon cancer peritoneal carcinomatosis. World J Gastroenterol 2014; 20:12493-12500. [PMID: 25253949 PMCID: PMC4168082 DOI: 10.3748/wjg.v20.i35.12493] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Revised: 04/10/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Peritoneal carcinomatosis (PC), the dissemination of cancer cells throughout the lining of the abdominal cavity, is the second most common presentation of colon cancer distant metastasis. Despite remarkable advances in cytotoxic chemotherapy and targeted therapy for colon cancer over the last 15 years, it has been repeatedly shown that these therapies remain ineffective for colon cancer PC. Recently, there has been a rapid accumulation of reports that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) prolongs the life of colon cancer PC patients. Here, we will review the clinical presentation, the mechanisms of disease progression, and current treatment options for colon cancer PC, with a focus on the benefits and limitations of CRS-HIPEC.
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Cytoreductive surgery in combination with hyperthermic intraperitoneal chemotherapy improves survival in patients with colorectal peritoneal metastases compared with systemic chemotherapy alone. Br J Cancer 2014; 111:1500-8. [PMID: 25225906 PMCID: PMC4200082 DOI: 10.1038/bjc.2014.419] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Accepted: 06/30/2014] [Indexed: 12/27/2022] Open
Abstract
Background: Colorectal cancer peritoneal metastasis (CPM) confers an exceptionally poor prognosis, and traditional treatment involving systemic chemotherapy (SC) is largely ineffective. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is increasingly advocated for selected patients with CPM; however, opinions are divided because of the perceived lack of evidence, high morbidity, mortality, and associated costs for this approach. As there is no clear consensus, the aim of this study was to compare outcomes following CRS+HIPEC vs SC alone for CPM using meta-analytical methodology, focusing on survival outcomes. Secondary outcomes assessed included morbidity, mortality, quality of life (QOL), and health economics (HE). Methods: An electronic literature search was conducted to identify studies comparing survival following CRS+HIPEC vs SC for CPM. The odds ratio (OR) was calculated using the Mantel–Haenszel method with corresponding 95% confidence intervals (CI) and P-values. Heterogeneity was examined using the Q-statistic and quantified with I2. The fixed-effect model (FEM) was used in the absence of significant heterogeneity. For included studies, 2- and 5-year survival was compared for CRS+HIPEC vs SC alone. Results: Four studies (three case–control, one RCT) provided comparative survival data for patients undergoing CRS+HIPEC (n=187) vs SC (n=155) for CPM. Pooled analysis demonstrated superior 2-year (OR 2.78; 95% CI 1.72–4.51; P=0.001) and 5-year (OR 4.07; 95% CI 2.17–7.64; P=0.001) survival with CRS+HIPEC compared with SC. Mortality ranged from 0 to 8%. No data were available for the assessment of QOL or HE. Conclusions: Although limited by between-study heterogeneity, the data support the assertion that in carefully selected patients, multimodal treatment of CPM with CRS+HIPEC has a highly positive prognostic impact on medium- and long-term survival compared with SC alone. There is a paucity of comparative data available on morbidity, QOL, and HE.
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Adjuvant HIPEC in Colorectal Cancer. CURRENT COLORECTAL CANCER REPORTS 2014. [DOI: 10.1007/s11888-014-0224-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Baratti D, Kusamura S, Iusco D, Bonomi S, Grassi A, Virzì S, Leo E, Deraco M. Postoperative complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal metastases from colorectal cancer: a two-center study of 101 patients. Dis Colon Rectum 2014; 57:858-68. [PMID: 24901687 DOI: 10.1097/dcr.0000000000000149] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is an effective but potentially morbid treatment for colorectal cancer peritoneal metastases. The impact of treatment-related morbidity on long-term survival has been reported in various malignancies, but it has never been assessed in this clinical setting. OBJECTIVE The aim of this study was to assess the impact of major postoperative complications on oncological outcomes after cytoreduction and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases. DESIGN Two prospective databases were reviewed. Major complications were defined as grade 3 to 5 according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The extent of peritoneal involvement was scored by the use of the Peritoneal Cancer Index. SETTINGS This study was conducted in 2 high-volume peritoneal malignancy management centers. PATIENTS One hundred one consecutive patients with peritoneal metastases potentially amenable to macroscopically complete cytoreduction were selected. INTERVENTIONS Peritonectomy procedures and multivisceral resections were used to remove all macroscopic tumor, and mitomycin-C plus cisplatin-based hyperthermic intraperitoneal chemotherapy was used to control microscopic residual disease. MAIN OUTCOME MEASURES The primary outcomes measured were overall and disease-specific survival. RESULTS Mortality and major morbidity were 3.0%, and 23.8%. Median follow-up was 44.9 months (95% CI, 24.1-65.7). Five-year disease-specific survival was 14.3% for patients who experienced major complications and 52.3% for those who did not (p = 0.001). Five-year overall survival was 11.7% for patients who experienced major complications, and 58.8% for those who did not (p = 0.003). At multivariate analysis, major morbidity correlated to both worse overall and disease-specific survival, along with a Peritoneal Cancer Index >19, and suboptimal cytoreduction. Poor performance status correlated only to worse disease-specific survival, and liver metastases correlated to worse overall survival. Longer operative time (OR, 4.1; 95% CI, 1.3-12.6; p = 0.01) and Peritoneal Cancer Index >19 (OR, 2.6; 95% CI, 1.1-6.0; p = 0.02) were independent risk factors for major morbidity. LIMITATIONS This study is limited by its observational design. CONCLUSIONS The prevention of major complications, by refining surgical technique and patient selection, is crucial because it affects oncologic outcome.
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Affiliation(s)
- D Baratti
- 1Peritoneal Surface Malignancy Program,Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy 2General Surgery Unit, Bentivoglio Hospital, Bentivoglio (BO), Italy 3Colorectal Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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Andréasson H, Lorant T, Påhlman L, Graf W, Mahteme H. Cytoreductive surgery plus perioperative intraperitoneal chemotherapy in pseudomyxoma peritonei: aspects of the learning curve. Eur J Surg Oncol 2014; 40:930-6. [PMID: 24656455 DOI: 10.1016/j.ejso.2014.03.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Revised: 01/19/2014] [Accepted: 03/02/2014] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Cytoreductive surgery (CRS) plus perioperative intraperitoneal chemotherapy is a highly invasive treatment of peritoneal metastasis and requires many surgical procedures before mastering. The aim of this study was to estimate how many procedures are needed before stabilization can be seen in surgical outcome (R1 surgery, adverse events and bleeding) in patients with pseudomyxoma peritonei (PMP). PATIENTS AND METHODS All 128 patients with PMP who were treated with CRS alone or CRS plus perioperative intraperitoneal chemotherapy between 2003 and 2008 at the Uppsala University Hospital, Uppsala, Sweden, were included. The learning curve was calculated using the partial least square (PLS) and cumulative sum control chart (CUSUM) graph. Two groups were formed based on the results of the learning curve. The learning curve plateau was considered the same as the stabilization in the CUSUM graph. Group I consisted of patients included during the learning period (n = 73) and Group II of patients treated after the learning period ended (n = 55). Comparisons between the groups were made on surgical outcome, survival and adverse events. RESULTS Stabilization was seen after 220 ± 10 procedures. A higher occurrence of R1 surgery was seen in Group II (80%) compared to Group I (48%; P = 0.0002). Overall survival increased at four years after surgery in Group II compared to Group I (80% vs. 63%; P = 0.02). CONCLUSION CRS plus perioperative intraperitoneal chemotherapy is a highly demanding procedure that requires more than 200 procedures before optimisation in surgical outcome is seen.
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Affiliation(s)
- H Andréasson
- Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala, Sweden.
| | - T Lorant
- Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala, Sweden; Department of Surgical Sciences, Section of Transplantation Surgery, Uppsala University, Uppsala, Sweden
| | - L Påhlman
- Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala, Sweden
| | - W Graf
- Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala, Sweden
| | - H Mahteme
- Department of Surgical Sciences, Uppsala University, S-751 85 Uppsala, Sweden
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Emoto S, Sunami E, Yamaguchi H, Ishihara S, Kitayama J, Watanabe T. Drug development for intraperitoneal chemotherapy against peritoneal carcinomatosis from gastrointestinal cancer. Surg Today 2014; 44:2209-20. [PMID: 24482110 DOI: 10.1007/s00595-014-0848-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Accepted: 10/21/2013] [Indexed: 12/23/2022]
Abstract
Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular-targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer.
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Affiliation(s)
- Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan
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Duraj FF, Cashin PH. Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal and hepatic metastases: a case-control study. J Gastrointest Oncol 2013; 4:388-96. [PMID: 24294511 DOI: 10.3978/j.issn.2078-6891.2013.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 04/26/2013] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Concomitant treatment of colorectal peritoneal metastases (PM) and hepatic metastases (HM) remains controversial. This study compares the cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) treatment of colorectal peritoneal metastases (PM) with the CRS/IPC/hepatic resection treatment of colorectal PM and HM. METHODS All patients from a prospective PM registry at the Uppsala institution treated concomitantly for PM/HM with CRS/IPC/hepatic resections were included in a PM/HM-group, n=11. They were matched 1(:)2 with patients from the registry being treated only for PM with CRS/IPC, n=22. Overall survival (OS), disease-free survival (DFS), morbidity, mortality, and recurrences were compared. RESULTS The PM/HM-group had median OS of 15 months (95% CI: 6-46 months) and the PM-group had a median OS of 34 months (95% CI: 19-37 months), P=0.2. The DFS was 10 months (95% CI: 3-14 months)
and 24 months (95% CI: 10-32 months) respectively, P=0.1. Morbidity was 27% in both groups and one postoperative death in the PM/HM-group. Currently, 1/10 (10%) patients with an R1 resection are
disease-free in the PM/HM group while 9/20 (45%) are disease-free in the PM group (P=0.05). CONCLUSIONS Concomitant treatment of PM and HM with CRS/IPC/hepatic resections is feasible with no significant increase in morbidity compared to CRS/IPC. The risk of recurrences is higher in the PM/HM group with a tendency towards worse DFS.
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Affiliation(s)
- Frans F Duraj
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Uppsala, Sweden
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Winer J, Zenati M, Ramalingam L, Jones H, Zureikat A, Holtzman M, Lee K, Ahrendt S, Pingpank J, Zeh HJ, Bartlett DL, Choudry HA. Impact of aggressive histology and location of primary tumor on the efficacy of surgical therapy for peritoneal carcinomatosis of colorectal origin. Ann Surg Oncol 2013; 21:1456-62. [PMID: 24201745 DOI: 10.1245/s10434-013-3328-4] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Indexed: 12/27/2022]
Abstract
BACKGROUND Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) for peritoneal carcinomatosis (PC) of colorectal origin increases survival (OS) compared to systemic chemotherapy alone. Signet ring histology demonstrates aggressive behavior with poor survival. We sought to determine whether CRS/HIPEC increases survival in this subset of patients. METHODS We reviewed 67 patients with PC of appendiceal (AP, n = 37) or colorectal origin (CRC, n = 30) with signet cell histology from a prospective database between May 2001 and August 2011. Survival analysis and multivariate Cox regression were used to determine prognostic factors for survival. RESULTS Complete CRS (CC-0/1) was achieved in 77 % (CRC) and 73 % (AP) of patients. Progression-free survival (PFS) and OS were 9 and 12 months in CRC and 12 and 21 months in AP patients. In the CRC group, univariate predictors of poor survival included female gender, age, American Society of Anesthesiologists score, preoperative albumin, completeness of cytoreduction, and morbidity. In a multivariate Cox regression model, incomplete cytoreduction (CC-2/3) and female gender were joint significant predictors of poor survival. In the AP group, significant univariate predictors of poor survival included higher EBL and PCI score. In a multivariate Cox regression model, blood loss of >500 ml and a body mass index of <25 kg/m(2) were joint significant predictors of poor survival. CONCLUSIONS AP signet cell tumors demonstrate a more favorable outcome than CRC signet cell tumors after CRC/HIPEC for carcinomatosis, suggesting an underlying difference in biology. CRS/HIPEC does not confer survival benefit in colorectal signet ring carcinomatosis unless complete cytoreduction can be achieved, whereas appendiceal signet ring carcinomatosis may benefit, regardless of resectability.
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Affiliation(s)
- Joshua Winer
- Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
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Michael M. Peritoneal carcinomatosis from colorectal cancer: hyperthermic intraperitoneal chemotherapy and the role of systemic chemotherapy. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.55] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
SUMMARY Peritoneal carcinomatosis is observed in up to 15% of colorectal cancer patients and represents 45% of all recurrences: 25% of these have peritoneal cavity-limited disease. Modern systemic chemotherapy has not substantially increased survival in this population to the same extent as those with nonperitoneal carcinomatosis colorectal cancer. Aggressive cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have now been used here, based on sound theoretical grounds. The resultant median survival achieved is up to 29 months and 5-year survival rates have increased to 20%. Patients who received complete cytoreduction benefit the most, with 5-year survival up to 50%. However, the overall level of trial evidence for CRS and HIPEC is low. The added benefit of modern systemic chemotherapy to CRS and HIPEC also requires evaluation.
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Affiliation(s)
- Michael Michael
- Colorectal Oncology Service & Division of Cancer Medicine, Peter MacCallum Cancer Centre, Locked Bag 1, A’Beckett Street, Melbourne, 8006, Victoria, Australia and Sir Peter MacCallum Department of Oncology, Faculty of Medicine & Health Sciences, The University of Melbourne, Melbourne, Australia
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Sedlacek AL, Gerber SA, Randall TD, van Rooijen N, Frelinger JG, Lord EM. Generation of a dual-functioning antitumor immune response in the peritoneal cavity. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:1318-1328. [PMID: 23933065 DOI: 10.1016/j.ajpath.2013.06.030] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 06/21/2013] [Accepted: 06/24/2013] [Indexed: 02/09/2023]
Abstract
Tumor cell metastasis to the peritoneal cavity is observed in patients with tumors of peritoneal organs, particularly colon and ovarian tumors. Following release into the peritoneal cavity, tumor cells rapidly attach to the omentum, a tissue consisting of immune aggregates embedded in adipose tissue. Despite their proximity to potential immune effector cells, tumor cells grow aggressively on these immune aggregates. We hypothesized that activation of the immune aggregates would generate a productive antitumor immune response in the peritoneal cavity. We immunized mice i.p. with lethally irradiated cells of the colon adenocarcinoma line Colon38. Immunization resulted in temporary enlargement of immune aggregates, and after challenge with viable Colon38 cells, we did not detect tumor growth on the omentum. When Colon38-immunized mice were challenged with cells from the unrelated breast adenocarcinoma line E0771 or the melanoma line B16, these tumors also did not grow. The nonspecific response was long-lived and not present systemically, highlighting the uniqueness of the peritoneal cavity. Cellular depletions of immune subsets revealed that NK1.1(+) cells were essential in preventing growth of unrelated tumors, whereas NK1.1(+) cells and T cells were essential in preventing Colon38 tumor growth. Collectively, these data demonstrate that the peritoneal cavity has a unique environment capable of eliciting potent specific and nonspecific antitumor immune responses.
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Affiliation(s)
- Abigail L Sedlacek
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Scott A Gerber
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Troy D Randall
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Nico van Rooijen
- Department of Molecular Cell Biology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands
| | - John G Frelinger
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York
| | - Edith M Lord
- Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York.
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Eriksson H, Haglund K, Leo Swenne C, Arakelian E. Patients' experiences of postoperative health related to cytoreductive surgery and hyperthermic intraoperative chemotherapy. J Clin Nurs 2013; 23:201-10. [DOI: 10.1111/jocn.12360] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2013] [Indexed: 12/11/2022]
Affiliation(s)
- Hanna Eriksson
- Department of Surgical Sciences; Uppsala University; Uppsala Sweden
| | | | - Christine Leo Swenne
- Department of Public Health and Caring Sciences; Uppsala University ; Uppsala Sweden
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Klaver YLB, Lemmens VEPP, de Hingh IHJT. Outcome of surgery for colorectal cancer in the presence of peritoneal carcinomatosis. Eur J Surg Oncol 2013; 39:734-41. [PMID: 23523316 DOI: 10.1016/j.ejso.2013.03.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Revised: 02/18/2013] [Accepted: 03/04/2013] [Indexed: 12/15/2022] Open
Abstract
AIM The detection of peritoneal carcinomatosis (PC) in colorectal cancer patients frequently results in a dilemma with regard to the optimal treatment strategy, especially when PC is encountered unexpectedly during surgery. The aim of this study was to evaluate outcomes of patients undergoing surgery for colorectal carcinoma in the presence of synchronous PC. METHODS Patients diagnosed with primary colorectal cancer and synchronous PC in three community hospitals were selected from the Eindhoven Cancer Registry database. Outcomes of postoperative complications, in-hospital mortality and overall survival were collected and analyzed according to the type of intervention performed. RESULTS Between 1995 and 2009, 169 colorectal cancer patients were diagnosed with synchronous PC, most of them unexpectedly during surgery (n = 130). 142 patients underwent surgery: primary tumor resection (n = 91), palliative procedure (n = 46) or exploration only (n = 5). In-hospital mortality was 41% after palliative surgery and 14% after primary tumor resection. Median survival was 12 weeks after palliative surgery or exploration as opposed to 55 weeks after primary tumor resection. CONCLUSION PC is most often encountered unexpectedly during surgery for colorectal cancer. Results of palliative procedures are very poor with a high in-hospital mortality rate and short survival. Resection of the primary tumor can be performed safely with relatively good outcomes but some patients could have benefited from an even more radical approach when the presence of PC would have been diagnosed at an earlier stage. Improvement of imaging techniques to detect PC prior to surgery is therefore urgently needed. Until this is the case, a high index of suspicion is required when subtle signs of PC are encountered.
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Affiliation(s)
- Y L B Klaver
- Department of Medical Oncology, Catharina Hospital, Post Box 1350, 5602 ZA Eindhoven, The Netherlands
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Park JH, Kim TY, Lee KH, Han SW, Oh DY, Im SA, Kang GH, Chie EK, Ha SW, Jeong SY, Park KJ, Park JG, Kim TY. The beneficial effect of palliative resection in metastatic colorectal cancer. Br J Cancer 2013; 108:1425-31. [PMID: 23481187 PMCID: PMC3629435 DOI: 10.1038/bjc.2013.94] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Background: We aimed to determine the role of palliative resection in metastatic colorectal cancer (mCRC) and ascertain which patient populations would benefit most from this treatment. Methods: A total of 1015 patients diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009 were retrospectively studied. Results: Of the 1015 patients, 168 patients with only liver and/or lung metastasis received curative resection. The remaining 847 patients were treated with palliative chemotherapy and/or palliative resection combined with best supportive care. Palliative resection was performed in 527 (62.2%) cases (complete resection with negative margin (R0) in 93, R1/2 in 434). Resected patients had a more prolonged median overall survival (OS) than unresected patients (21.3 vs 14.1 months; P<0.001). In multivariate analysis, R0 resection was found to be associated with a superior OS compared with R1/2 resection (51.3 vs 19.1 months; P<0.001) and no resection (51.3 vs 14.1 months; P<0.001). When we performed propensity score matching, palliative resection was found to be related to prolonged OS (hazard ratio=0.72, 95% confidence interval=0.59–0.89; P=0.003). Conclusion: Palliative resection without residual disease and chemotherapy confers a longer-term survival outcome than palliative chemotherapy alone in mCRC patient subset.
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Affiliation(s)
- J H Park
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, 101 Daehang-ro, Jongno-gu, Seoul 110-744, Republic of Korea
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Zhu Y, Hanna N, Boutros C, Alexander HR. Assessment of clinical benefit and quality of life in patients undergoing cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for management of peritoneal metastases. J Gastrointest Oncol 2013; 4:62-71. [PMID: 23450068 DOI: 10.3978/j.issn.2078-6891.2012.053] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2012] [Accepted: 09/28/2012] [Indexed: 12/21/2022] Open
Abstract
Peritoneal metastasis is a significant clinical challenge; life expectancy following diagnosis is usually very short. Surgical cytoreduction with HIPEC is being used with increasing frequency in selected patients; most outcome data have shown that prolonged median survivals can be observed in selected patients. This review summarizes the published data related to outcome and quality of life after cytoreduction and HIPEC to provide insights into its use in patients with peritoneal carcinomatosis.
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Affiliation(s)
- Yue Zhu
- Division of Surgical Oncology, Department of Surgery and the Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Pelz JOW, Vetterlein M, Grimmig T, Kerscher AG, Moll E, Lazariotou M, Matthes N, Faber M, Germer CT, Waaga-Gasser AM, Gasser M. Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis: role of heat shock proteins and dissecting effects of hyperthermia. Ann Surg Oncol 2013; 20:1105-13. [PMID: 23456378 DOI: 10.1245/s10434-012-2784-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2012] [Indexed: 12/27/2022]
Abstract
BACKGROUND In patients with isolated peritoneal carcinomatosis (PC) of gastrointestinal cancer, hyperthermic intraperitoneal chemotherapy (HIPEC) represents a promising treatment option integrated into multimodal concepts. Heat shock proteins (HSP) seem to play a major role in cellular stress during HIPEC therapy. We analyzed differentially hyperthermic conditions and HSPs responsible for cell stress-mediated repair mechanisms in tumor tissues from patients who underwent HIPEC therapy and in an in vitro hyperthermic model. METHODS Tumor tissues from our patient cohort with isolated PC were selected for further analysis when representative material was available before and after HIPEC therapy. To further dissect the role of HSPs under conditions of hyperthermia, gene and protein expression was additionally determined, together with cellular apoptosis and proliferation in human HT-29 colon cancer cells. RESULTS Differently up-regulated HSP70/72 and HSP90 gene and protein expression was found in all investigated patient tumors. In vitro studies confirmed observations from clinical tumor analysis as underlying HSP-mediated cell stress mechanisms. Moreover, results from proliferation and apoptosis assays combined with differentiated HSP expression analysis demonstrated the relevance of preselecting specific target temperatures to achieve optimal toxic effects on remaining tumor cells in vivo. CONCLUSIONS Therapeutic approaches like HIPEC to achieve antiproliferative and apoptosis-inducing cellular effects in patients with PC are negatively influenced by highly conserved HSP mechanisms in tumor cells. This study shows for the first time that specific hyperthermic conditions are necessary to be established to achieve optimal toxic effects on tumor cells during HIPEC therapy, a finding that opens potentially new therapeutic strategies.
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Affiliation(s)
- Joerg O W Pelz
- Department of Surgery I, University of Wuerzburg, Wuerzburg, Germany
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Glockzin G, Rochon J, Arnold D, Lang SA, Klebl F, Zeman F, Koller M, Schlitt HJ, Piso P. A prospective multicenter phase II study evaluating multimodality treatment of patients with peritoneal carcinomatosis arising from appendiceal and colorectal cancer: the COMBATAC trial. BMC Cancer 2013; 13:67. [PMID: 23391248 PMCID: PMC3575316 DOI: 10.1186/1471-2407-13-67] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2012] [Accepted: 02/04/2013] [Indexed: 12/15/2022] Open
Abstract
Background Peritoneal carcinomatosis is regarded as a common sign of advanced tumor stage, tumor progression or local recurrence of appendiceal and colorectal cancer and is generally associated with poor prognosis. Although survival of patients with advanced stage CRC has markedly improved over the last 20 years with systemic treatment, comprising combination chemotherapy +/− monoclonal antibodies, the oncological outcome—especially of the subgroup of patients with peritoneal metastases—is still unsatisfactory. In addition to systemic therapy, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are specific treatment options for a selected group of these patients and may provide an additional therapeutic benefit in the framework of an interdisciplinary treatment concept. Methods/design The COMBATAC trial is a prospective, multicenter, open-label, single-arm, single-stage phase II trial investigating perioperative systemic polychemotherapy including cetuximab in combination with CRS and HIPEC patients with histologically proven wild-type KRAS colorectal or appendiceal adenocarcinoma and synchronous or metachronous peritoneal carcinomatosis. The planned total number of patients to be recruited is 60. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival (OS), perioperative morbidity and treatment-associated toxicity, feasibility of the combined treatment regimen, quality of life (QoL) and histopathological regression after preoperative chemotherapy. Discussion The COMBATAC trial is designed to evaluate the feasibility and efficacy of the combined multidisciplinary treatment regimen consisting of perioperative systemic combination chemotherapy plus cetuximab and CRS plus bidirectional HIPEC with intraperitoneal oxaliplatin. Trial registration ClinicalTrials.gov Identifier: NCT01540344, EudraCT number: 2009-014040-11
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Affiliation(s)
- Gabriel Glockzin
- Department of Surgery, University Medical Center Regensburg, Regensburg 93042, Germany.
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