|
1
|
Aguirre-Allende I, Pereira-Pérez F, Manzanedo-Romero I, Fernandez-Briones P, Muñoz-Martín M, Serrano-Moral Á, Perez-Viejo E. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastases: A pragmatic comparison of oncological outcomes in synchronous versus metachronous disease. Surg Oncol 2025; 58:102183. [PMID: 39778343 DOI: 10.1016/j.suronc.2024.102183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 11/24/2024] [Accepted: 12/18/2024] [Indexed: 01/11/2025]
Abstract
BACKGROUND disease burden (PCI), completeness of cytoreduction or histological features, are known to influence survival after CRS-HIPEC for colorectal peritoneal metastases (CPM). However, there is still debate about influence of CPM onset. The aim of this study is to determine the impact of CPM onset on oncological outcomes after CRS-HIPEC. METHODS all patients with CPM scheduled for CRS-HIPEC at one reference center between December 2007 and September 2022 were included. s-PM were defined as those diagnosed at primary disease treatment; m-PM were considered those diagnosed during follow-up. Survival outcomes and recurrence rates were compared using a pragmatic analysis. RESULTS 125 patients with s-CPM and 170 patients with m-CPM were analyzed. Median follow-up was 58.6 and 50.6 months in s-CPM and m-CPM groups(p = 0.11). Complete cytoreduction (CCS-0/-1) rates were comparable: 84 % s-CPM vs. 88.2 % m-CPM(p = 0.190). Overall survival (OS) was significantly shorter in s-CPM: 24.7 vs. 46.6 months (p = 0.024). Conversely, median disease-free survival was similar in both groups, 10 months vs. 11 months(p = 0.155). Patients in the s-CPM group presented more pN+(p = 0.001), higher histologic grade(p = 0.007) and PCI(p = 0.04), and higher rate of concurrent liver metastases(p = 0.004). RAS/BRAF gene mutations and microsatellite instability did not differ significantly. Perioperative chemotherapy regimens and tolerance were also similar. CONCLUSIONS despite s-CPM being associated with impaired OS after CRS-HIPEC, the onset of PM was not found to be an independent determinant for survival. High-risk molecular and histological features strongly influence oncological outcomes after CRS-HIPEC. This is valuable data that could aid in preoperative patient selection process for CRS-HIPEC.
Collapse
Affiliation(s)
- Ignacio Aguirre-Allende
- Hepatobiliary and Peritoneal Surface Malignancies Unit. General and Digestive Surgery Department, Donostia University Hospital-IHO Donostialdea, IIS Biodonostia, Spain.
| | - Fernando Pereira-Pérez
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Israel Manzanedo-Romero
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Paula Fernandez-Briones
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - María Muñoz-Martín
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Ángel Serrano-Moral
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| | - Estibalitz Perez-Viejo
- Peritoneal Surface Malignancies Unit, General and Digestive Surgery Department, Fuenlabrada University Hospital, Madrid, Spain
| |
Collapse
|
|
2
|
Patel S, Sheshadri RA, Saklani A, Sp S, Kumar R, Singh S, Sukumar V, Bhatt A. INDEPSO-ISPSM Consensus on Peritoneal Malignancies: Management of Colorectal Peritoneal Metastases. JCO Glob Oncol 2024; 10:e2400306. [PMID: 39637347 DOI: 10.1200/go-24-00306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Accepted: 10/15/2024] [Indexed: 12/07/2024] Open
Abstract
PURPOSE This manuscript reports the results of the Indian Network for Development of Peritoneal Surface Oncology and Indian Society of Peritoneal Surface Malignancies (INDEPSO-ISPSM) consensus that aimed to provide recommendations for some important aspects management of patients with colorectal peritoneal metastases (CPM) and address some issues unique to India. METHODS The modified Delphi technique was used with two rounds of voting. There were 29 questions on nine main topics-the role of cytoreductive surgery (CRS), patient selection for CRS, preoperative workup, role of systemic chemotherapy (SC), CPM with other visceral metastases, molecular profile, hyperthermic intraperitoneal chemotherapy (HIPEC) and other modalities of intraperitoneal chemotherapy (IPC), prophylactic/preventive strategies, and surveillances after CRS. A consensus was achieved if anyone option received >70 votes (strong consensus >90%). RESULTS Forty-eight surgical (n = 41) and gastrointestinal (n = 7) oncologists were invited; 44 agreed to participate. The response rate was 95.4% (42/44) in round 1 and 93.1% (41/44) in round 2. Overall, a consensus was achieved on 23/29 (79.3%) questions (strong consensus on 6/29 [20.6%]). The panel strongly recommended considering surgery for limited CPM with limited liver metastases (92.5%), not altering the surgical approach in patients with KRAS mutations (91.67%), and limiting the use of IPC for unresectable CPM outside clinical trials (95%). Adjuvant SC was recommended for all patients undergoing CRS (89.47%). CRS is a therapeutic option for selected patients with CPM including those with metachronous CPM (79.49) and signet ring cell cancers (76.92%). HIPEC was recommended outside clinical trials only for patients with peritoneal cancer index 11-15(80%). CONCLUSION The panel recommended CRS for most indications but was very selective in recommending HIPEC and IPC outside clinical trials. These recommendations should be a useful resource in clinical decision making for clinicians treating CPM in India and regions with a similar sociodemographic background.
Collapse
Affiliation(s)
- Swapnil Patel
- Department of Surgical Oncology, Upkar Hospital and Cancer Institute, Varanasi, India
| | | | - Avanish Saklani
- Department of Colorectal Surgery and GI Surgery, Tata Memorial Hospital, Mumbai, India
| | - Somashekhar Sp
- Department of Surgical Oncology, Aster International Institute of Oncology, Bangalore, India
| | - Rohit Kumar
- Department of Surgical Oncology, Aster International Institute of Oncology, Bangalore, India
| | - Shivendra Singh
- Department of GI and HPB Surgery, Rajiv Gandhi Cancer Institute, New Delhi, India
| | - Vivek Sukumar
- Department of Surgical Oncology, Specialty Surgical Oncology, Mumbai, India
| | - Aditi Bhatt
- Department of Surgical Oncology, Shalby Cancer and Research Institute, Ahmedabad, India
| |
Collapse
|
|
3
|
Sarfaty E, Khajoueinejad N, Yu AT, Hiotis S, Golas BJ, Sarpel U, Labow DM, Cohen NA. Actual 5-Year Survival After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Patients with Peritoneal Carcinomatosis of Colorectal Origin. Ann Surg Oncol 2024; 31:1970-1979. [PMID: 37989953 DOI: 10.1245/s10434-023-14608-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/31/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS/HIPEC) improves survival compared with chemotherapy alone in patients with peritoneal carcinomatosis (PC) of colorectal (CRC) origin, however, long-term survival data are lacking. We report the actual survival of patients who underwent CRS/HIPEC for PC of CRC origin with a minimum potential 5-year follow-up period to identify factors that preclude long-term survival. METHODS We performed a retrospective analysis of a prospective database, analyzing patients undergoing CRS/HIPEC for PC of CRC origin from 2007 to 2017. Patients with aborted CRS/HIPEC, postoperative follow-up <90 days, or non-CRC histology were excluded. Overall survival (OS) and disease-free survival (DFS) were measured from date of surgery. Surviving patients with <60 months of follow-up were censored at date of last follow-up. RESULTS A total of 103 patients met inclusion criteria and were analyzed. CC score 0-1 was achieved in 89.3% of patients, and median peritoneal cancer index (PCI) was 9 (interquartile range [IQR] 5-17). Ninety-day mortality was 2.9%. The median follow-up of survivors was 88 months. Five-year OS was 36%, and median OS was 42.5 months. Factors independently associated with poor survival included high PCI (PCI = 14-20, hazard ratio [HR] 3.1, p = 0.007, and PCI > 20, HR 5.3, p ≤ 0.001) and incomplete CRS (CC score-2, HR 2.96, p = 0.02). Patients with low PCI (0-6) had 5-year OS 60.7%. CONCLUSIONS Actual 5-year OS was 36% and median OS was 42.5 months. Our study demonstrates that patients with PC from CRC origin with low PCI who undergo complete surgical resection can achieve favorable long-term survival.
Collapse
Affiliation(s)
- Elad Sarfaty
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Nazanin Khajoueinejad
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Allen T Yu
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Spiros Hiotis
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Benjamin J Golas
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Umut Sarpel
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel M Labow
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Noah A Cohen
- Division of Surgical Oncology, Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
4
|
Dressler J, Njor SH, Rasmussen M, Jørgensen LN. Treatment of patients with screen-detected colorectal cancer is less strenuous: a nationwide cohort study with long-term follow-up. Public Health 2024; 227:169-175. [PMID: 38232565 DOI: 10.1016/j.puhe.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 10/15/2023] [Accepted: 12/08/2023] [Indexed: 01/19/2024]
Abstract
OBJECTIVE During the last two decades, organised colorectal cancer (CRC) screening has been widely implemented. It remains to be established if screen-detected CRC (SD-CRC) is associated with reduced long-term requirements for treatment as compared with patients with non-screen-detected CRC (NSD-CRC). STUDY DESIGN AND METHODS This nationwide cohort study evaluated differences in treatment and healthcare contacts from the date of diagnosis to two years after comparing patients with SD-CRC and NSD-CRC. Data were collected from national healthcare registers, including patients aged 50-75 years and diagnosed with CRC between January 1st 2014 and March 31st 2018. Analyses were stratified into UICC stages and adjusted for sex, 5-year age groups, type of cancer (colonic/rectal), and Charlson comorbidity index score to address healthy user bias. RESULTS In total, 12,040 patients were included, 4708 with SD-CRC and 7332 with NSD-CRC. In patients with SD-CRC, the duration of hospitalisation and rate of emergency surgery were reduced by 38 % (relative risk [RR] = 0.62) and 66 % (RR = 0.34), respectively. Moreover, this group was characterised by a 75 % reduction in oncological outpatient visits (RR = 0.35) and a reduced number of treatments with chemotherapy (RR = 0.57) and radiotherapy (RR = 0.50). There were no significant differences between the two populations in the rates of metastasectomy and the number of contacts with primary healthcare providers. CONCLUSION Compared to patients with NSD-CRC, patients with SD-CRC experience less hospitalisation and treatment within the first two years after diagnosis.
Collapse
Affiliation(s)
- J Dressler
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark.
| | - S H Njor
- Research Clinic for Cancer Screening, Randers Regional Hospital, Denmark; Department of Clinical Medicine, Aarhus University, Denmark
| | - M Rasmussen
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark
| | - L N Jørgensen
- Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Denmark; Department of Clinical Medicine, University of Copenhagen, Denmark
| |
Collapse
|
|
5
|
Kozman MA, Fisher OM, Liauw W, Morris DL, Cashin PH. External validation of prognostic scores and comparison of predictive accuracy for patients with colorectal cancer with peritoneal metastases considered for cytoreductive surgery and intraperitoneal chemotherapy. J Surg Oncol 2023; 128:1150-1159. [PMID: 37602499 DOI: 10.1002/jso.27416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/28/2023] [Accepted: 07/26/2023] [Indexed: 08/22/2023]
Abstract
BACKGROUND AND OBJECTIVES Prognostic scores are developed to facilitate the selection of patients with colorectal cancer peritoneal metastases (CRPM) for treatment with cytoreductive surgery (CRS) ± intraperitoneal chemotherapy (IPC). Three prominent prognostic scores are the Peritoneal Surface Disease Severity Score (PSDSS), the Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), and the modified COloREctal-Pc (mCOREP). We externally validate these scores and compare their predictive accuracy. METHODS Data from consecutive CRPM patients who underwent CRS/IPC from 1996 to 2018 was used to externally validate COMPASS, PSDSS, and mCOREP. Analysis evaluated the efficacy of each score in predicting (1) open-close laparotomy-those found at laparotomy to not be eligible for curative intent CRS/IPC, (2) surgical futility-those who underwent open-close laparotomy, palliative debulking surgery, or had an overall survival of less than 12 months, and (3) overall and recurrence-free survival (OS, RFS). RESULTS Prognostic scores were calculated for the 174-patient external validation cohort. COMPASS was most accurate in predicting open-close laparotomy, futile surgery, and survival (OS and RFS). Area under the curve (AUC) for open-close prediction was 0.78 (95% confidence interval, CI: 0.68-0.87), representing useful discrimination. However, AUC for futility prediction was 0.62 (95% CI: 0.52-0.71), and C-statistic for OS was 0.65 indicating only possibly helpful discrimination. C-statistic for RFS was 0.59 indicating poor discrimination. CONCLUSION While COMPASS showed the best statistical behavior, accuracy for several clinically relevant outcomes remains low, and thus applicability to clinical practice limited.
Collapse
Affiliation(s)
- Mathew A Kozman
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- Cancer Care Centre, St George Hospital, Kogarah, New South Wales, Australia
| | - Oliver M Fisher
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
- School of Medicine, University of Notre Dame, Sydney, New South Wales, Australia
| | - Winston Liauw
- Cancer Care Centre, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - David L Morris
- Department of Surgery, Hepatobiliary and Surgical Oncology Unit, St George Hospital, Kogarah, New South Wales, Australia
- St George Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia
| | - Peter H Cashin
- Department of Surgical Sciences, Section of Surgery, Uppsala University, Akademiska Sjukhuset, Uppsala, Sweden
| |
Collapse
|
|
6
|
Ghabra S, Desale S, Sugarbaker PH. Clinical and Histopathologic Features of 35 Patients Treated for Colorectal Peritoneal Metastases Who Survived 5 Years. Dis Colon Rectum 2023; 66:1329-1338. [PMID: 36856661 DOI: 10.1097/dcr.0000000000002448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2023]
Abstract
BACKGROUND Currently, patients with a limited extent of peritoneal metastases from colon and rectal cancer are treated by cytoreductive surgery combined with perioperative chemotherapy performed at experienced centers. OBJECTIVE To statistically evaluate features that may impact survival of ≥5 years. These data are used in the risk/benefit analyses performed by the multidisciplinary team. DESIGN This was a retrospective review of a prospective database. SETTINGS This single-institution study was conducted at an academic center. PATIENTS All patients who had biopsy-proven colon or rectal peritoneal metastases treated by systemic chemotherapy, complete cytoreductive surgery, and perioperative surgery were included. MAIN OUTCOME MEASURES The primary outcomes measured were the clinical-, histologic-, and treatment-related features that had an impact on 5-year survival. RESULTS From 131 patients who had complete cytoreduction, 35 patients (26.7%) were identified as 5-year survivors. The median survival time was 27 months. The median age was 50.5 (range, 25-80) years. By univariant analysis, an absence of lymph node involvement at the time of primary colorectal cancer resection (HR 1.899 [95% CI, 1.064-3.388]; p = 0.03), complete or near-complete response to neoadjuvant chemotherapy (HR 0.251 [95% CI, 0.092-0.684]; p = 0.007), peritoneal cancer index ≤17 (HR 0.509 [95% CI, 0.329-0.788]; p = 0.002), complete visible resection of disease indicated by the completeness of cytoreduction score of 0 (HR 0.412 [95% CI, 0.224-0.756]; p = 0.004), and well-differentiated tumor (HR 0.34 [95% CI, 0.157-0.737]; p = 0.006) were significantly associated with ≥5 years survival. LIMITATIONS Limitations include its retrospective nature, unmeasured confounders, and data from a single institution. CONCLUSIONS The tumor biology as revealed by lymph node status and tumor differentiation plus extent of disease as measured by the response to neoadjuvant chemotherapy, peritoneal cancer index, and no visible residual disease indicated a favorable outcome. See Video Abstract at http://links.lww.com/DCR/C62 . CARACTERSTICAS CLNICAS E HISTOPATOLGICAS EN PACIENTES TRATADOS POR METASTASIS PERITONEALES DE ORGEN COLORECTAL Y QUE SOBREVIVIERON AOS ANTECEDENTES:Actualmente, los pacientes con extensión limitada de metástasis peritoneales de orígen colorectal son tratados mediante cirugía citorreductora asociada con una quimioterapia peri-peratoria realizadas en centros experimentados.OBJETIVO:Estúdio y evaluación estadística de las características que puedan impactar en la sobrevida de los pacientes a 5 años o más. Se utilizaron estos datos en el análisis de riesgo /beneficio realizados por un equipo multidisciplinario.DISEÑO:Revisión retrospectiva de una base de datos prospectiva.AJUSTES:Estudio realizado en una sola institución académica.PACIENTES:Todos aquellos que presentaban metástasis peritoneales de orígen colorectal, comprobadas por biopsia y tratadas con quimioterapia sistémica, cirugía peri-operatoria y citorreductora completas.MEDIDAS DE RESULTADO PRINCIPALES:Las medidads de resultados primarios fueron las características clínicas, histológicas y relacionadas con el tratamiento que tuvieron un impacto en la sobrevida a 5 años.RESULTADOS:De 131 pacientes que tuvieron una cirugía de citorreducción completa, 35 pacientes (26, 7%) fueron identificados como sobrevivientes a 5 años. La mediana de sobrevida fué de 27 meses. Se identificarion 16 varones. La mediana de edad fue de 50, 5 años con un rango de 25 a 80 años. Según análisis univariante, la ausencia de compromiso de los ganglios linfáticos en el momento de la resección del cáncer colorrectal primario (HR 1,899 (1,064, 3,388) p = 0,03), la respuesta completa o casi completa al tratamiento neoadyuvante con quimioterapia (HR 0,251 (0,092, 0,684) p = 0,007), el índice de cáncer peritoneal ≤17 (HR 0,509 (0,329, 0,788) p = 0,002), la resección completa y visible de la enfermedad indicada por la puntuación de citorreducción de 0 (HR 0,412 (0,224), 0,756) p = 0,004) y los tumores bien diferenciados (HR 0,34 (0,157, 0,737) p = 0,006) se asociaron significativamente con 5 o más años de sobrevida.LIMITACIONES:El estudio se encontró limitado por su naturaleza retrospectiva, por la no medida de factores de confusión y por los datos provenientes de una sola institución.CONCLUSIONES:La biología tumoral demostrada según el estado de los ganglios linfáticos y la diferenciación tumoral, agregada a la extensión de la enfermedad medida por la respuesta a la quimioterapia neoadyuvante, el índice de cáncer peritoneal y la ausencia visible de enfermedad residual, demostraron un resultado favorable. Consulte Video Resumen en http://links.lww.com/DCR/C62(Traducción-Dr. Xavier Delgadillo ).
Collapse
Affiliation(s)
- Shadin Ghabra
- Department of Surgery, MedStar Washington Hospital Center, Washington, DC
| | - Sameer Desale
- Biostatistics and Biomedical Informatics Department, MedStar Health Research Institute, Hyattsville, Maryland
| | - Paul H Sugarbaker
- Department of Surgery, MedStar Washington Hospital Center, Washington, DC
| |
Collapse
|
|
7
|
Saito A, Kitayama J, Nagai R, Aizawa K. Anatomical Targeting of Anticancer Drugs to Solid Tumors Using Specific Administration Routes: Review. Pharmaceutics 2023; 15:1664. [PMID: 37376112 DOI: 10.3390/pharmaceutics15061664] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 06/02/2023] [Accepted: 06/04/2023] [Indexed: 06/29/2023] Open
Abstract
Despite remarkable recent progress in developing anti-cancer agents, outcomes of patients with solid tumors remain unsatisfactory. In general, anti-cancer drugs are systemically administered through peripheral veins and delivered throughout the body. The major problem with systemic chemotherapy is insufficient uptake of intravenous (IV) drugs by targeted tumor tissue. Although dose escalation and treatment intensification have been attempted in order to increase regional concentrations of anti-tumor drugs, these approaches have produced only marginal benefits in terms of patient outcomes, while often damaging healthy organs. To overcome this problem, local administration of anti-cancer agents can yield markedly higher drug concentrations in tumor tissue with less systemic toxicity. This strategy is most commonly used for liver and brain tumors, as well as pleural or peritoneal malignancies. Although the concept is theoretically reasonable, survival benefits are still limited. This review summarizes clinical results and problems and discusses future directions of regional cancer therapy with local administration of chemotherapeutants.
Collapse
Affiliation(s)
- Akira Saito
- Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
| | - Joji Kitayama
- Department of Surgery, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0431, Japan
- Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi, Tochigi 329-0498, Japan
| | - Ryozo Nagai
- Department of Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| | - Kenichi Aizawa
- Division of Translational Research, Clinical Research Center, Jichi Medical University Hospital, Tochigi, Tochigi 329-0498, Japan
- Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan
| |
Collapse
|
|
8
|
Sugarbaker PH. Selection Factors for Treatment and Stratification of Rare Abdominal or Pelvic Tumors with Peritoneal Metastases. Indian J Surg Oncol 2023; 14:7-14. [PMID: 37359915 PMCID: PMC10284755 DOI: 10.1007/s13193-022-01593-9] [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: 04/01/2022] [Accepted: 07/12/2022] [Indexed: 10/16/2022] Open
Abstract
To maximize the results of treatments for peritoneal metastases for rare abdominal or pelvic tumors, selection of patients with a possibility for long-term success is necessary. Because these malignancies are rare, data from which these selection factors can be extracted do not exist. In order to facilitate knowledgeable patient selection for treatment, the well established clinical and histopathologic features of the common malignancies treated for peritoneal metastases were reviewed. The potential application of selection factors for common diagnoses was explored in an attempt to provide selection factors for rare tumors. The histopathologic grade, the lymph node status, the Ki-67 proliferation index, prior surgical score (PSS), preoperative radiologic imaging, preoperative laparoscopic assessment, response to neoadjuvant chemotherapy, peritoneal cancer index (PCI), and completeness of cytoreduction score were all included in this search for relevant selection factors for a rare disease. To facilitate the use of selection factors from common peritoneal metastases diagnoses, these diseases were divided into four groups. Placement of the rare cause of peritoneal metastases into one of these four groups will allow knowledgeable selection for treatment. Rare diseases with a natural history resembling low-grade appendiceal neoplasms are in group 1, diseases resembling lymph node negative colorectal cancer are in group 2, diseases resembling lymph node positive colorectal peritoneal metastases in group 3, and diseases resembling gastric cancer in group 4.
Collapse
Affiliation(s)
- Paul H. Sugarbaker
- Program in Peritoneal Surface Malignancy, Washington Cancer Institute, 3629 Fulton St. NW, Washington, DC 20007 USA
| |
Collapse
|
|
9
|
Nguyen QA, Chou WH, Hsieh MC, Chang CM, Luo WT, Tai YT, Chang WC. Genetic alterations in peritoneal metastatic tumors predicted the outcomes for hyperthermic intraperitoneal chemotherapy. Front Oncol 2023; 13:1054406. [PMID: 37182141 PMCID: PMC10170308 DOI: 10.3389/fonc.2023.1054406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 03/27/2023] [Indexed: 05/16/2023] Open
Abstract
Introduction Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered for patients with peritoneal metastasis (PM). However, patients selection that relies on conventional prognostic factors is not yet optimal. In this study, we performed whole exome sequencing (WES) to establish tumor molecular characteristics and expect to identify prognosis profiles for PM management. Methods In this study, blood and tumor samples were collected from patients with PM before HIPEC. Tumor molecular signatures were determined using WES. Patient cohort was divided into responders and non-responders according to 12-month progression-free survival (PFS). Genomic characteristics between the two cohorts were compared to study potential targets. Results In total, 15 patients with PM were enrolled in this study. Driver genes and enriched pathways were identified from WES results. AGAP5 mutation was found in all responders. This mutation was significantly associated with better OS (p = 0.00652). Conclusions We identified prognostic markers that might be useful to facilitate decision-making before CRS/HIPEC.
Collapse
Affiliation(s)
- Quynh-Anh Nguyen
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Wan-Hsuan Chou
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Mao-Chih Hsieh
- Department of General Surgery, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Che-Mai Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Wei-Tzu Luo
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Yu-Ting Tai
- Department of Anesthesiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
- Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Master Program in Clinical Genomics and Proteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Department of Pharmacy, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
- Integrative Research Center for Critical Care, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
| |
Collapse
|
|
10
|
Hu X, Zheng Z, Han J, Li B, Guo G, Guo P, Yang Y, Li D, Yan Y, Niu W, Zhou C, Meng Z, Feng J, Yu B, Liu Q, Wang G. Effect of intra-operative chemotherapy with 5-fluorouracil and leucovorin on the survival of patients with colorectal cancer after radical surgery: a retrospective cohort study. Chin Med J (Engl) 2023; 136:830-839. [PMID: 37027445 PMCID: PMC10150917 DOI: 10.1097/cm9.0000000000002598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND The effect of intra-operative chemotherapy (IOC) on the long-term survival of patients with colorectal cancer (CRC) remains unclear. In this study, we evaluated the independent effect of intra-operative infusion of 5-fluorouracil in combination with calcium folinate on the survival of CRC patients following radical resection. METHODS 1820 patients were recruited, and 1263 received IOC and 557 did not. Clinical and demographic data were collected, including overall survival (OS), clinicopathological features, and treatment strategies. Risk factors for IOC-related deaths were identified using multivariate Cox proportional hazards models. A regression model was developed to analyze the independent effects of IOC. RESULTS Proportional hazard regression analysis showed that IOC (hazard ratio [HR]=0.53, 95% confidence intervals [CI] [0.43, 0.65], P < 0.001) was a protective factor for the survival of patients. The mean overall survival time in IOC group was 82.50 (95% CI [80.52, 84.49]) months, and 71.21 (95% CI [67.92, 74.50]) months in non-IOC group. The OS in IOC-treated patients were significantly higher than non-IOC-treated patients ( P < 0.001, log-rank test). Further analysis revealed that IOC decreased the risk of death in patients with CRC in a non-adjusted model (HR=0.53, 95% CI [0.43, 0.65], P < 0.001), model 2 (adjusted for age and gender, HR=0.52, 95% CI [0.43, 0.64], P < 0.001), and model 3 (adjusted for all factors, 95% CI 0.71 [0.55, 0.90], P = 0.006). The subgroup analysis showed that the HR for the effect of IOC on survival was lower in patients with stage II (HR = 0.46, 95% CI [0.31, 0.67]) or III disease (HR=0.59, 95% CI [0.45, 0.76]), regardless of pre-operative radiotherapy (HR=0.55, 95% CI [0.45, 0.68]) or pre-operative chemotherapy (HR=0.54, 95% CI [0.44, 0.66]). CONCLUSIONS IOC is an independent factor that influences the survival of CRC patients. It improved the OS of patients with stages II and III CRC after radical surgery. TRIAL REGISTRATION chictr.org.cn, ChiCTR 2100043775.
Collapse
Affiliation(s)
- Xuhua Hu
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Zhaoxu Zheng
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jing Han
- Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Baokun Li
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Ganlin Guo
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Peiyuan Guo
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Yang Yang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Daojuan Li
- Department of Cancer Institute, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Yiwei Yan
- Department of Pediatrics, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Wenbo Niu
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Chaoxi Zhou
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Zesong Meng
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Jun Feng
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Bin Yu
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Guiying Wang
- The Second Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050001, China
- Department of General Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050050, China
| |
Collapse
|
|
11
|
Sommariva A, Tonello M, Coccolini F, De Manzoni G, Delrio P, Pizzolato E, Gelmini R, Serra F, Rreka E, Pasqual EM, Marano L, Biacchi D, Carboni F, Kusamura S, Sammartino P. Colorectal Cancer with Peritoneal Metastases: The Impact of the Results of PROPHYLOCHIP, COLOPEC, and PRODIGE 7 Trials on Peritoneal Disease Management. Cancers (Basel) 2022; 15:cancers15010165. [PMID: 36612161 PMCID: PMC9818482 DOI: 10.3390/cancers15010165] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/29/2022] Open
Abstract
HIPEC is a potentially useful locoregional treatment combined with cytoreduction in patients with peritoneal colorectal metastases. Despite being widely used in several cancer centers around the world, its role had never been investigated before the results of three important RCTs appeared on this topic. The PRODIGE 7 trial clarified the role of oxaliplatin-based HIPEC in patients treated with radical surgery. Conversely, the PROPHYLOCHIP and the COLOPEC were designed to chair the role of HIPEC in patients at high risk of developing peritoneal metastases. Although all three trials demonstrated the relative ineffectiveness of HIPEC for treating or preventing peritoneal metastases, these results are not sufficient to abandon this technique. In addition to some criticisms relating to the design of the trials and their statistical value, the oxaliplatin-based HIPEC was found to be ineffective in preventing or treating peritoneal colorectal metastases, especially in patients already treated with systemic platinum-based chemotherapy. Several studies are ongoing investigating further HIPEC drugs and regimens. The review deeply discussed all the aspects and relapses of this new evidence.
Collapse
Affiliation(s)
- Antonio Sommariva
- Advanced Surgical Oncology Unit, Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
- Correspondence: ; Tel.: +39-423-421306
| | - Marco Tonello
- Advanced Surgical Oncology Unit, Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Federico Coccolini
- General, Emergency and Trauma Surgery, Pisa University Hospital, 56124 Pisa, Italy
| | | | - Paolo Delrio
- Colorectal Surgical Oncology, Abdominal Oncology Department, “Fondazione Giovanni Pascale” IRCCS, 80131 Naples, Italy
| | - Elisa Pizzolato
- Advanced Surgical Oncology Unit, Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, 35128 Padova, Italy
| | - Roberta Gelmini
- SC Chirurgia Generale d’Urgenza ed Oncologica, AOU Policlinico di Modena, 41124 Modena, Italy
| | - Francesco Serra
- SC Chirurgia Generale d’Urgenza ed Oncologica, AOU Policlinico di Modena, 41124 Modena, Italy
| | - Erion Rreka
- General and Peritoneal Surgery, Department of Surgery, Pisa University Hospital, 56124 Pisa, Italy
| | - Enrico Maria Pasqual
- DAME University of Udine-AOUD Center Advanced Surgical Oncology, 33100 Udine, Italy
| | - Luigi Marano
- Department of Medicine, Surgery, and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, 53100 Siena, Italy
| | - Daniele Biacchi
- CRS and HIPEC Unit, Pietro Valdoni, Umberto I Policlinico di Roma, 00161 Roma, Italy
| | - Fabio Carboni
- Peritoneal Tumours Unit, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
| | - Shigeki Kusamura
- Peritoneal Surface Malignancies Unit, Fondazione Istituto Nazionale Tumori IRCCS, 20133 Milano, Italy
| | - Paolo Sammartino
- CRS and HIPEC Unit, Pietro Valdoni, Umberto I Policlinico di Roma, 00161 Roma, Italy
| |
Collapse
|
|
12
|
Jansson Y, Graf W, Ghanipour L. The prognostic impact of lead times in colorectal cancer patients undergoing cytoreductive surgery and HIPEC. World J Surg Oncol 2022; 20:300. [PMID: 36117176 PMCID: PMC9484226 DOI: 10.1186/s12957-022-02765-1] [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: 06/20/2022] [Accepted: 09/06/2022] [Indexed: 12/04/2022] Open
Abstract
Background National lead time goals have been implemented across Sweden to standardize and improve cancer patient care. However, the prognostic impact of lead times has not yet been studied in patients with colorectal cancer and peritoneal metastases scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Aim To study the correlation between lead times and overall survival and operability. Methods One hundred forty-eight patients with peritoneal metastases originating from colorectal cancer and scheduled for CRS + HIPEC from June 2012 to December 2019 were identified using a HIPEC register at Uppsala University Hospital. Data were collected from medical records concerning operability, overall survival, recurrence and time from diagnosis, and decision to operate to the date of surgery. Patients who had neoadjuvant therapy or no malignant cells in the resected specimens were excluded. Statistical calculations were made with the chi-squared test, Cox regression analysis, and log-rank test. Results The median age was 66 years (27–82). Ninety-five were women and 53 were men. One hundred six underwent CRS + HIPEC, 13 CRS only, and 29 were inoperable (open-close). No difference in overall survival was seen when comparing patients with lead times ≤ 34 days and ≥ 35 days from the decision to operate at the multidisciplinary conference to the surgery but there was a higher frequency of open-close (p = 0.023) in the group with longer lead time. Factors that impacted overall survival were open-close (p < 0.001), liver metastases (p = 0.003), and peritoneal cancer index score ≥ 20 (p < 0.001). Conclusion A long lead time from multidisciplinary conference to surgery has no direct impact on overall survival but can result in more cases of inoperability. In a larger cohort, this might translate into decreased survival, and efforts should therefore be made to complete preoperative work up as soon as possible and reduce overall time span. Important factors for survival are related to patient selection and extent of disease.
Collapse
Affiliation(s)
- Ylva Jansson
- Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden
| | - Wilhelm Graf
- Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden
| | - Lana Ghanipour
- Department of Surgical Sciences, Uppsala University, 751 85, Uppsala, Sweden.
| |
Collapse
|
|
13
|
Patients with Metachronous Peritoneal Metastatic Mucinous Colorectal Adenocarcinoma Benefit More from Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) than Their Synchronous Counterparts. Cancers (Basel) 2022; 14:cancers14163978. [PMID: 36010972 PMCID: PMC9406628 DOI: 10.3390/cancers14163978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Background: Mucinous adenocarcinoma is a frequent subtype in colorectal cancer (CRC). A higher initial T-stage, poorer differentiation, worse response to anti-tumor therapies, and shorter survival are characteristic of mucinous CRC. Moreover, the therapeutic benefit of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) in mucinous CRC has not been significantly investigated. Methods: A retrospective analysis of 218 CRC patients with synchronous or metachronous peritoneal metastases was conducted. Results: 129 and 89 patients had synchronous and metachronous metastases, and 36 (27.8%) and 22 (24.8%) of these were mucinous CRC, respectively. Mucinous CRC was more frequent in the proximal colon, with a higher T-stage and N-stage and with an average peritoneal carcinomatosis index that was 2 values higher. Disease-specific survival was significantly worse in the synchronous mucinous group (median survival: 22.4 months vs. 36.3 months, p = 0.0229). In contrast, no such difference was observed in the metachronous cohort (32.6 months vs. 34.4 months, p = 0.6490). Conclusions: In the case of synchronous peritoneal metastases originating from mucinous CRC, the positive effect of CRS+HIPEC cannot be verified, and the added value of this highly invasive treatment is therefore somewhat questioned. However, CRS + HIPEC is recommended for metachronous metastases, since no difference between the two CRC-subtypes could be verified.
Collapse
|
|
14
|
Dietz MV, van Kooten JP, Said I, Brandt-Kerkhof ARM, Verhoef C, Bremers AJA, de Wilt JHW, de Reuver PR, Madsen EVE. Survival Outcomes After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy in Patients with Synchronous Versus Metachronous Onset of Peritoneal Metastases of Colorectal Carcinoma. Ann Surg Oncol 2022; 29:6566-6576. [PMID: 35513588 PMCID: PMC9492568 DOI: 10.1245/s10434-022-11805-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 04/04/2022] [Indexed: 12/14/2022]
Abstract
Background Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) is a treatment option for peritoneal metastases (PM) from colorectal carcinoma (CRC). Because of considerable morbidity, optimal patient selection is essential. This study was designed to determine the impact of the onset of PM (synchronous vs. metachronous) on survival outcomes after CRS-HIPEC. Methods Patients undergoing CRS-HIPEC for colorectal PM in two academic centers in the Netherlands between 2010 and 2020 were eligible for inclusion. Patients were classified as synchronous (s-PM, i.e., diagnosis at time of presentation, staging, or primary surgery) or metachronous onset (m-PM, i.e., diagnosis during follow-up) of colorectal PM. Survival outcomes were compared between groups by Kaplan–Meier survival and Cox regression analyses. Results Of 390 included patients, 179 (45.9%) had synchronous onset of colorectal PM. These patients more often presented with higher TN-stage and poor differentiation/signet cell histology. Treatment with perioperative chemotherapy was more common in s-PM patients. m-PM patients experienced more serious postoperative complications (Clavien-Dindo ≥ III). There was no significant difference in disease-free survival (DFS) between s-PM (median 9 months, interquartile range [IQR] 5–15) and m-PM patients (median 8 months, IQR 5–17). Overall survival (OS) was significantly shorter for s-PM (median 28 months, IQR 11–48) versus m-PM patients (median 33 months, IQR 18–66, p = 0.049). Synchronous onset of PM was not independently associated with OS in a multivariable analysis. Conclusions Synchronous onset of colorectal PM was associated with poor tumor characteristics and more advanced disease, but was not an independent predictor of survival outcomes after CRS-HIPEC.
Collapse
Affiliation(s)
- Michelle V Dietz
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
| | - Job P van Kooten
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ibrahim Said
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | | | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Andreas J A Bremers
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Johannes H W de Wilt
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Philip R de Reuver
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Eva V E Madsen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| |
Collapse
|
|
15
|
Said I, Ubink I, Ewalds RSG, Arkesteijn JGT, Verheul HMW, de Wilt JHW, Dekker HM, Bremers AJA, de Reuver PR. In Patients Undergoing CRS/HIPEC for Colorectal Adenocarcinoma with Peritoneal Metastases, Presence of Ascites on Computed Tomography Imaging is not a Prognostic Marker for Survival. Ann Surg Oncol 2022; 29:5256-5262. [PMID: 35430666 PMCID: PMC9246798 DOI: 10.1245/s10434-022-11718-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 03/16/2022] [Indexed: 11/18/2022]
Abstract
Abstract
Background
Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a potentially curative treatment for patients with colorectal peritoneal metastases (CRPM). Patient selection is key to optimizing outcomes after CRS/HIPEC. The aim of this study was to determine the prognostic value of ascites diagnosed on preoperative imaging.
Methods
A prospective database of patients eligible for CRS/HIPEC between 2010 and 2020 was retrospectively analyzed. The presence of ascites, postoperative complications, overall survival (OS), disease-free survival (DFS), and completeness of cytoreduction were assessed. Univariable and multivariable logistic regression was performed to identify independent predictors for outcome.
Results
Of the 235 included patients, 177 (75%) underwent CRS/HIPEC while 58 (25%) were not eligible for CRS/HIPEC. In 42 of the 177 patients (24%) who underwent CRS/HIPEC, ascites was present on preoperative computed tomography (CT) imaging. Peritoneal Cancer Index (PCI) score was significantly higher in patients with preoperative ascites compared with patients without (11 [range 2–30] vs. 9 [range 0–28], respectively; p = 0.011) and complete cytoreduction was more often achieved in patients without ascites (96.3% vs. 85.7%; p = 0.007). There was no significant difference in median DFS and OS after CRS/HIPEC between patients with and without ascites {10 months (95% confidence interval [CI] 7.1–12.9) vs. 9 months (95% CI 7.2–10.8), and 25 months (95% 9.4–40.6) vs. 27 months (95% CI 22.4–31.6), respectively}.
Conclusions
Ascites on preoperative imaging was not associated with worse survival in CRS/HIPEC patients with CRPM. Therefore, excluding patients from CRS/HIPEC based merely on the presence of ascites is not advisable.
Collapse
Affiliation(s)
- Ibrahim Said
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
| | - Inge Ubink
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Roos S G Ewalds
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Johanna G T Arkesteijn
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Henk M W Verheul
- Department of Medical Oncology, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Johannes H W de Wilt
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Helena M Dekker
- Department of Medical Imaging, Radboudumc, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Andreas J A Bremers
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| | - Philip R de Reuver
- Department of Surgery, Radboudumc, Radboud Institute for Health Sciences, Nijmegen, The Netherlands
| |
Collapse
|
|
16
|
Neutrophil to lymphocyte ratio based perioperative prediction of prognosis model on early mortality after cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. Asian J Surg 2022; 45:2676-2685. [PMID: 35260332 DOI: 10.1016/j.asjsur.2022.01.104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/23/2021] [Accepted: 01/04/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Combined cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) to treat peritoneal surface malignancy (PSM) has gained a positive result compared with palliative chemotherapy alone in several cancer types. However, its postoperative care could be challenging. We aimed to develop a predicting model on early mortality. METHODS We retrospectively reviewed 132 PSM patients who had received CRS-HIPEC. The optimal cut-off value of the neutrophil-to-lymphocyte ratio (NLR) was determined as 4.4 by using the receiver operating characteristic curve analysis with an area under the curve (AUC) of 0.75. The impact of NLR on survival was elucidated by comparing the pre-operative low (NLR≤ 4.4, n = 101) and high (NLR> 4.4, n = 31) groups using the Kaplan-Meier method. The significant variables selected in multivariate analysis on early mortality were used in prediction model development. RESULTS Multivariate analysis showed that incomplete CRS, major postoperative complications, higher pre-operative NLR, and dynamic NLR changes were significant predictors of early mortality. Our perioperative prediction of prognosis (triple P) model contained four independent risks, and the AUC after classification was 0.860 (95% confidence interval [CI]: 0.773-0.947). External validation confirmed positive discrimination ability (AUC: 0.808, 95% CI: 0.666-0.950). CONCLUSION In conclusion, our triple P model provides great determination in outcomes prediction and it is easily obtained, reliable, and applicable in routine practice.
Collapse
|
|
17
|
Peritoneal metastases from colorectal cancer in the absence of lymph node metastases show a high survival rate despite unfavorable prognostic indicators. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2022; 48:1619-1625. [DOI: 10.1016/j.ejso.2022.02.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/20/2022] [Accepted: 02/01/2022] [Indexed: 12/11/2022]
|
|
18
|
Sugarbaker PH, Chang D. Revised prognostic indicators for treatment of lymph node positive colorectal peritoneal metastases. J Surg Oncol 2022; 125:889-900. [PMID: 35032331 DOI: 10.1002/jso.26792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/03/2021] [Accepted: 01/03/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND Peritoneal metastases from colon and rectal cancer presents a new target for a regional approach to treatment. Proper patient selection requires an understanding of the natural history of the disease progression. METHODS Data from colorectal cancer patients treated for peritoneal metastases by cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy and the records from the primary colon or rectal cancer surgery were analyzed to assess their impact on survival. Data regarding the anatomic sites of colorectal peritoneal metastases was gathered at the time of a complete CRS. RESULTS A cohort of 73 patients with peritoneal metastases and lymph node metastases but no liver metastases provided the information. All patients had a complete cytoreduction. Left-sided primary cancer and a complete or near complete response to neoadjuvant chemotherapy (NAC) indicated improved survival. Tumor progression within the abdominal incision, carcinoembryonic antigen (CEA) >10, peritoneal cancer index >9 and peritoneal metastases present in the abdominopelvic regions 6 and 11 carried an especially guarded prognosis. CONCLUSIONS Reduced survival occurred with a right-sided or rectal primary cancer, a CEA >10, tumor cell entrapment, and involvement of abdominopelvic regions 6 and 11. Effective NAC showed a favorable outcome.
Collapse
Affiliation(s)
- Paul H Sugarbaker
- Washington Cancer Institute, Program in Peritoneal Surface Malignancy, Washington, District of Columbia, USA
| | - David Chang
- Westat, Rockville, Washington Cancer Institute, Program in Peritoneal Surface Malignancy, Washington, Maryland, USA
| |
Collapse
|
|
19
|
Parikh MS, Johnson P, Romanes JP, Freitag HE, Spring ME, Garcia-Henriquez N, Monson JRT. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Colorectal Peritoneal Metastases: A Systematic Review. Dis Colon Rectum 2022; 65:16-26. [PMID: 34636780 DOI: 10.1097/dcr.0000000000002315] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Combined treatment modality of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is emerging as an alternative option for colorectal peritoneal metastases, but there is ambiguity regarding patient selection, treatment protocols, and efficacy. OBJECTIVE To elaborate on the patient characteristics, hyperthermic intraperitoneal chemotherapy protocol and health outcomes in colorectal peritoneal metastases patients undergoing a combination of hyperthermic intraperitoneal chemotherapy and cytoreductive surgery and provide guidance for future studies. DATA SOURCES A Medline search for English language studies published between 2004 and 2019. STUDY SELECTION Medical subject headings and key terms, including: hyperthermic intraperitoneal chemotherapy, colorectal peritoneal metastases, colorectal cancer and combinations thereof as per guidelines. MAIN OUTCOME MEASURES Overall survival, disease-free survival, and morbidity and mortality rates. RESULTS Of the 26 included studies, 42% were published between 2016 and 2019. More than half of the studies were retrospective in nature and conducted in tertiary specialized centers outside of the United States. The median age range was 44 to 62 years. Mitomycin C-based therapy was seen in 50% of studies. Mean weighted median disease-free survival for 11 studies was 15 months (9 to 36 months). Median OS ranged from 12 to 63 months, with an average of 33.6 months among 20 studies. Overall morbidity varied from 11% to 56%, with a weighted mean of 29% in 18 studies. Mortality ranged from 0 to 34%, with a weighted mean of 4% in 15 studies. LIMITATIONS Despite careful study selection, variability in methodology of the included studies can limit review findings. CONCLUSION Due to study heterogeneity, and a recent large, randomized trial showing no overall benefit, use of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in colorectal peritoneal metastases patients is highly controversial. Further standardized controlled studies can help uniformly define and build consensus among the medical community on patient eligibility and the optimal hyperthermic intraperitoneal chemotherapy techniques. PROSPERO Registered on March 3, 2020, CRD42020146942.
Collapse
Affiliation(s)
- Manasi S Parikh
- Center for Colon and Rectal Cancer, Surgical Health Outcomes Consortium, AdventHealth Orlando, Orlando, Florida
| | - Paul Johnson
- Center for Colon and Rectal Cancer, Surgical Health Outcomes Consortium, AdventHealth Orlando, Orlando, Florida
| | | | - Harvey E Freitag
- Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Mary E Spring
- Nova Southeastern University College of Osteopathic Medicine, Fort Lauderdale, Florida
| | - Norbert Garcia-Henriquez
- Center for Colon and Rectal Cancer, Surgical Health Outcomes Consortium, AdventHealth Orlando, Orlando, Florida
| | - John R T Monson
- Center for Colon and Rectal Cancer, Surgical Health Outcomes Consortium, AdventHealth Orlando, Orlando, Florida
| |
Collapse
|
|
20
|
García-Fadrique A, Estevan Estevan R, Sabater Ortí L. Quality Standards for Surgery of Colorectal Peritoneal Metastasis After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. Ann Surg Oncol 2021; 29:188-202. [PMID: 34435297 DOI: 10.1245/s10434-021-10642-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 07/27/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND The standardization of surgical outcomes throughout surgical procedures is mandatory. Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) should provide proficient oncological and surgical outcomes. STUDY DESIGN The aim of this study was to identify clinically relevant quality indicators and their quality standard, and to determine their acceptable quality limit. A systematic review on cytoreductive results from 2000 to 2018 was performed focusing on clinical guidelines, consensus conferences, and publications. After the selection of quality indicators, a systematic review of indexed references was performed in order to calculate the quality standard for each indicator. STUDY SELECTION Unicentric/multicentric series, comparative studies, and clinical trials. Studies were to include outcomes after cytoreduction of colorectal origin and series with more than 50 patients. Quality indicators with at least 10 series were mandatory and objective measurements were also mandatory for inclusion. MAIN OUTCOME MEASUREMENTS Quality indicators selected were 1- to 5-year survival, overall disease-free survival, 1- to 5-year disease-free survival, complete surgical resection, duration of surgery, length of stay, overall morbimortality, major morbidity, re-intervention, postoperative hemorrhage, intestinal fistula, anastomotic leakage, wound infection, postoperative medical complications, overall recurrence, and failure to rescue. RESULTS The most relevant quality indicators and critical quality limits were overall disease-free survival and 5-year overall disease-free survival (14 months and <10 months, and 14% and <4%, respectively), completeness of surgical resection (89% and <80%, respectively), overall mortality (3% and >8%, respectively), overall morbidity (47% and >63%, respectively), failure to rescue (12% and <30%, respectively), reintervention (13 and <22%, respectively), anastomotic leakage (6% and <13%, respectively), and overall recurrence (60% and <74%, respectively). CONCLUSION This is the first study to assess quality standards in CRS + HIPEC for colorectal peritoneal metastases. The current data are of particular relevance for future studies to control the variability of this surgery.
Collapse
Affiliation(s)
| | | | - Luis Sabater Ortí
- Hospital Clínico Universitario, Department of Surgery, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain
| |
Collapse
|
|
21
|
van Stein RM, Aalbers AGJ, Sonke GS, van Driel WJ. Hyperthermic Intraperitoneal Chemotherapy for Ovarian and Colorectal Cancer: A Review. JAMA Oncol 2021; 7:1231-1238. [PMID: 33956063 DOI: 10.1001/jamaoncol.2021.0580] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Importance The peritoneal surface is a common site of disease in ovarian and colorectal cancer. Peritoneal metastases carry a poor prognosis, despite maximal therapeutic efforts, including surgical removal of tumor deposits and intravenous chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a single intraoperative procedure that delivers chemotherapy directly into the abdominal cavity, leading to high intracellular drug concentration at the peritoneal surface. This review describes the current knowledge regarding the mechanism of action, safety, and efficacy of HIPEC in the treatment of peritoneal metastases from epithelial ovarian and colorectal cancers and explores current knowledge gaps. Observations Toxic effects of HIPEC are limited. Evidence from a randomized trial shows improved recurrence-free and overall survival after HIPEC in patients with ovarian cancer who are ineligible for primary cytoreductive surgery (CRS). The effect of HIPEC for patients with ovarian cancer undergoing primary CRS or CRS for recurrent disease has not yet been determined, and results of ongoing trials must be awaited. A recent study in patients with peritoneal metastases from colorectal cancer did not show a benefit of HIPEC when added to perioperative chemotherapy. Conclusions and Relevance Based on available evidence, various international guidelines include the option to add HIPEC to interval CRS for patients with stage III ovarian cancer. The role of HIPEC in colorectal cancer is less well defined. Future studies will need to tailor patient selection, timing, and optimal regimens of HIPEC to improve the effectiveness of this specialized treatment in ovarian, colorectal, and other tumor types.
Collapse
Affiliation(s)
- Ruby M van Stein
- Department of Gynecologic Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Arend G J Aalbers
- Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Gabe S Sonke
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam
| | - Willemien J van Driel
- Center for Gynecologic Oncology Amsterdam, The Netherlands Cancer Institute, Amsterdam
| |
Collapse
|
|
22
|
Simkens GA, Wintjens AGWE, Rovers KP, Nienhuijs SW, de Hingh IH. Effective Strategies to Predict Survival of Colorectal Peritoneal Metastases Patients Eligible for Cytoreductive Surgery and HIPEC. Cancer Manag Res 2021; 13:5239-5249. [PMID: 34234566 PMCID: PMC8257566 DOI: 10.2147/cmar.s277912] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/16/2021] [Indexed: 12/11/2022] Open
Abstract
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), often combined with systemic therapy, can be offered to selected colorectal peritoneal metastases (PM) patients. However, clinical heterogeneity and the lack of high-level evidence challenges determination of the correct treatment strategy. This review aims to provide an overview of current strategies to predict survival of colorectal PM patients treated with CRS and HIPEC, guiding clinicians to select a suitable treatment-strategy and to inform patients about their prognosis. First, the prognostic relevance of several clinicopathological prognostic factors, such as extent of PM, location of primary tumor, histology type, and the presence of lymph node or liver metastases will be discussed. Subsequently, special attention will be given to recent developments in several aspects of tumor biology such as RAF/RAS mutations, circulating tumor DNA, immunoprofiling, and consensus molecular subtypes. Finally, currently available prognostic models to predict survival will be evaluated, concluding these models perform moderate to good, but most of them partly rely on intra-operative data. New insights in tumor biology, as well as the reliable assessment of extent of peritoneal disease by diffusion weighted MRI pose promising opportunities to establish an adequate and clinically meaningful preoperative prognostic model in the near future.
Collapse
Affiliation(s)
- Geert A Simkens
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands.,Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Anne G W E Wintjens
- NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
| | - Koen P Rovers
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands
| | - Simon W Nienhuijs
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands
| | - Ignace H de Hingh
- Department of Surgery, Catharina Cancer Institute, Eindhoven, The Netherlands.,GROW - School for Oncology and Development Biology, Maastricht University, Maastricht, The Netherlands
| |
Collapse
|
|
23
|
The Characteristics of 206 Long-Term Survivors with Peritoneal Metastases from Colorectal Cancer Treated with Curative Intent Surgery: A Multi-Center Cohort from PSOGI. Cancers (Basel) 2021; 13:cancers13122964. [PMID: 34199234 PMCID: PMC8231850 DOI: 10.3390/cancers13122964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/01/2021] [Accepted: 06/09/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy improves survival in selected patients with peritoneal metastases from colorectal cancer (CRC). However, the characteristics of long-term survivors are not well documented. This study set out to investigate the patient characteristics associated with the long-term survival of peritoneal metastases from CRC. We retrospectively analyzed 206 long-term survivors who underwent CRS for peritoneal metastases from CRC. We found that most long-term survivors showed low peritoneal cancer index (PCI), low PCI of small bowel subsets, and complete cytoreduction (CC-0), while some exhibited characteristics considered associated with poor prognosis. Abstract Background: We conducted this study to review the patient characteristics associated with long-term survival in patients with peritoneal metastases from colorectal cancer who underwent cytoreductive surgery (CRS). Methods: We retrospectively investigated patients with peritoneal metastases from CRC treated with curative intent surgery with or without hyperthermic intraperitoneal chemotherapy at 13 institutions worldwide between January 1985 and April 2015 and survived longer than five years after the first CRS for peritoneal metastases. Clinical and oncological features and therapeutic parameters were described and analyzed. Results: Two hundred six long-term survivors were available for study. The median peritoneal cancer index (PCI) of this cohort was 4 (interquartile range (IQR), 2–7), and the median score of the small bowel regions of the PCI (SB-PCI) was 0 (IQR, 0–2). Complete cytoreduction (CC-0) was achieved in 180 (87.4%) patients. Recurrence was observed in 122 (59.2%) patients at a median of 1.8 (IQR, 1.2–2.6) years. Conclusions: While most long-term survivors showed low PCI/SB-PCI and CCR-0, some had characteristics considered associated with poor prognosis. Curative intent treatments may be considered in well-informed and fit patients showing negative factors affecting survival outcome.
Collapse
|
|
24
|
Kamada Y, Hida K, Ishibashi H, Sako S, Mizumoto A, Ichinose M, Padmanabhan N, Yoshida S, Yonemura Y. Thirty-three long-term survivors after cytoreductive surgery in patients with peritoneal metastases from colorectal cancer: a retrospective descriptive study. World J Surg Oncol 2021; 19:31. [PMID: 33509224 PMCID: PMC7845127 DOI: 10.1186/s12957-021-02145-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 01/20/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in selected patients with peritoneal metastasis (PM) from colorectal cancer (CRC). However, little has been reported on characteristics and clinical course of long-term survivors with CRC-PM beyond 5 years. The objective of this study was to identify the clinical and oncological features affecting long-term survival of CRC-PM after comprehensive treatment. METHODS Between January 1990 and April 2015, CRC-PM patients who underwent CRS with or without HIPEC in two Japanese tertiary hospitals were analyzed. Clinicopathological parameters and therapeutic details for long-term survivors (patients surviving ≥ 5 years after CRS) were described and compared with those for non-survivors (patients surviving < 5 years). RESULTS The study identified 236 patients with CRC-PM who underwent CRS, with a median follow-up period of 2.5 years. Thirty-three patients (14.0%) were considered as long-term survivors. Compared with non-survivors, long-term survivors had a lower median peritoneal cancer index (PCI) [4 (1-27) vs 9 (0-39), p < 0.001]. Complete cytoreduction (CCR-0) was achieved in all long-term survivors, with a significantly higher rate [33/33 (100%) vs 141/203 (69.8%), p < 0.001]. Metachronous onsets of PM were more frequently observed in the long-term survivor group [26/33 (78.8%) vs 103/203 (50.3%), p = 0.018]. Regarding histopathology, long-term survivors more frequently had mucinous adenocarcinoma than non-survivors [8/33 (24.2%) vs 27/203 (13.3%)] and less likely exhibited poorly differentiated or signet ring cell carcinoma [2/33 (6.1%) vs 48/203 (23.7%)] (p < 0.001). CONCLUSIONS One in seven patients with CRC-PM achieved the long-term milestone after CRS. A long-term survival was associated with the presence of low PCI, CCR-0, metachronous onset, and mucinous histology.
Collapse
Affiliation(s)
- Yasuyuki Kamada
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54, Shogoin-Kawahara-Cho, Sakyo-Ku, Kyoto, Japan. .,NPO to support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto, Japan. .,Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan.
| | - Koya Hida
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54, Shogoin-Kawahara-Cho, Sakyo-Ku, Kyoto, Japan
| | - Haruaki Ishibashi
- NPO to support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto, Japan.,Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan
| | - Shouzou Sako
- NPO to support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto, Japan.,Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan
| | - Akiyoshi Mizumoto
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga, Japan
| | - Masumi Ichinose
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga, Japan
| | - Naveen Padmanabhan
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan.,Department of Surgical Oncology, Apollo Cancer Institute, Chennai, India
| | - Shinya Yoshida
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54, Shogoin-Kawahara-Cho, Sakyo-Ku, Kyoto, Japan
| | - Yutaka Yonemura
- NPO to support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto, Japan.,Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Japan.,Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga, Japan
| |
Collapse
|
|
25
|
Akyuz C, Sunamak O. Surgical Treatment Approaches to the Colorectal Cancers in the Light of the Current Guidelines. COLON POLYPS AND COLORECTAL CANCER 2021:269-284. [DOI: 10.1007/978-3-030-57273-0_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
26
|
Milito P, Battaglia L, Cosimelli M, Antista M, Guaglio M, Deraco M, Baratti D. Management and complete resection of peritoneal and bone metastases from mucinous rectal carcinoma. TUMORI JOURNAL 2020; 107:NP20-NP23. [PMID: 33297874 DOI: 10.1177/0300891620977695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Surgical management of patients with multiple metastases from mucinous rectal carcinoma is feasible. CASE DESCRIPTION We present a case of a 66-year-old woman with a late onset of peritoneal and coccygeal metastasis from a mucinous rectal carcinoma treated with cytoreductive surgery. After 30 months from rectal resection, the patient underwent exploratory laparotomy with resection of all tumor localizations by means of pelvic peritonectomy, complete supracolic omentectomy, jejuneal resection, appendectomy, and excision of the mobile part of the coccyx. CONCLUSION This report aims to point out the atypical late-onset recurrence presentation and management of a mucinous carcinoma of the rectum.
Collapse
Affiliation(s)
- Pamela Milito
- Colorectal Cancer Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Luigi Battaglia
- Colorectal Cancer Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maurizio Cosimelli
- Colorectal Cancer Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Maria Antista
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Lombardia, Italy
| | - Marcello Guaglio
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marcello Deraco
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Dario Baratti
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| |
Collapse
|
|
27
|
Brind'Amour A, Dubé P, Tremblay JF, Soucisse ML, Mack L, Bouchard-Fortier A, McCart JA, Govindarajan A, Bischof D, Haase E, Giacomantonio C, Hebbard P, Younan R, MacNeill A, Boulanger-Gobeil C, Sidéris L. Canadian guidelines on the management of colorectal peritoneal metastases. Curr Oncol 2020; 27:e621-e631. [PMID: 33380878 PMCID: PMC7755452 DOI: 10.3747/co.27.6919] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Modern management of colorectal cancer (crc) with peritoneal metastasis (pm) is based on a combination of cytoreductive surgery (crs), systemic chemotherapy, and hyperthermic intraperitoneal chemotherapy (hipec). Although the role of hipec has recently been questioned with respect to results from the prodige 7 trial, the role and benefit of a complete crs were confirmed, as observed with a 41-month gain in median survival in that study, and 15% of patients remaining disease-free at 5 years. Still, crc with pm is associated with a poor prognosis, and good patient selection is essential. Many questions about the optimal management approach for such patients remain, but all patients with pm from crc should be referred to, or discussed with, a pm surgical oncologist, because cure is possible. The objective of the present guideline is to offer a practical approach to the management of pm from crc and to reflect on the new practice standards set by recent publications on the topic.
Collapse
Affiliation(s)
- A Brind'Amour
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, chu de Québec-Université Laval, Quebec City
| | - P Dubé
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - J F Tremblay
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - M L Soucisse
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| | - L Mack
- Department of Surgery, University of Calgary, Calgary, AB
| | | | - J A McCart
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - A Govindarajan
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - D Bischof
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON
- Department of Surgery, University of Toronto, Toronto, ON
| | - E Haase
- Department of Surgery, University of Alberta, Edmonton, AB
| | | | - P Hebbard
- Department of Surgery, University of Manitoba, Winnipeg, MB
| | - R Younan
- Department of Surgery, University of Montreal, Montreal, QC
- Department of Surgery, Centre Hospitalier de l'Université de Montréal, Montreal, QC
| | - A MacNeill
- Department of Surgery, University of British Columbia, Vancouver, BC
| | | | - L Sidéris
- Department of Surgery, Hôpital Maisonneuve-Rosemont, Montreal
- Department of Surgery, University of Montreal, Montreal, QC
| |
Collapse
|
|
28
|
Chen C, Wang J, Zhao Y, Ge X, Wang Z, Yu S, Song Y, Ding K, Zhang S, Zheng S, Sun L. Factors Prognostic for Peritoneal Metastases from Colorectal Cancer Treated with Surgery. Cancer Manag Res 2020; 12:10587-10602. [PMID: 33149668 PMCID: PMC7602918 DOI: 10.2147/cmar.s270830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 09/14/2020] [Indexed: 11/29/2022] Open
Abstract
Purpose To analysis factors prognostic for peritoneal metastases (PM) from colorectal cancer (CRC) treated with surgery using data from two sources and investigate the origin and effective treatment of ovarian metastases (OM). Patients and Methods Data from CRC patients with PM who had undergone surgery were collected from the Surveillance, Epidemiology, and End Results (SEER) database (n = 639) and a single Chinese institution (n = 60). Cumulative survival was evaluated by Kaplan–Meier analysis. Factors associated with overall survival (OS) and progression-free survival (PFS) prognosis were assessed using Cox’s proportional hazard regression models. Results Median OS values for patients who underwent surgery were 19 and 32 months in the SEER database and Chinese center, respectively. Age was an independent predictor of OS in both datasets. Signet-ring cell cancer and perineural invasion were independent predictors of inferior OS only in the SEER dataset, while completeness of cytoreduction (CC) and peritoneal carcinomatosis index were independent predictors for OS and PFS only in the Chinese center. Median OS was 24 months in CRC patients with PM alone and 36 months in those with both PM and OM (p = 0.181). Further, median PSF in patients with PM alone was 10 months, while that in individuals with both PM and OM was 20 months (p = 0.181). Conclusion Surgical treatment of the primary and metastatic sites is effective and safe for CRC patients with PM. CC-0 is recommended for improved prognosis. Moreover, OM should be recognized as a feature of PM, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is beneficial for CRC patients with OM.
Collapse
Affiliation(s)
- Chao Chen
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Jian Wang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yamei Zhao
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Xiaoxu Ge
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China.,Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Zhanhuai Wang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Shaojun Yu
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Yongmao Song
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Suzhan Zhang
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China.,Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Shu Zheng
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China.,Department of Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| | - Lifeng Sun
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, People's Republic of China
| |
Collapse
|
|
29
|
Narasimhan V, Tan S, Kong J, Pham T, Michael M, Ramsay R, Warrier S, Heriot A. Prognostic factors influencing survival in patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for isolated colorectal peritoneal metastases: a systematic review and meta-analysis. Colorectal Dis 2020; 22:1482-1495. [PMID: 32027455 DOI: 10.1111/codi.15003] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 12/15/2019] [Indexed: 12/13/2022]
Abstract
AIM Peritoneal metastases from colorectal cancer confer the worst survival among all metastatic sites. The adoption of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with isolated colorectal peritoneal metastases (CRPM) a favourable long-term survival. There are numerous factors postulated to influence survival in patients undergoing CRS and HIPEC. The aim of this study was to identify the key perioperative prognostic factors that influence survival in patients undergoing CRS and HIPEC for isolated CRPM. METHOD A systematic review and meta-analysis were conducted to evaluate prognostic factors influencing survival in patients undergoing CRS and HIPEC for isolated CRPM. RESULTS Thirty-three studies fitted the inclusion criteria for the systematic review, with 25 studies included in the meta-analysis. On pooled analysis, incomplete cytoreduction, increasing peritoneal carcinoma index (PCI) and lymph node involvement were significantly associated with a worse survival. Additionally, a rectal primary [hazard ratio (HR) 1.93, 95% CI 1.10-3.37], adjuvant chemotherapy (HR 0.71, 95% CI 0.54-0.93) and perioperative grade III/IV morbidity (HR 1.59, 95% CI 1.17-2.16) were also found to significantly influence survival. Notably, tumour differentiation and signet ring cell histology did not influence survival on pooled analysis. CONCLUSION This meta-analysis confirms that in patients undergoing CRS and HIPEC for isolated CRPM, incomplete cytoreduction, high PCI and lymph node involvement have a negative influence on survival. In addition, a rectal primary, adjuvant chemotherapy use and grade III/IV morbidity are important factors that also significantly influence survival.
Collapse
Affiliation(s)
- V Narasimhan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - S Tan
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - J Kong
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - T Pham
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - M Michael
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - R Ramsay
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| | - S Warrier
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - A Heriot
- Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia
| |
Collapse
|
|
30
|
Hulshof EC, Lim L, de Hingh IHJT, Gelderblom H, Guchelaar HJ, Deenen MJ. Genetic Variants in DNA Repair Pathways as Potential Biomarkers in Predicting Treatment Outcome of Intraperitoneal Chemotherapy in Patients With Colorectal Peritoneal Metastasis: A Systematic Review. Front Pharmacol 2020; 11:577968. [PMID: 33117169 PMCID: PMC7575928 DOI: 10.3389/fphar.2020.577968] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022] Open
Abstract
Background The introduction of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC) with either oxaliplatin or mitomycin C for patients with colorectal peritoneal metastasis (CPM) has resulted in a major increase in overall survival. Nonetheless, despite critical patient selection, the majority of patients will develop recurrent disease within one year following CRS + HIPEC. Therefore, improvement of patient and treatment selection is needed and may be achieved by the incorporation of genetic biomarkers. This systematic review aims to provide an overview of genetic biomarkers in the DNA repair pathway that are potentially predictive for treatment outcome of patients with colorectal peritoneal metastases treated with CRS + HIPEC with oxaliplatin or mitomycin C. Methods A systematic review was conducted according to the PRISMA guidelines. Given the limited number of genetic association studies of intraperitoneal mitomycin C and oxaliplatin in patients with CPM, we expanded the review and extrapolated the data from biomarker studies conducted in colorectal cancer patients treated with systemic mitomycin C– and oxaliplatin-based chemotherapy. Results In total, 43 papers were included in this review. No study reported potential pharmacogenomic biomarkers in patients with colorectal cancer undergoing mitomycin C–based chemotherapy. For oxaliplatin-based chemotherapy, a total of 26 genetic biomarkers within 14 genes were identified that were significantly associated with treatment outcome. The most promising genetic biomarkers were ERCC1 rs11615, XPC rs1043953, XPD rs13181, XPG rs17655, MNAT rs3783819/rs973063/rs4151330, MMR status, ATM protein expression, HIC1 tandem repeat D17S5, and PIN1 rs2233678. Conclusion Several genetic biomarkers have proven predictive value for the treatment outcome of systemically administered oxaliplatin. By extrapolation, these genetic biomarkers may also be predictive for the efficacy of intraperitoneal oxaliplatin. This should be the subject of further investigation.
Collapse
Affiliation(s)
- Emma C Hulshof
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, Netherlands.,Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands
| | - Lifani Lim
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands
| | - Ignace H J T de Hingh
- Department of Surgical Oncology, Catharina Hospital, Eindhoven, Netherlands.,GROW, School for Oncology and Development Biology, Maastricht University, Maastricht, Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | - Henk-Jan Guchelaar
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands.,Leiden Network for Personalized Therapeutics, Leiden, Netherlands
| | - Maarten J Deenen
- Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, Netherlands.,Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, Netherlands
| |
Collapse
|
|
31
|
Sommariva A, Ansaloni L, Baiocchi GL, Cascinu S, Cirocchi R, Coccolini F, Deraco M, Fiorentini G, Gelmini R, Di Giorgio A, Lippolis PV, Pasqual EM, Sassaroli C, Macrì A, Sammartino P, Scaringi S, Valle M, Vaira M. Diagnostic and therapeutic algorithm for colorectal peritoneal metastases. A consensus of the peritoneal surface malignancies onco-team of the Italian society of surgical oncology. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2020; 47:164-171. [PMID: 33028502 DOI: 10.1016/j.ejso.2020.09.035] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/04/2020] [Accepted: 09/26/2020] [Indexed: 11/30/2022]
Abstract
AIM the surgical workup for colorectal cancer peritoneal metastases (CRCPM) is complex and should be managed in specialized centers. Diagnostic and therapeutic algorithms (DTA) have been proposed to balance optimal patients management and correct use of resources. Aim of this study was to establish a consensus on DTA for CRCPM patients in Italy. METHOD a panel of 18 delegated members of centers afferent to Peritoneal Surface Malignancies Onco-team of the Italian Society of Surgical Oncology was established. A list of statements regarding the DTA of patients with CRCPM was prepared according to different activities and decision-making nodes with a defined entry and exit point. Consensus was obtained through RAND UCLA methodology. RESULTS two different DTA were defined and approved according to the modality of presentation of CRCPM (synchronous and metachronous). A consensus was also obtained on 17 of the 19 statements related to DTA. CONCLUSION a shared model of DTA is now available for healthcare providers to monitor appropriateness in diagnosis and treatment of patients with isolated peritoneal metastases from CRC.
Collapse
Affiliation(s)
- Antonio Sommariva
- Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Luca Ansaloni
- Unit of General and Emergency Surgery, Bufalini Hospital, Cesena, Italy
| | - Gian Luca Baiocchi
- Department of Clinical and Experimental Sciences, University of Brescia, Italy
| | - Stefano Cascinu
- Department of Medical Oncology Vita-Salute, San Raffaele University IRCCS, Milan, Italy
| | - Roberto Cirocchi
- General Surgery and Clinical Anatomy, University of Perugia, Perugia, Italy
| | | | - Marcello Deraco
- Peritoneal Surface Malignancies Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Gianmaria Fiorentini
- Department of Onco-Hematology, Azienda Ospedaliera 'Ospedali Riuniti Marche Nord', Pesaro, Italy
| | - Roberta Gelmini
- General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia, Italy
| | - Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
| | | | - Enrico Maria Pasqual
- Advanced Surgical Oncology Unit, Department Area Medica, University of Udine, Italy
| | - Cinzia Sassaroli
- Abdominal Oncology Department, Fondazione Giovanni Pascale, IRCCS, Naples, Italy
| | - Antonio Macrì
- Department of Human Pathology, Peritoneal Surface Malignancy and Soft Tissue Sarcoma Program, University of Messina, Italy
| | - Paolo Sammartino
- Department of Surgery 'P. Valdoni', Sapienza University of Rome, Rome, Italy
| | - Stefano Scaringi
- Digestive Surgery Unit - IBD Unit, Careggi University Hospital, Florence, Italy
| | - Mario Valle
- Surgical Oncology Peritoneum and Abdomen Pathologies, National Cancer Institute "Regina Elena" Rome, Italy
| | - Marco Vaira
- Unit of Surgical Oncology, Candiolo Cancer Institute, Turin, Italy
| |
Collapse
|
|
32
|
Baratti D, Kusamura S, Niger M, Perrone F, Milione M, Cattaneo L, Guaglio M, Bartolini V, Pietrantonio F, Deraco M. Prognostic Impact of Primary Side and RAS/RAF Mutations in a Surgical Series of Colorectal Cancer with Peritoneal Metastases. Ann Surg Oncol 2020; 28:3332-3342. [PMID: 32974694 DOI: 10.1245/s10434-020-09161-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 08/31/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Selecting patients with colorectal cancer peritoneal metastases (CRC-PMs) for surgery is still a concern. Biological features have the potential to improve prognostic stratification, but their significance in this clinical setting is still unclear. We assessed the prognostic impact of primary side and KRAS/NRAS/BRAF/PIK3CA mutations in patients treated with either cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) or CRS alone. METHODS We reviewed a prospective database of 152 CRC-PM patients selected to undergo perioperative systemic chemotherapy and CRS with or without HIPEC. Extensive mutational analysis of KRAS, NRAS, BRAF, and PIK3CA was performed by polymerase chain reaction (PCR). In 68 patients, Ion Torrent next-generation sequencing technology was used to characterize the hotspot regions of 50 genes. RESULTS The primary tumor was right-sided in 61 patients (40.1%) and left-sided in 91 patients (59.9%). Right-sided primaries were associated with mutated KRAS (p = 0.01) and normal carcinoembryonic antigen (CEA; p = 0.03). KRAS was mutated in 71/152 patients (46.7%), NRAS in 7/152 patients (4.6%), BRAF in 10/152 patients (6.6%), PIK3CA in 17/78 patients (25.0%), TP53 in 37/68 patients (54.4%), APC in 25/68 patients (36.7%), SMAD4 in 13/68 patients (19.1%), and FBXW7 in 5/68 patients (7.4%). Median follow-up was 54.9 months and median survival from PM diagnosis was 45.1 months. The right-sided primary (hazard ratio [HR] 1.62, 95% confidence interval [CI] 0.43-0.89; p = 0.011), BRAF mutations (HR 2.21, 95% CI 1.05-4.63; p = 0.038), and Peritoneal Cancer Index (HR 1.47, 95% CI 1.03-2.10; p = 0.036) independently correlated with poorer survival, while APC mutations univariately correlated with better survival (p = 0.03). CONCLUSIONS BRAF mutations and right-sided primary are adverse prognostic factors that may be used to optimize therapeutic strategies. APC may be involved in CRC-PM development and progression.
Collapse
Affiliation(s)
- Dario Baratti
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
| | - Shigeki Kusamura
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Monica Niger
- Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Federica Perrone
- Laboratory of Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Laura Cattaneo
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marcello Guaglio
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Valentina Bartolini
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo Pietrantonio
- Department of Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marcello Deraco
- Peritoneal Malignancy Program, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| |
Collapse
|
|
33
|
Prabhu A, Brandl A, Wakama S, Sako S, Ishibashi H, Mizumoto A, Takao N, Noguchi K, Motoi S, Ichinose M, Liu Y, Yonemura Y. Retrospective Analysis of Patients with Signet Ring Subtype of Colorectal Cancer with Peritoneal Metastasis Treated with CRS & HIPEC. Cancers (Basel) 2020; 12:E2536. [PMID: 32906609 PMCID: PMC7565458 DOI: 10.3390/cancers12092536] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 08/21/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
Signet ring cell subtype (SRC) of colorectal cancer (CRC) is a rare subtype and occurs in approximately 1% of all patients with CRC. Patients with peritoneal metastasis (PM) of SRC have a poor prognosis, and this subtype is frequently considered as a contra-indication for extensive surgical treatment. This retrospective study from two dedicated peritoneal surface malignancy centers in Japan included all patients treated with CRS ± hyperthermic intraperitoneal chemotherapy (HIPEC) between July 1994 and December 2017 from a prospectively maintained database. Preoperative, operative, and postoperative parameters were recorded, including complication rates and follow-up. Sixty of the 320 patients treated with CRS due to CRC were diagnosed with SRC subtype. The mean age of the patients was 51.4 years, and the mean peritoneal carcinomatosis index (PCI) was 13.1. Complete cytoreduction was achieved in 61.7% of cases. The postoperative morbidity rate was 25% and the mortality rate was 1.7%. The median overall survival (OS) was 14.4 months. Cox regression analysis revealed small bowel PCI > 2 (hazard ratio (HR) 6.5; p = 0.008) as the most important factor for OS. With accurate patient selection (e.g., PCI ≤ 12 or small bowel PCI ≤ 2), even patients with PM of CRC with SRC subtype may benefit from CRS and HIPEC, with median OS from 17.8 to 20.8 months and 5-year OS of 11.6%.
Collapse
Affiliation(s)
- Aruna Prabhu
- Department of Surgical Oncology, Thangam Cancer Center, Namakkal 637001, Tamil Nadu, India;
| | - Andreas Brandl
- Digestive Unit, Champalimaud Foundation, 1400-038 Lisbon, Portugal;
| | - Satoshi Wakama
- Department of surgery, Graduate school of medicine, Kyoto University, Kyoto 606-8303, Japan;
| | - Shouzou Sako
- Department of Regional Cancer therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka 596-0042, Japan; (S.S.); (H.I.); (Y.L.)
- NPO to Support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto 600-8189, Japan
| | - Haruaki Ishibashi
- Department of Regional Cancer therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka 596-0042, Japan; (S.S.); (H.I.); (Y.L.)
| | - Akiyoshi Mizumoto
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| | - Nobuyuki Takao
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| | - Kousuke Noguchi
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| | - Shunsuke Motoi
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| | - Masumi Ichinose
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| | - Yang Liu
- Department of Regional Cancer therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka 596-0042, Japan; (S.S.); (H.I.); (Y.L.)
| | - Yutaka Yonemura
- Department of Regional Cancer therapy, Peritoneal Surface Malignancy Center, Kishiwada Tokushukai Hospital, Kishiwada, Osaka 596-0042, Japan; (S.S.); (H.I.); (Y.L.)
- NPO to Support Peritoneal Surface Malignancy Treatment, Japanese/Asian School of Peritoneal Surface Oncology, Kyoto 600-8189, Japan
- Department of Regional Cancer Therapy, Peritoneal Surface Malignancy Center, Kusatsu General Hospital, Shiga 525-8585, Japan; (A.M.); (N.T.); (K.N.); (S.M.); (M.I.)
| |
Collapse
|
|
34
|
Sluiter NR, van der Bilt JD, Croll DMR, Vriens MR, de Hingh IHJT, Hemmer P, Aalbers AGJ, Bremers AJA, Ceelen W, D'Hoore A, Schoonmade LJ, Coupé V, Verheul H, Kazemier G, Tuynman JB. Cytoreduction and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) Versus Surgery Without HIPEC for Goblet-Cell Carcinoids and Mixed Adenoneuroendocrine Carcinomas: Propensity Score-Matched Analysis of Centers in the Netherlands and Belgium. Clin Colorectal Cancer 2020; 19:e87-e99. [PMID: 32651131 DOI: 10.1016/j.clcc.2020.01.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 07/22/2019] [Accepted: 01/06/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND The value of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneally metastasized goblet-cell carcinoids (GCCs) and mixed adenoneuroendocrine carcinomas (MANECs) is currently unclear. We compared outcomes of CRS-HIPEC to surgery alone for peritoneally metastasized GCCs and MANECs. PATIENTS AND METHODS Two cohorts were obtained from the Netherlands Cancer Registry (n = 569): patients with peritoneally metastasized GCCs and MANECs treated with CRS-HIPEC in Dutch and Belgian centers (n = 45), and patients treated with surgery alone. Primary outcome was overall survival (OS). Secondary outcomes were morbidity and hospital mortality. After propensity score matching, OS was compared in univariate and multivariate analyses. A systematic literature review was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines from database inception to June 25, 2018. RESULTS After matching for sex, tumor stage, lymph node stage, and liver metastases, CRS-HIPEC was associated with improved median OS in the combined GCC and MANEC group and the separate GCC subgroup in univariate (GCC + MANEC: 39 vs. 12 months, P < .001; GCC: 39 vs. 12 months, P = .017) and multivariate analysis (GCC + MANEC: hazard ratio 4.27, 95% confidence interval 1.88-9.66, P = .001; GCC: hazard ratio 2.77, 95% confidence interval 1.06-7.26, P = .038). Acceptable grade III-IV morbidity (17.5%) and mortality (0) were seen after CRS-HIPEC. The literature review supported these findings. CONCLUSION CRS-HIPEC is associated with substantial survival benefit in patients with peritoneally metastasized GCCs and MANECs compared to surgery alone and is a safe treatment option. These data support centralized care of GCC and MANEC patients with peritoneal spread in expert centers offering CRS-HIPEC.
Collapse
Affiliation(s)
- Nina R Sluiter
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
| | | | - Dorothée M R Croll
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Menno R Vriens
- Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Patrick Hemmer
- Department of Surgery, University Medical Center Groningen, Groningen, The Netherlands
| | - Arend G J Aalbers
- Department of Surgery, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Andreas J A Bremers
- Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Wim Ceelen
- Department of Surgery, University Hospital Ghent, Gent, Belgium
| | - Andre D'Hoore
- Department of Surgery, University Hospital Leuven, Leuven, Belgium
| | - Linda J Schoonmade
- Medical Library, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Veerle Coupé
- Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Henk Verheul
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Geert Kazemier
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Jurriaan B Tuynman
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
35
|
Zou Y, Chen X, Zhang X, Shen Z, Cai J, Tan Y, Weng J, Rong Y, Lin X. Clinical outcomes of curative treatment for colorectal liver metastases combined with cytoreductive surgery and intraperitoneal chemotherapy for peritoneal metastases: a systematic review and meta-analysis of current evidence. Int J Hyperthermia 2020; 37:944-954. [PMID: 32787474 DOI: 10.1080/02656736.2020.1803424] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND The optimal treatment for colorectal cancer (CRC) with synchronous peritoneal carcinomatosis (PC) and liver metastases (LM) remains controversial. We aimed to investigate clinical outcomes in patients with CRC and concomitant PC and LM who had undergone curative surgery, including resections at both metastatic sites and synchronous intraabdominal chemotherapy. METHODS We searched PubMed, EMBASE, and Web of Science databases for eligible studies. Studies focusing on the clinical effects of curative surgery and synchronous intraabdominal chemotherapy for patients with CRC and concomitant PC and LM were included. Meta-analysis results were recorded as hazard ratios (HRs), risk ratios (RRs) and mean differences. RESULTS We included 9 of 998 identified studies in the meta-analysis, involving 746 patients (221 patients with PC + LM, 525 patients with PC). Overall survival (pooled HR 1.68, 95% confidence interval [CI] 1.33-2.13, p < 0.01) and disease-free survival (pooled HR 1.82, 95% CI 1.51-2.20, p < 0.01) were both lower in patients with PC + LM. A higher recurrence rate (RR 1.22, 95% CI 1.04-1.44, p = 0.02) and major postoperative morbidity (RR 1.47, 95% CI 1.19-1.82, p < 0.01) were also observed in patients with PC + LM. CONCLUSION Liver resection in combination with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for patients with CRC and synchronous hepatic and peritoneal metastases may be associated with worse survival and higher morbidity compared with patients with isolated PC. More restricted patient inclusion criteria should be established to facilitate an optimal prognosis for this patient group.
Collapse
Affiliation(s)
- Yifeng Zou
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xi Chen
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xinzhi Zhang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zhihong Shen
- Department of General surgery, Jieyang City Chinese Medicine Hospital, Jieyang, Guangdong, China
| | - Jiawei Cai
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yingxin Tan
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - JingRong Weng
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Yuming Rong
- Department of VIP Region, Cancer Center of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xutao Lin
- Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.,Department of Gastrointestinal Endoscopy, Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| |
Collapse
|
|
36
|
Ba M, Chen C, Long H, Gong Y, Wu Y, Lin K, Tu Y, Zhang B, Wu W. Cytoreductive surgery and HIPEC for malignant ascites from colorectal cancer - a randomized study. Medicine (Baltimore) 2020; 99:e21546. [PMID: 32872001 PMCID: PMC7437737 DOI: 10.1097/md.0000000000021546] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
INTRODUCTION The efficacy of different timings of cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in controlling malignant ascites caused by peritoneal carcinomatosis of colorectal cancer (CRC) is not well defined. The study aims to investigate the clinical efficacy and safety of different timings of CRS with HIPEC for malignant ascites caused by peritoneal carcinomatosis from CRC. MATERIALS AND METHODS This was a preliminary randomized controlled study performed at the Intracelom Hyperthermic Perfusion Therapy Center of the Cancer Hospital of Guangzhou Medical University (China) from December 2008 to December 2016. The patients were randomized to: CRS, followed by HIPEC (CRS+HIPEC; n = 14), and ultrasound-guided HIPEC, followed by CRS 1 to 2 weeks later (HIPEC+ delayed cytoreductive surgery (dCRS) group, n = 14). The endpoints were complete remission rate of ascites, successful complete CRS rate, and overall survival. RESULTS Malignant ascites in all patients showed complete remission; the total effective rate was 100%. Complete CRS was not feasible in any patient. The median follow-up of the 2 groups was 41.9 and 42.3 months in the CRS+HIPEC and HIPEC+dCRS groups, respectively. Overall survival was 14.5 (95%CI: 7-19 months) and 14.3 months (95%CI: 4-21 months) (P > .05). The adverse effects of HIPEC were manageable. CONCLUSIONS CRS+HIPEC and HIPEC+dCRS have the same efficacy in controlling malignant ascites caused by CRC and peritoneal carcinomatosis. The timing of CRS and HIPEC does not prolong the survival of patients with peritoneal carcinomatosis from CRC, even when a complete CRS is not feasible.
Collapse
Affiliation(s)
- Mingchen Ba
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Cheng Chen
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Hui Long
- Department of Pharmacy, Guangzhou Dermatology Institute, Guangzhou, P.R. China
| | - Yuanfeng Gong
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Yinbin Wu
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Kunpeng Lin
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Yinuo Tu
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Bohuo Zhang
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| | - Wanbo Wu
- Intracelom Hyperthermic Perfusion Therapy Center, Affiliated Cancer Hospital & Institute of Guangzhou Medical University
| |
Collapse
|
|
37
|
Chin KM, Tan GHC, Chia CS, Ong JCA, Teo MCC. Novel prognostic score for outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal cancer with metachronous peritoneal carcinomatosis. ANZ J Surg 2020; 90:1958-1964. [PMID: 32159299 DOI: 10.1111/ans.15783] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/29/2020] [Accepted: 02/09/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND This study aimed to determine pre- and peri-operative parameters with significant predictive value for post-operative outcomes in patients with recurrent colorectal cancer presenting as peritoneal carcinomatosis undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), and to develop a novel prognostic scoring system for prediction of survival outcomes. METHODS A single-institution review of prospectively collected data from all patients who underwent CRS-HIPEC between October 2005 and October 2017 was conducted. Univariate and multivariate analyses were used to identify significant parameters for prediction of post-CRS-HIPEC disease-free survival and overall survival (OS). RESULTS A total of 278 patients underwent CRS-HIPEC, of whom 72 were for peritoneal carcinomatosis from recurrent colorectal cancer. Disease-free interval (DFI; P = 0.006), peritoneal cancer index (PCI; P = 0.001) and left upper quadrant disease (P = 0.023) were significant independent predictors of 3-year OS. DFI (0.007), PCI (P < 0.001) and intraoperative blood loss (BL; P = 0.001) were significant independent predictors of 5-year OS. PCI and BL were significant independent predictors of both 3-year (P = 0.026, PCI; P = 0.009, BL) and 5-year (P = 0.002, PCI; P = 0.011, BL) disease-free survival. Predictive models were developed for risk stratification of OS. CONCLUSION PCI, DFI, left upper quadrant disease and BL have significant predictive value for post-CRS-HIPEC outcomes. Risk stratification models allow for more prudent patient selection and ultimately more accurate prognostication of post-operative outcomes.
Collapse
Affiliation(s)
- Ken Min Chin
- Department of General Surgery, Singapore General Hospital, Singapore
| | - Grace Hwei Ching Tan
- Department of General Surgery, Singapore General Hospital, Singapore.,Division of Surgical Oncology, National Cancer Centre Singapore, Singapore
| | - Claramae Shulyn Chia
- Department of General Surgery, Singapore General Hospital, Singapore.,Division of Surgical Oncology, National Cancer Centre Singapore, Singapore
| | - Johnny Chin Ann Ong
- Department of General Surgery, Singapore General Hospital, Singapore.,Division of Surgical Oncology, National Cancer Centre Singapore, Singapore
| | - Melissa Ching Ching Teo
- Department of General Surgery, Singapore General Hospital, Singapore.,Division of Surgical Oncology, National Cancer Centre Singapore, Singapore
| |
Collapse
|
|
38
|
Levinsky NC, Morris MC, Wima K, Sussman JJ, Ahmad SA, Cloyd JM, Kimbrough C, Fournier K, Lee A, Dineen S, Dessureault S, Veerapong J, Baumgartner JM, Clarke C, Zaidi MY, Staley CA, Maithel SK, Leiting J, Grotz T, Lambert L, Hendrix RJ, Ronnekleiv-Kelly S, Pokrzywa C, Raoof M, Eng OS, Johnston FM, Greer J, Patel SH. Should We Be Doing Cytoreductive Surgery with HIPEC for Signet Ring Cell Appendiceal Adenocarcinoma? A Study from the US HIPEC Collaborative. J Gastrointest Surg 2020; 24:155-164. [PMID: 31428960 DOI: 10.1007/s11605-019-04336-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Accepted: 07/19/2019] [Indexed: 01/31/2023]
Abstract
BACKGROUND Appendiceal adenocarcinoma with signet ring cells (SCA) is associated with worse overall survival (OS), and it is unclear whether cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) should be pursued in this patient population. We assessed the prognostic implications of signet ring cells in patients with appendiceal adenocarcinoma and peritoneal carcinomatosis undergoing CRS-HIPEC. METHODS The US HIPEC Collaborative, a 12-center, multi-institutional database of patients undergoing CRS-HIPEC, was reviewed for patients with SCA. Univariate and multivariate analyses were performed. RESULTS Of 514 patients undergoing CRS-HIPEC for appendiceal adenocarcinoma, 125 (24%) had SCA. The SCA and non-SCA groups had similar baseline characteristics. SCA had worse OS compared with non-SCA (32.0 vs 91.4 months, p < 0.001). In univariate analysis for only SCA cases, there was worse OS in patients with poorly differentiated tumors, positive lymph nodes, LVI, PCI > 20, or incomplete cytoreduction (CC-2/3). However, multivariate analysis showed only positive lymph nodes (HR 1.14 [95% CI 1.00-1.31], p = 0.04), poor differentiation (5.60 [1.29-24.39], p = 0.02), and incomplete cytoreduction (4.90 [1.11-12.70], p = 0.03) were independently associated with decreased OS for SCA. CONCLUSION While signet cells are a negative prognostic feature, they should not be a contraindication to CRS-HIPEC in patients with well-moderately differentiated tumors with negative lymph nodes, where complete cytoreduction can be achieved.
Collapse
Affiliation(s)
- Nick C Levinsky
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA
| | - Mackenzie C Morris
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA
| | - Koffi Wima
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA
| | - Jeffrey J Sussman
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA
| | - Syed A Ahmad
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA
| | - Jordan M Cloyd
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Charles Kimbrough
- Division of Surgical Oncology, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Keith Fournier
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew Lee
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sean Dineen
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Department of Oncologic Sciences, Morsani College of Medicine, Tampa, FL, USA
| | - Sophie Dessureault
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Department of Oncologic Sciences, Morsani College of Medicine, Tampa, FL, USA
| | - Jula Veerapong
- Division of Surgical Oncology, Department of Surgery, University of California, San Diego, CA, USA
| | - Joel M Baumgartner
- Division of Surgical Oncology, Department of Surgery, University of California, San Diego, CA, USA
| | - Callisia Clarke
- Division of Surgical Oncology, Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Mohammad Y Zaidi
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Charles A Staley
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Shishir K Maithel
- Division of Surgical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA
| | - Jennifer Leiting
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
| | - Travis Grotz
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA
| | - Laura Lambert
- Division of Surgical Oncology, Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA
| | - Ryan J Hendrix
- Division of Surgical Oncology, Department of Surgery, University of Massachusetts Medical School, Worcester, MA, USA
| | - Sean Ronnekleiv-Kelly
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin, Madison, WI, USA
| | - Courtney Pokrzywa
- Division of Surgical Oncology, Department of Surgery, University of Wisconsin, Madison, WI, USA
| | - Mustafa Raoof
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | - Oliver S Eng
- Division of Surgical Oncology, Department of Surgery, City of Hope National Medical Center, Duarte, CA, USA
| | | | - Jonathan Greer
- Department of Surgery, Johns Hopkins University, Baltimore, MD, USA
| | - Sameer H Patel
- Division of Surgical Oncology, Department of Surgery, University of Cincinnati College of Medicine, 231 Albert Sabin Way ML-0558, Cincinnati, OH, 45267-0558, USA.
| |
Collapse
|
|
39
|
Yang SY, Kang JH, Kim HS, Han YD, Min BS, Lee KY. Status of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinomatosis from colorectal cancer. J Gastrointest Oncol 2019; 10:1251-1265. [PMID: 31949946 DOI: 10.21037/jgo.2019.01.36] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Peritoneal carcinomatosis (PC) was previously considered an incurable disease with a poor survival outcome. As our understanding of its biology evolved, the paradigm of the management of PC from colorectal cancer (CRC) has changed, including the combination of macroscopic disease control, cytoreductive surgery (CRS), maximal regional chemotherapy to treat residual microscopic disease, and hyperthermic intraperitoneal chemotherapy (HIPEC). As with many surgical innovations, CRS with HIPEC has evolved faster than data to support it, leaving many skeptics and critics. This review highlights the recent evidence of current practice and outcome of CRS with HIPEC. Furthermore, it also summarizes the ongoing clinical trials and potential future progress of this treatment modality.
Collapse
Affiliation(s)
- Seung Yoon Yang
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Jae Hyun Kang
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Ho Seung Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Yoon Dae Han
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Byung Soh Min
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Kang Young Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| |
Collapse
|
|
40
|
Delta peritoneal cancer index (ΔPCI): A new dynamic prognostic parameter for survival in patients with colorectal peritoneal metastases. Eur J Surg Oncol 2019; 46:590-599. [PMID: 31806520 DOI: 10.1016/j.ejso.2019.11.515] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Revised: 09/30/2019] [Accepted: 11/18/2019] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND The peritoneal cancer index (PCI) calculated during exploratory laparotomy is a strong prognostic factor for overall survival (OS) in patients with colorectal peritoneal metastases (PM) who undergo cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Progression of the PCI between diagnostic laparoscopy (DLS) and potential CRS + HIPEC (ΔPCI) might be a more dynamic prognostic factor for OS after CRS + HIPEC. MATERIALS AND METHODS Between 2012 and 2018, all colorectal PM patients who underwent an exploratory laparotomy for potential CRS + HIPEC after DLS were retrospectively identified from a prospectively maintained database. Patients were divided into stable disease (ΔPCI 0-3), mild progression (ΔPCI 4-9), or severe progression (ΔPCI ≥10). Kaplan-Meier analysis and a multivariate Cox regression were performed. RESULTS Eighty-four patients (ΔPCI 0-3, n = 35; ΔPCI 4-9, n = 34; and ΔPCI ≥10, n = 15) were analysed. Median OS after CRS + HIPEC was significantly decreased in patients with a ΔPCI of 4-9 (35.1 [95% CI 25.5-44.6]) or ΔPCI ≥10 (24.1 [95% CI 11.7-36.5]) compared to patients with a ΔPCI of 0-3 (47.9 [95% CI 40.0-55.7], p = 0.004). In multivariate regression analysis, ΔPCI remained an independent risk factor for OS: ΔPCI 4-9 HR 3.1 (95% CI 1.4-7.2, p = 0.007) and ΔPCI ≥10 HR 4.4 (95% CI 1.5-13.1, p = 0.007). CONCLUSION A high ΔPCI is an independent dynamic prognostic factor for OS and might reflect a more aggressive tumour biology in patients with colorectal PM. HIPEC surgeons should be aware of a high-ΔPCI-associated diminished prognosis and should reconsider CRS + HIPEC when confronted with a ΔPCI ≥10.
Collapse
|
|
41
|
Systematic review of published literature on oxaliplatin and mitomycin C as chemotherapeutic agents for hyperthermic intraperitoneal chemotherapy in patients with peritoneal metastases from colorectal cancer. Crit Rev Oncol Hematol 2019; 142:119-129. [PMID: 31400583 DOI: 10.1016/j.critrevonc.2019.06.014] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Accepted: 06/28/2019] [Indexed: 12/31/2022] Open
|
|
42
|
Graf W, Cashin PH, Ghanipour L, Enblad M, Botling J, Terman A, Birgisson H. Prognostic Impact of BRAF and KRAS Mutation in Patients with Colorectal and Appendiceal Peritoneal Metastases Scheduled for CRS and HIPEC. Ann Surg Oncol 2019; 27:293-300. [PMID: 31571052 PMCID: PMC6925063 DOI: 10.1245/s10434-019-07452-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Indexed: 01/01/2023]
Abstract
Background KRAS and BRAF mutations are prognostic and predictive tools in metastatic colorectal cancer, but little is known about their prognostic value in patients scheduled for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Therefore, we analyzed the prognostic impact of KRAS and BRAF mutations in patients with peritoneal metastases scheduled for CRS and HIPEC. Patients and Methods In a consecutive series of 399 patients scheduled for CRS and HIPEC between 2009 and 2017, 111 subjects with peritoneal metastases from primaries of the appendix, colon, or rectum were analyzed for KRAS mutation and 92 for BRAF mutation. Results Mutation in KRAS was present in 51/111 (46%), and mutated BRAF was found in 10/92 (11%). There was no difference in overall survival between KRAS mutation tumors and KRAS wild type, whereas BRAF mutation was associated with short survival. No subject with BRAF mutation survived 2 years. On multivariate analysis, completeness of cytoreduction score (CCS, p = 0.000001), presence of signet cell differentiation (p = 0.000001), and BRAF mutation (p = 0.0021) were linked with poor prognosis. Conclusions BRAF mutation is a marker of poor prognosis in patients with appendiceal and colorectal peritoneal metastases scheduled for CRS and HIPEC, whereas survival outcome in subjects with mutated KRAS does not differ from wild-type KRAS. This finding suggests that those with BRAF mutation should be considered for alternative treatment options.
Collapse
Affiliation(s)
- Wilhelm Graf
- Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden.
| | - Peter H Cashin
- Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| | - Lana Ghanipour
- Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| | - Malin Enblad
- Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| | - Johan Botling
- Department of Immunology, Genetics and Pathology, Clinical and Experimental Pathology, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| | - Alexei Terman
- Department of Immunology, Genetics and Pathology, Clinical and Experimental Pathology, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| | - Helgi Birgisson
- Department of Surgical Sciences, Akademiska sjukhuset, Uppsala University, Uppsala, Sweden
| |
Collapse
|
|
43
|
Hentzen JEKR, van der Plas WY, Constansia RDN, Been LB, Hoogwater FJH, van Ginkel RJ, van Dam GM, Hemmer PHJ, Kruijff S. Role of diagnostic laparoscopy in patients with suspicion of colorectal peritoneal metastases to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy. BJS Open 2019; 3:812-821. [PMID: 31832588 PMCID: PMC6887897 DOI: 10.1002/bjs5.50193] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 05/13/2019] [Indexed: 01/05/2023] Open
Abstract
Background The aim of the present study was to determine the feasibility and safety of performing diagnostic laparoscopy (DLS) routinely in patients with suspicion of colorectal peritoneal metastases (PM) to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Methods Data for consecutive patients who underwent DLS between 2012 and 2018 were extracted retrospectively from an institutional database. The primary outcome was the degree of visibility of the abdominal cavity during DLS. Good laparoscopic evaluation of the abdominal cavity was defined as visibility of at least the regions of the diaphragm, pelvis and small bowel. Secondary outcomes were reasons for perioperative exclusion for CRS + HIPEC, major postoperative complications (Clavien–Dindo grade III or above) and difference in overall survival (OS) between patients deemed suitable or unsuitable for CRS + HIPEC. Kaplan–Meier analyses were performed. Results Some 184 patients were analysed. Good laparoscopic evaluation was possible in 138 patients (75·0 per cent), and 24 (13·0 per cent) had conversion to an open procedure. Ninety‐three patients (50·5 per cent) were excluded for CRS + HIPEC, most commonly because of absence of colorectal PM (34 patients, 37 per cent) or extensive disease (Peritoneal Cancer Index 20 or above) (33 patients, 35 per cent). Major complications occurred in five patients (2·7 per cent), with no postoperative deaths. Median OS was significantly decreased in patients who were excluded due to extensive disease (14 (95 per cent c.i. 10 to 18) months) compared with patients suitable for CRS + HIPEC (36 (27 to 45) months) (P < 0·001). Conclusion Routinely performing DLS in patients with suspicion of colorectal PM to evaluate suitability for CRS + HIPEC is feasible and safe, avoiding the morbidity of an unnecessary laparotomy in patients with extensive disease.
Collapse
Affiliation(s)
- J E K R Hentzen
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - W Y van der Plas
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - R D N Constansia
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - L B Been
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - F J H Hoogwater
- Department of Surgery, Division of Hepatopancreatobiliary Surgery and Liver Transplantation University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - R J van Ginkel
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - G M van Dam
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands.,Department of Nuclear Medicine and Molecular Imaging and Intensive Care University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - P H J Hemmer
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| | - S Kruijff
- Department of Surgery, Division of Surgical Oncology University Medical Centre Groningen, University of Groningen Groningen the Netherlands
| |
Collapse
|
|
44
|
Elekonawo FMK, Lütje S, Franssen GM, Bos DL, Goldenberg DM, Boerman OC, Rijpkema M. A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer. EJNMMI Res 2019; 9:86. [PMID: 31485790 PMCID: PMC6726731 DOI: 10.1186/s13550-019-0551-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 08/09/2019] [Indexed: 12/18/2022] Open
Abstract
Background Image-guided surgery may improve surgical outcome for colorectal cancer patients. Here, we evaluated the feasibility of a pretargeting strategy for multimodal imaging in colorectal cancer using an anti-carcinoembryonic antigen (CEA) x anti-histamine-succinyl-glycine (HSG) bispecific antibody (TF2) in conjunction with the dual-labeled diHSG peptide (RDC018), using both a fluorophore for near-infrared fluorescence imaging and a chelator for radiolabeling. Methods Nude mice with subcutaneous (s.c) CEA-expressing LS174T human colonic tumors and CEA-negative control tumors were injected with TF2. After 16 h, different doses of 111In-labeled IMP-288 (non-fluorescent) or its fluorescent derivative RDC018 were administered to compare biodistributions. MicroSPECT/CT and near-infrared fluorescence imaging were performed 2 and 24 h after injection. Next, the biodistribution of the dual-labeled humanized anti-CEA IgG antibody [111In]In-DTPA-hMN-14-IRDye800CW (direct targeting) was compared with the biodistribution of 111In-RDC018 in mice with TF2-pretargeted tumors, using fluorescence imaging and gamma counting. Lastly, mice with intraperitoneal LS174T tumors underwent near-infrared fluorescence image-guided resection combined with pre- and post-resection microSPECT/CT imaging. Results 111In-RDC018 showed specific tumor targeting in pretargeted CEA-positive tumors (21.9 ± 4.5 and 10.0 ± 4.7% injected activity per gram (mean ± SD %IA/g), at 2 and 24 hours post-injection (p.i.), respectively) and a biodistribution similar to 111In-IMP288. Both fluorescence and microSPECT/CT images confirmed preferential tumor accumulation. At post mortem dissection, intraperitoneal tumors were successfully identified and removed using pretargeting with TF2 and 111In-RDC018. Conclusion A pretargeted approach for multimodal image-guided resection of colorectal cancer in a preclinical xenograft model is feasible, enables preoperative SPECT/CT, and might facilitate intraoperative fluorescence imaging. Electronic supplementary material The online version of this article (10.1186/s13550-019-0551-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Fortuné M K Elekonawo
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
| | - Susanne Lütje
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Gerben M Franssen
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Desirée L Bos
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - David M Goldenberg
- Garden State Cancer Center, Center for Molecular Medicine and Immunology, Morris Plains, NJ, USA
| | - Otto C Boerman
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Mark Rijpkema
- Department of Radiology and Nuclear Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| |
Collapse
|
|
45
|
Yong ZZ, Tan GHC, Shannon N, Chia C, Teo MCC. P.R.O.P.S. - A novel Pre-Operative Predictive Score for unresectability in patients with colorectal peritoneal metastases being considered for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). World J Surg Oncol 2019; 17:138. [PMID: 31391066 PMCID: PMC6686533 DOI: 10.1186/s12957-019-1673-x] [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: 04/15/2019] [Accepted: 07/22/2019] [Indexed: 12/01/2022] Open
Abstract
Background Twenty to thirty percent of planned cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS and HIPEC) procedures are abandoned intra-operatively. Pre-operative factors associated with unresectability identified previously were used to develop a Pre-Operative Predictive Score (PROPS), which was compared with current selection criteria—Peritoneal Surface Disease Severity Score (PSDSS), Verwaal’s Prognostic Score (PS) and Colorectal Peritoneal Metastases Prognostic Surgical Score (COMPASS), to determine which score provides the best prediction for unresectability. Methods Fifty-six patients with peritoneal metastases of colorectal origin were included. Beta-coefficient values of significant variables (p < 0.05) were determined from multivariate analysis to develop PROPS. PROPS, PSDSS, PS and COMPASS were compared using a receiver operating characteristic curve to calculate its accuracy, sensitivity and specificity. Results PROPS consisted of nine patient and tumour factors which were categorised into three groups: (i) poor tumour biology: previous inadequate resection, underwent multiple lines of chemotherapy and poorly differentiated or signet cell histology; (ii) heavy tumour burden: abdominal distension, palpable abdominal mass and computed tomography findings of ascites, small bowel disease and/or omental thickening; and (iii) active tumour proliferation: elevated tumour markers. Overall, PROPS achieved 86% accuracy with 100% sensitivity and 68% specificity, PSDSS achieved 85% accuracy with 100% sensitivity and 63% specificity, PS achieved 73% accuracy with 100% sensitivity and 68% specificity and COMPASS achieved 61% accuracy with 27% sensitivity and 100% specificity. Conclusions PROPS is more effective in predicting unresectability as compared to PSDSS, PS and COMPASS, and has the added advantage of using solely pre-operative factors.
Collapse
Affiliation(s)
- Zachary Zihui Yong
- Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Grace Hwei Ching Tan
- Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Nicholas Shannon
- Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Claramae Chia
- Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore
| | - Melissa Ching Ching Teo
- Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
| |
Collapse
|
|
46
|
Kitai T, Yamanaka K, Sugimoto N, Inamoto O. Surgical management for peritoneal carcinomatosis of appendiceal origin with a high-tumor burden. Surg Today 2019; 50:171-177. [PMID: 31363844 DOI: 10.1007/s00595-019-01856-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 07/17/2019] [Indexed: 12/17/2022]
Abstract
PURPOSE Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is the active treatment for peritoneal carcinomatosis of appendiceal origin. However, surgical management is sometimes difficult in patients with a high-tumor burden. METHODS A high-tumor burden was defined as a peritoneal cancer index (PCI) ≥ 28. Among 49 patients receiving CRS + HIPEC, 29 had a PCI ≥ 28. RESULTS Complete cytoreduction (CC-0/1) was achieved in 20 of the 29 patients with a PCI ≥ 28 and in all 20 patients with a PCI < 28. Among the patients achieving CC-0/1, gastrectomy or total colectomy was performed more frequently, the hospital stay was longer and postoperative complications were more frequent in those with a PCI ≥ 28 than in those with a PCI < 28. If CC-0/1 was achieved, the overall survival was comparable between patients with a PCI ≥ 28 and a PCI < 28. However, the recurrence-free survival was significantly worse for patients with a PCI ≥ 28 than for those with a PCI < 28 (5-year survival: 73.7% vs. 5.9%). Patients with recurrence who underwent repeat CRS showed a better overall survival than those without repeat CRS. Among patients with a PCI ≥ 28, a performance status (PS) of 2/3 was a significant prognostic factor (hazard ratio = 5.132). CONCLUSIONS In patients with a high-tumor burden undergoing CRS + HIPEC, postoperative complications were more frequent, and the recurrence rate was higher than in those without a high-tumor burden. Repeat CRS improved the survival of patients with recurrence. The PS was a key indicator when selecting patients suitable for aggressive resection.
Collapse
Affiliation(s)
- Toshiyuki Kitai
- Department of Surgery, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada, Osaka, 596-8501, Japan.
| | - Kenya Yamanaka
- Department of Surgery, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada, Osaka, 596-8501, Japan
| | - Naoko Sugimoto
- Department of Surgery, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada, Osaka, 596-8501, Japan
| | - Osamu Inamoto
- Department of Surgery, Kishiwada City Hospital, 1001 Gakuhara-cho, Kishiwada, Osaka, 596-8501, Japan
| |
Collapse
|
|
47
|
Shannon NB, Tan JWS, Tan HL, Wang W, Chen Y, Lim HJ, Tan QX, Hendrikson J, Ng WH, Loo LY, Skanthakumar T, Wasudevan SD, Kon OL, Lim TKH, Tan GHC, Chia CS, Soo KC, Ong CAJ, Teo MCC. A set of molecular markers predicts chemosensitivity to Mitomycin-C following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for colorectal peritoneal metastasis. Sci Rep 2019; 9:10572. [PMID: 31332257 PMCID: PMC6646658 DOI: 10.1038/s41598-019-46819-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 05/28/2019] [Indexed: 12/21/2022] Open
Abstract
Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is associated with significant perioperative morbidity and mortality. We aim to generate and validate a biomarker set predicting sensitivity to Mitomycin-C to refine selection of patients with colorectal peritoneal metastasis (CPM) for this treatment. A signature predicting Mitomycin-C sensitivity was generated using data from Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas. Validation was performed on CPM patients who underwent CRS-HIPEC (n = 62) using immunohistochemistry (IHC). We determined predictive significance of our set using overall survival as a surrogate endpoint via a logistic regression model. Three potential biomarkers were identified and optimized for IHC. Patients exhibiting lower expression of PAXIP1 and SSBP2 had poorer survival than those with higher expression (p = 0.045 and 0.140, respectively). No difference was observed in patients with differing DTYMK expression (p = 0.715). Combining PAXIP1 and SSBP2 in a set, patients with two dysregulated protein markers had significantly poorer survival than one or no dysregulated marker (p = 0.016). This set independently predicted survival in a Cox regression model (HR 5.097; 95% CI 1.731–15.007; p = 0.003). We generated and validated an IHC prognostic set which could potentially identify patients who are likely to benefit from HIPEC using Mitomycin-C.
Collapse
Affiliation(s)
| | - Joey Wee-Shan Tan
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Hwee Leong Tan
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Weining Wang
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Yudong Chen
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Hui Jun Lim
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Qiu Xuan Tan
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Josephine Hendrikson
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Wai Har Ng
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Li Yang Loo
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Seettha D Wasudevan
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Oi Lian Kon
- Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore
| | - Tony Kiat Hon Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore
| | - Grace Hwei Ching Tan
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Claramae Shulyn Chia
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Khee Chee Soo
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | - Chin-Ann Johnny Ong
- Division of Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | | |
Collapse
|
|
48
|
Sánchez-Hidalgo JM, Rodríguez-Ortiz L, Arjona-Sánchez Á, Rufián-Peña S, Casado-Adam Á, Cosano-Álvarez A, Briceño-Delgado J. Colorectal peritoneal metastases: Optimal management review. World J Gastroenterol 2019; 25:3484-3502. [PMID: 31367152 PMCID: PMC6658395 DOI: 10.3748/wjg.v25.i27.3484] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/20/2019] [Accepted: 06/23/2019] [Indexed: 02/06/2023] Open
Abstract
The peritoneum is a common site of dissemination for colorrectal cancer, with a poorer prognosis than other sites of metastases. In the last two decades, it has been considered as a locoregional disease progression and treated as such with curative intention treatments. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is the actual reference treatment for these patients as better survival results have been reached as compared to systemic chemotherapy alone, but its therapeutic efficacy is still under debate. Actual guidelines recommend that the management of colorectal cancer with peritoneal metastases should be led by a multidisciplinary team carried out in experienced centers and consider CRS + HIPEC for selected patients. Accumulative evidence in the last three years suggests that this is a curative treatment that may improve patients disease-free survival, decrease the risk of recurrence, and does not increase the risk of treatment-related mortality. In this review we aim to gather the latest results from referral centers and opinions from experts about the effectiveness and feasibility of CRS + HIPEC for treating peritoneal disease from colorectal malignancies.
Collapse
Affiliation(s)
| | - Lidia Rodríguez-Ortiz
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Álvaro Arjona-Sánchez
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Sebastián Rufián-Peña
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Ángela Casado-Adam
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Antonio Cosano-Álvarez
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| | - Javier Briceño-Delgado
- Department of General and Digestive Surgery, Reina Sofia University Hospital, Cordoba 14004, Spain
| |
Collapse
|
|
49
|
Hallam S, Tyler R, Price M, Beggs A, Youssef H. Meta-analysis of prognostic factors for patients with colorectal peritoneal metastasis undergoing cytoreductive surgery and heated intraperitoneal chemotherapy. BJS Open 2019; 3:585-594. [PMID: 31592510 PMCID: PMC6773657 DOI: 10.1002/bjs5.50179] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
Background Up to 15 per cent of colorectal cancers present with peritoneal metastases (CPM). Cytoreductive surgery and heated intraperitoneal chemotherapy (CRS + HIPEC) aims to achieve macroscopic tumour resection combined with HIPEC to destroy microscopic disease. CRS + HIPEC is a major operation with significant morbidity and effects on quality of life (QoL). Improving patient selection is crucial to maximize patient outcomes while minimizing morbidity and mortality. The aim of this study was to identify prognostic factors for patients with CPM undergoing CRS + HIPEC. Methods A systematic search of MEDLINE, Embase and Cochrane Library electronic databases was performed using terms for colorectal cancer, peritoneal metastasis and CRS + HIPEC. Included studies focused on the impact of prognostic factors on overall survival following CRS + HIPEC in patients with CPM. Results Twenty-four studies described 3128 patients. Obstruction or perforation of the primary tumour (hazard ratio (HR) 2·91, 95 per cent c.i. 1·5 to 5·65), extent of peritoneal metastasis as described by the Peritoneal Carcinomatosis Index (PCI) (per increase of 1 PCI point: HR 1·07, 1·02 to 1·12) and the completeness of cytoreduction (CC score above zero: HR 1·75, 1·18 to 2·59) were associated with reduced overall survival after CRS + HIPEC. Conclusion Primary tumour obstruction or perforation, PCI score and CC score are valuable prognostic factors in the selection of patients with CPM for CRS + HIPEC.
Collapse
Affiliation(s)
- S Hallam
- Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK
| | - R Tyler
- Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK
| | - M Price
- Institute of Applied Health Research University of Birmingham Birmingham UK
| | - A Beggs
- Institute of Cancer and Genomic Sciences University of Birmingham Birmingham UK
| | - H Youssef
- Colorectal Surgery, Good Hope Hospital University Hospitals Birmingham NHS Foundation Trust Birmingham UK
| |
Collapse
|
|
50
|
Arjona-Sanchez A, Rodriguez-Ortiz L, Baratti D, Schneider MA, Gutiérrez-Calvo A, García-Fadrique A, Tuynman JB, Cascales-Campos PA, Martín VC, Morales R, Salti GI, Arteaga X, Pacheco D, Alonso-Gomez J, Yalkin O, Villarejo-Campos P, Sanchez-Hidalgo JM, Casado-Adam A, Cosano-Alvarez A, Rufian-Peña S, Briceño J. RAS Mutation Decreases Overall Survival After Optimal Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy of Colorectal Peritoneal Metastasis: A Modification Proposal of the Peritoneal Surface Disease Severity Score. Ann Surg Oncol 2019; 26:2595-2604. [PMID: 31111351 DOI: 10.1245/s10434-019-07378-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Indexed: 11/18/2022]
Abstract
BACKGROUND Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are currently the most accepted treatment for peritoneal metastases from colorectal cancer. Restrictive selection criteria are essential to obtain the best survival benefits for this complex procedure. The most widespread score for patient selection, the peritoneal surface disease severity score (PSDSS), does not include current biological factors that are known to influence on prognosis. We investigated the impact of including RAS mutational status in the selection criteria for these patients. METHODS We studied the risk factors for survival by multivariate analysis using a prospective database of consecutive patients with carcinomatosis from colorectal origin treated by CRS and HIPEC in our unit from 2009 to 2017. The risk factors obtained were validated in a multicentre, international cohort, including a total of 520 patients from 15 different reference units. RESULTS A total of 77 patients were selected for local análisis. Only RAS mutational status (HR: 2.024; p = 0.045) and PSDSS stage (HR: 2.90; p = 0.009) were shown to be independent factors for overall survival. Early PSDSS stages I and II associated to RAS mutations impaired their overall survival with no significant differences with PSDSS stage III overall survival (p > 0.05). These results were supported by the international multicentre validation. CONCLUSIONS By including RAS mutational status, we propose an updated RAS-PSDSS score that outperforms PSDSS alone providing a quick and feasible preoperative assessment of the expected overall survival for patients with carcinomatosis from colorectal origin undergone to CRS + HIPEC.
Collapse
Affiliation(s)
- A Arjona-Sanchez
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain. .,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, University Hospital Reina Sofıa, Córdoba, Spain.
| | - L Rodriguez-Ortiz
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain
| | - D Baratti
- Peritoneal Surface Malignancy Program, Department of Surgery, Fondazione IRCCS Instituto Nazionale Tumori, Milan, Italy
| | - M A Schneider
- Department of Surgery and Transplantation, University Hospital of Zurich, Zurich, Switzerland
| | - A Gutiérrez-Calvo
- Surgery Department, Unit of Peritoneal Oncologic Surgery, Hospital Príncipe de Asturias, Alcalá de Henares, Madrid, Spain
| | - A García-Fadrique
- Department of Surgery, Instituto Valenciano de Oncología, Valencia, Spain
| | - J B Tuynman
- Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
| | - P A Cascales-Campos
- Departamento De Cirugía General, Unidad De Cirugía De La Carcinomatosis Peritoneal, Virgen De La Arrixaca University Hospital, Murcia, Spain
| | - V Concepción Martín
- Unit of Peritoneal Oncologic Surgery and Colorectal Surgery, Hospital University Nuestra Señora de la Candelaria, Tenerife, Spain
| | - R Morales
- Unit of Oncologic and Pancreatic Surgery, Hospital Son Spaces, Palma de Mallorca, Spain
| | - G I Salti
- Division of Surgical Oncology, The University of Illinois at Chicago Hospital and Health Sciences System, Chicago, IL, USA
| | - X Arteaga
- Department of Surgery, Donostia Hospital, San Sebastián, Spain
| | - D Pacheco
- Gastroenterology Service, Liver Transplantation Unit, Rio Hortega Hospital, Valladolid, Spain
| | - J Alonso-Gomez
- Department of Surgery, H.U. Gran Canaria Dr. Negrín, Canarias, Spain
| | - O Yalkin
- Department of Surgical Oncology, Ankara University Faculty of Medicine, Ankara, Turkey
| | - P Villarejo-Campos
- Department of Surgical Oncology, University Hospital Ciudad Real, Ciudad Real, Spain
| | - J M Sanchez-Hidalgo
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, University Hospital Reina Sofıa, Córdoba, Spain
| | - A Casado-Adam
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, University Hospital Reina Sofıa, Córdoba, Spain
| | - A Cosano-Alvarez
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain
| | - S Rufian-Peña
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, University Hospital Reina Sofıa, Córdoba, Spain
| | - J Briceño
- Oncologic and Pancreatic Surgery Unit, University Hospital Reina Sofıa, Córdoba, Spain.,Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, University Hospital Reina Sofıa, Córdoba, Spain
| |
Collapse
|