Goal-directed therapy in cytoreductive surgery with hyperthermic intraperitoneal chemotherapy: a prospective observational study.

BACKGROUND: Cytoreductive surgery (CRS) with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in peritoneal carcinomatosis treatment causes significant hemodynamic, metabolic, and hematological alterations. Studies on the anesthetic intraoperative management are heterogeneous and scarce. There is a great heterogeneity in the anesthetic management of CRS and HIPEC. The aim of this study is to analyze perioperative hemodynamic goal-directed management and to evaluate the complications arisen until the seventh postoperative day. METHODS: Prospective, observational study of all CRS and HIPEC patients from March 2014 to May 2017. Hemodynamic and clinical parameters were registered during surgery and the first 3 postoperative days. We correlated intraoperative data with the postoperative course until the seventh day. RESULTS: A total of 92 patients were included in the study (age 58.5 ± 10.9 years, 47% colorectal carcinoma, and 38% ovarian carcinoma). Peritoneal Carcinomatosis Index (PCI) (median and ranges) was 10 [0-39]. Cardiac Index (CI) 3.15 l/min-1/m-2 [1.79-5.60]) and Systolic Volume Variation (SVV) (10% [3%-17%]) remained within the values of normality in all surgery phases. A large difference was observed between the minimum and maximum ranges of fluid therapy administered (median 9.8 ml/kg/h [5.3-24.3]), showing a great interindividual variation in the fluids requirement. A direct relationship was observed between PCI and surgery duration, fluid therapy, and intraoperative transfusion percentage (p < 0.02). CONCLUSIONS: There is a great variability in the intraoperative fluid therapy needs of the patients. SVV monitoring makes it possible to adjust the fluid therapy needs in each surgery phase. The use of a hemodynamic goal-directed anesthetic protocol in CRS and HIPEC enables to individually adjust the fluid therapy, avoiding over-hydration and ensuring hemodynamic stability in all surgery phases.

Peritoneal carcinomatosis arising from rectal or colonic adenocarcinoma treated with cytoreductive surgery (CRS) hyperthermic intraperitoneal chemotherapy (HIPEC): two different diseases.

PURPOSE: Peritoneal carcinomatosis (PC) from colorectal cancer (CRC) has poor survival. Multi-modal treatment including systemic chemotherapy, cytoreductive surgery (CRS), and hyperthermic intraperitoneal chemotherapy (HIPEC) can be used in selected patients with curative intent. The majority published works consider PC of CRC origin as a homogenous disease. Aim of this study is to stress the different biological behaviors and survival of PC according to colonic or rectal origin. METHODS: Data of CRS and HIPEC procedures for PC of CRC origin performed at MD Anderson Cancer Center-Madrid (Spain) have been collected, dividing patients into two groups according to colonic or rectal PC. Clinical, operatory, and postoperatory variables of the two groups have been analyzed to compare survival-related rates and PC origin. RESULTS: In the years 2004-2015, 114 procedures of CRS followed by HIPEC for peritoneal metastasis of different origin have been performed; of these, 36 procedures were for colorectal PC (31 patients in colonic and 5 in rectal group). Two groups are homogenous after analysis of clinical, operatory, and follow-up data. Median survival (OS) is significantly higher in colonic compared to rectal group (47.83 vs. 22.0 months, p 0.008). 3- and 5-year survival rate is 74 and 50% in colonic group vs. 20 and 0% in rectal group. CONCLUSION: Rectal origin PC has a more aggressive behavior compared to colonic origin, reflecting in a worst prognosis of patients affected by rectal origin PC. According to our data and literature, indications of multi-modal treatment including CRS and HIPEC should be more restrictive for rectal cancer PC. Authors should differentiate colonic and rectal origin of PC when reporting cases in the literature.

Neoadjuvant intraperitoneal chemotherapy followed by radical surgery and HIPEC in patients with very advanced gastric cancer and peritoneal metastases: report of an initial experience in a western single center.

BACKGROUND: The association of preoperative systemic and intraperitoneal chemotherapy has been described in Eastern patients with very good outcomes in treatment responders. The aim of this paper is to describe the initial results of this multidisciplinary regimen in gastric cancer patients with very advanced peritoneal metastases. CASE PRESENTATION: We present here the first four cases who received the treatment protocol. They had a baseline PCI between 19 and 33. Two patients had received systemic chemotherapy prior to this regimen. Three of them had significant response and were taken to cytoreductive surgery, while one patient who had 12 cycles of chemotherapy previously showed signs of disease progression and subsequently died. There was no significant postoperative morbidity, and three patients remain alive, two of them with no signs of recurrence. CONCLUSION: Systemic and intraperitoneal chemotherapy led to a marked response in peritoneal disease extent in our initial experience and allowed three of four patients with very advanced disease to be treated with cytoreductive surgery.

Isolated limb infusion with hyperthermia and chemotherapy for advanced limb malignancy: factors influencing toxicity.

BACKGROUND: The isolated limb infusion (ILI) technique is a simpler and less invasive alternative to isolated limb perfusion, which allows regional administration of high-dose chemotherapy to patients with advanced melanoma and other malignancies restricted to a limb. METHODS: Patients from two institutions, treated by ILI between 1998 and 2009 for extensive disease restricted to a limb, were included. The cohort included 31 patients with melanoma who presented with in-transit metastases or an extensive primary lesion, one patient with squamous cell carcinoma and another with epithelioid sarcoma not suitable for local surgical treatment. RESULTS: A complete response was achieved in 26.3% of patients and a partial response in 52.6%. Toxicity was assessed according to the Wieberdink limb toxicity scale. Grade II toxicity was noted in 39.5% of patients, grade III in 50% and grade IV in 10.5%. Toxicity was correlated with the results of a number of clinical and laboratory tests. The toxicity of melphalan and actinomycin D was dose-dependent. For melphalan, the relationship between toxicity and mean dose was as follows: grade II--34.7 mg; grades III and IV--47.5 mg (P = 0.012). The relationship between toxicity and maximum serum creatine phosphokinase (CPK) was as follows: grade II--431.5 U/L; grades III and IV--3228 U/L (P = 0.010). CONCLUSION: Toxicity after ILI is dose-dependent and serum CPK correlates with toxicity.

Outcome analysis of a decade-long experience of isolated hepatic perfusion for unresectable liver metastases at a single institution.

OBJECTIVE: To evaluate outcomes of isolated hepatic perfusion (IHP) on isolated liver metastases (LMs). BACKGROUND: Isolated unresectable LMs are often the main determinant of overall survival (OS) for colorectal cancer (CRC) and other solid malignancies. We hypothesized that IHP can be performed safely and yield impressive responses for a variety of solid tumor pathology, using different perfusion agents. METHODS: Retrospective review of a prospectively collected database of patients undergoing IHP for unresectable solid tumor LM. RESULTS: Between 2003 and 2012, IHP was completed in 91 patients. Primary tumor pathology was CRC = 54, non-CRC = 37 (ocular/cutaneous melanoma = 32, cholangiocarcinoma = 3, appendiceal = 1, and breast = 1). IHP employed Melphalan (n = 69) (CRC = 32, non-CRC = 37), Oxaliplatin (n = 10) (CRC), or Oxaliplatin + 5FU (n = 12) (CRC). Hepatic arterial infusion (HAI) pumps were placed in all CRC patients. There were 3(3.3%) perioperative deaths. Response rates for CRC, melanoma, and cholangiocarcinoma were 68.2%, 57.1%, and 100% respectively. Response rates for CRC patients using 5FU + Oxaliplatin, Oxaliplatin, or Melphalan were 83.3%, 66.7%, and 60.9%, respectively. Median OS for the CRC patients (from IHP date) was 23 months (95% confidence interval: 15-28 months). On univariate analysis, receipt of HAI-FUDR (floxuridine) within 1 year of IHP was the only factor associated with improved OS (P = 0.043) in CRC patients. CONCLUSIONS: IHP results in excellent response rates for patients with unresectable liver metastasis from solid tumors. Improved local control for CRC patients undergoing IHP-HAI may improve survival.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis: initial experience in Oaxaca, Mexico.

Peritoneal carcinomatosis (PC) has been traditionally considered a terminal disease with median survivals reported in the literature of 6 to 12 months. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) are playing an ever increasing role in the treatment of these patients. Excellent results have been achieved in well-selected patients but there is a very steep learning curve when starting a new program. A program for peritoneal surface malignancies in which patients with PC of gastrointestinal or gynecological origin were treated using multimodality therapy with combinations of systemic therapy, cytoreductive surgery (CRS), and HIPEC was initiated in December 2007 at "Hospital Regional de Alta Especialidad de Oaxaca," Mexico. We present the results of our initial experience. From December 2007 to February 2011, 26 patients were treated with CRS and HIPEC. There were 21 female patients. Most common indication (46%) was recurrent ovarian cancer. Mean duration of surgery was 260 minutes. Mean Peritoneal Cancer Index was 9. Twenty-three (88.5%) patients had a complete cytoreduction. Major morbidity and mortality rates were 19.5 and 3.8 per cent, respectively. Mean hospital stay was 8 days. At a mean follow-up of 20 months, median survival has not been reached. Rigorous preoperative workup, strict selection criteria, and mentoring from an experienced cytoreductive surgeon are mandatory and extremely important when starting a center for PC.

Isolated limb perfusion with hyperthermia and chemotherapy: predictive factors for regional toxicity.

OBJECTIVE: Isolated limb perfusion combined with melphalan is an accepted treatment for obtaining locoregional control in advanced melanoma of the extremities and other malignant neoplasias restricted to the limb. This study aims to examine the factors associated with toxicity caused by the regional method. We considered the technical aspects of severe complications associated with the procedure in an attempt to diminish the patient morbidity that occurs during the learning curve. METHODS: We conducted a retrospective analysis of the records of patients who underwent perfusion at the AC Camargo Hospital in São Paulo, Brazil between January 2000 and January 2009. The Wieberdink scale was applied to classify local toxicity and its relation to clinical and laboratory variables. RESULTS: Fifty-eight perfusions were performed in 55 patients. Most patients (86.2%) presented a toxicity level between I and III. Grade V toxicity was seen in five cases (8.6%), four of which occurred in the first 2 years. Creatine phosphokinase, an important predictive factor for toxicity, had an average value of 231.8 for toxicity grades I-III and 1286.2 for toxicity grades IV-V (p = 0.001). There was a relationship between the melphalan dose and toxicity, which was 77 mg (25 to 130 mg) for toxicity grades I-II and 93.5 mg (45 to 120 mg) for toxicity grades IV-V (p = 0.0204). CONCLUSION: It is possible to prevent the toxicity associated with melphalan by adjusting the dose according to the patient's body weight (especially for women and obese patients) and the creatine phosphokinase values in the postoperative period.

Carcinoma inflamatório de mama em cadela: caracterização da resposta inflamatória, achados clínicos e anatomo-histopatológicos

Os tumores mamários são as neoplasias mais frequentes na cadela. Uma forma considerada rara e extremamente agressiva desta doença é o carcinoma inflamatório de mama (CIM). Este tipo tumoral apresenta evolução hiper aguda, elevada capacidade de metástase e por vezes pode cursar em alterações hemostáticas, sendo a sobrevida inferior a 100 dias. Foram realizados dois experimentos distintos utilizando cadelas carcinoma mamários, com os objetivos de: 1) caracterizar, por citometria de fluxo, a resposta inflamatória associada ao tumor, realizar a imunofenotipagem dos leucócitos no sangue periférico e mensurar quimiocinas e citocinas no soro e comparar este perfil, nas cadelas portadoras de CIM e de carcinoma não inflamatórios de mama (CINM); 2) descrever as alterações clínicas e anatomo-histopatológicas, avaliando as prováveis causas mortis das pacientes com CIM e os efeitos da quimioterapia na sobrevida. A partir da avaliação clínica dos 50 animais e histopatológica dos tumores foram constituidos três grupos: carcinomas em tumores mistos (CATMB=12) carcinomas (CA=13) e carcinomas inflamatórios de mama (CIM= 25) os quais foram submetidos análise morfométrica das células inflamatórias, avaliação clínico-patológica sistemática, além da determinação da taxa de sobrevida das cadelas. Além disso, foram avaliadas características clínicas e histopatológicas de 26 cadelas com CIM, sendo realizada necropsia em 14 destas. A partir da caracterização clínica e anatomo-patológica observou-se comportamento agressivo, por vezes cursando com coagulação intravascular disseminada (CID) e baixa sobrevida, sendo esta significativamente maior nos pacientes tratados com quimioterapia antineoplásica. A resposta inflamatória foi significativamente maior no grupo CIM, sendo o linfócito o tipo celular predominante independente do grupo, com intensidade inversamente correlacionada a sobrevida[...]

Isolated limb perfusion with hyperthermia and chemotherapy: predictive factors for regional toxicity

OBJECTIVE: Isolated limb perfusion combined with melphalan is an accepted treatment for obtaining locoregional control in advanced melanoma of the extremities and other malignant neoplasias restricted to the limb. This study aims to examine the factors associated with toxicity caused by the regional method. We considered the technical aspects of severe complications associated with the procedure in an attempt to diminish the patient morbidity that occurs during the learning curve. METHODS: We conducted a retrospective analysis of the records of patients who underwent perfusion at the AC Camargo Hospital in São Paulo, Brazil between January 2000 and January 2009. The Wieberdink scale was applied to classify local toxicity and its relation to clinical and laboratory variables. RESULTS: Fifty-eight perfusions were performed in 55 patients. Most patients (86.2%) presented a toxicity level between I and III. Grade V toxicity was seen in five cases (8.6%), four of which occurred in the first 2 years. Creatine phosphokinase, an important predictive factor for toxicity, had an average value of 231.8 for toxicity grades I-III and 1286.2 for toxicity grades IV-V (p = 0.001). There was a relationship between the melphalan dose and toxicity, which was 77 mg (25 to 130 mg) for toxicity grades I-II and 93.5 mg (45 to 120 mg) for toxicity grades IV-V (p = 0.0204). CONCLUSION: It is possible to prevent the toxicity associated with melphalan by adjusting the dose according to the patient's body weight (especially for women and obese patients) and the creatine phosphokinase values in the postoperative period.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignant disease.

Peritoneal Malignant Disease (PMD) is the presence of tumoral tissue on the peritoneal surface from primary tumors or tumors from other locations (e.g. digestive or gynecologic). It is a regional disease with poor prognosis when treated with repeated "debulking" and traditional systemic chemotherapy. Cytoreduction plus hyperthermic intraperitoneal chemotherapy (HIPEC) is a combined multimodal regional procedure aimed at reducing the macroscopic tumoral mass as much as possible and treating with chemotherapy the microscopic disease that is out of the scope of the surgeon. This combined treatment may change the natural history of PMD, it is translated into a higher overall survival and cancer-free survival and it offers the option of cure in selected cases. The high-complexity procedure is also associated with complications and mortality, but in similar rates as other major oncologic procedures.

Carcinomatosis peritoneal de origen colorrectal. Cirugía citorreductora y quimioterapia hipertérmica intraperitoneal / Colorectal peritoneal carcinomatosis: citoreductive surgery and hyperthermic intraperitoneal chemotherapy

Antecedentes: El pronóstico de los pacientes con carcinomatosis peritoneal de origen colorrectal es pobre. Tradicionalmente, para su tratamiento se utilizó la quimioterapia sistémica mientras que la cirugía estuvo reservada al tratamiento de las complicaciones. Objetivo: Establecer el estado actual de la cirugía citorreductora y la quimioterapia hipertérmica y valorar sus alcances en parámetros objetivos de acuerdo con la bibliografía. Material y Métodos: Se utilizaron para la búsqueda todos los artículos publicados acerca del tema en inglés y francés entre los años 1990 y 2008 en las bases de datos de PubMed de la Biblioteca Nacional de Medicina de los EEUU. Resultados: La cirugía citorreductora actúa sobre las masas neoplásicas macroscópicas, mientras que la quimioterapia hipertérmica intraperitoneal (QTHIP) es útil para tratar la enfermedad residual microscópica. La asociación entre ambas se debe a que la primera intenta resecar todo el tumor visible o, en su defecto, hasta 2 mm de espesor, a fin de permitir la acción de las drogas quimioterápicas, que pueden penetrar esa distancia como máximo en los tejidos tumorales. Los pacientes con un aceptable estado clínico (“performance status”), sin diseminación extraabdominal, con metástasis ganglionares y/o hepáticas resecables, baja carga de enfermedad peritoneal y potencialmente pasibles de una citorreducción completa, se considerarían para este tratamiento combinado. Los factores predictivos más utilizados en la actualidad lo constituyen el Índice de Cáncer Peritoneal (ICP) y la Citorreducción Completa. La mayoría de los autores coincide en admitir que los beneficios de la cirugía citorreductora (CC) más la QTHIP dependen principalmente de la capacidad de la cirugía de alcanzar una resección completa. La quimioterapia intraperitoneal no ha podido, por sí sola, tratar grandes volúmenes de carcinomatosis: solamente se han reportado tratamientos exitosos con el tratamiento combinado...

Background: Colorectal peritoneal carcinomatosis leads to a poor prognosis. Traditionally, its treatment has consisted in systemic chemotherapy, whereas surgery has been reserved to the management of complications. Objective: To establish the current state of cytoreductive surgery (CRS) and hyperthermic chemotherapy (HIPEC), and to assess their implications with objective parameters according to literature. Material and Methods: All papers published in english and french about the subject between 1990 and 2008 in the PubMed database were retrieved. Results: Cytoreductive surgery works over macroscopic neoplastic masses, as on microscopic residual disease HIPEC does. Their association is realted with their goals: the first one tries to resect all visible tumor or at least less than 2 mm, to allow chemoterapic drugs a deep penetration in tumoral tissues. Patients with an adequate performance status, with no extraabdominal spread, with resectable lymph nodes and/or hepatic metastasis, low burden of peritoneal disease and potentially fit for a complete cytoreduction, would be considered for this treatment. Nowadays, the most utilized predictive factors are constituted by the Peritoneal Cancer Index and Completeness of Cytoreduction. Most authors agree in the consideration that CRS plus HIPEC benefits depends mainly on the possibility of a complete surgical resection. Intraperitoneal chemotherapy could not, for its own, treat large tumoral masses: there are only reported successful treatments with the combined modality. At the same time, most papers prove that HIPEC combined with an optimum cytoreductive surgery cures about 25 per cent of the patients considered as unresectable. Benefits in survival related to this treatment are reached in spite of a high morbidity and mortality. The most severe complications are represented by anastomotic fistulas...

Zonation of alanine metabolism in the bivascularly perfused rat liver.

AIMS/BACKGROUND: Zonation of alanine metabolism was investigated in the bivascularly perfused rat liver, a technique in which a selective area of the periportal region can be reached via the hepatic artery. METHODS: Bivascular liver perfusion was done in both the antegrade and retrograde modes. Predominance of a given metabolic parameter in the periportal or perivenous area was deduced from comparisons of the changes caused by alanine infusion into the hepatic artery in antegrade and retrograde perfusion. RESULTS: Confirming previous notions, glutamine synthesis predominated in the perivenous area, however, the contribution of the periportal area was significant. Gluconeogenesis and the associated extra oxygen consumption were more pronounced in the periportal region. The capacity of urea synthesis in the periportal region was relatively small as indicated by the ratios of urea to glucose production, which were lower in this region. Ammonia in the periportal region was considerably above the mean ammonia production of whole the liver parenchyma. The overflows of pyruvate and lactate were considerably smaller in the periportal region. CONCLUSION: The distribution of alanine metabolism seems to reflect mainly zonation of the fates of the carbon skeleton (mainly gluconeogenesis). The production of glutamine in the periportal area is in agreement with recent reports about the presence of glutamine synthetase in Kupffer and endothelial cells.

Perfusión regional hipertérmica en el melanoma maligno de las extremidades, usando cis platinum y actinomicina D / Regional perfusion hypertermic malignant-melanoma of the extremities utilizing cis platinum and actinomycin D

Debido a la relativa refractariedad del melanoma a la quimioterapia citotóxica sistémica, nuevas formas de tratamiento se han ensayado continuamente a fin de mejorar la supervivencia y disminuir la tasa de recurrencias. En este artículo analizamos tres aspectos: a) La experiencia mundial sobre las diferentes formas de tratamiento del melanoma de las extremidades y, concluímos que, el mejor tratamiento de la lesión primaria consiste en realizar en el mismo acto operatorio: escisión local, vaciamiento ganglionar y perfusión hipertérmica regional. Si el melanoma es recurrente, la terapia ideal consiste en vaciamiento ganglionar (si éste no fue realizado anteriormente) más perfusión; b) Se describen las pautas para selecionar los pacientes que serán sometidos a este procedimiento y detalladamente la técnica de la perfusión, basándonos en la forma como lo describió Oscar Creech en 1958 y como lo planificamos conjuntamente con el Servicio de Cirugía Cardiovascular y Hematología y Oncología; c) Describimos la experiencia que hemos acumulado con este procedimiento practicado en dos pacientes que teníam melanoma en las extremidades inferiores, atendidos el Servicio de Cirugía IV del Hostal Universitario de Caracas. El primero, con melanoma recurrente, fue sometido a perfusión hipertérmica usando Cis-Platinum y Actinomicina D, con respuesta objetiva del 50 por ciento. El segundo caso es una paciente con melanoma primario en el talón izquierdo, a quien se le practicó, en el mismo acto operatorio, escisión local del primario, vaciamiento ganglionar ínguino-ilíaco perfusión hipertérmica del miembro inferior izquierdo usando Cis-Platinum y Actinomicina D. En este caso, se llegó a la desarticulación de la cadera izquierda por trombosis arterial y venosa de los vasos femorales, complicación atribuída a 2 hechos: 1. Anomalía anatómica de los vasos femorales comunes que estaban practicamente ausentes y 2. Falta de heparinización terapéutica en el post-operatorio