Murine Models of Intraperitoneal Perfusion for Disseminated Colorectal Cancer.

BACKGROUND: Reproduction of the perfusion used in therapy (hyperthermic intraperitoneal chemotherapy) procedures preclinically represents a valuable asset for investigating new therapeutic agents that may improve patient outcomes. This article provides technical descriptions of our execution of closed and open "coliseum" abdominal perfusion techniques in a mouse model of peritoneal carcinomatosis of colorectal cancer. MATERIALS AND METHODS: BALB/c mice presenting with disseminated colorectal cancer (CT26-luciferin cells) underwent 30-min perfusions mimicking either the closed perfusion or the coliseum perfusion technique. Disease burden was monitored by bioluminescence signaling using an in vivo imaging system. Perfusion circuits consisted of single inflow lines with either a single or dual outflow line. RESULTS: Twelve mice presenting with disseminated disease underwent the closed perfusion technique. Surgical complications included perfusate leakage and organ constriction/suction into the outflow line(s). Nine mice underwent the coliseum perfusion technique with surgical debulking, using bipolar cauterization to remove tumors attached to the peritoneum. All mice survived the coliseum perfusion with limited intraoperative complications. CONCLUSIONS: Fewer intraoperative complications were experienced with our coliseum perfusion technique than the closed perfusion. The methods described here can be used as a guideline for developing future perfusion murine models for investigating perfusion models useful for delivery of chemotherapy or other tumor-sensitization agents, including selective targeted agents, nanoparticles, and heat.

Hyperthermic isolated limb perfusion. The switch from Steinmann pins to Omni-tract assisted isolation.

BACKGROUND: Hyperthermic isolated limb perfusion (HILP) represents an alternative to amputation for patients with either in-transit melanoma or unresectable soft tissue sarcoma, entailing delivery of high-dose chemotherapy after isolation of the extremity, under hyperthermic conditions. Stabilization of the Esmarch elastic bandage is so far performed with the use of Steinmann pins. In this study, we presented our experience with HILP and demonstrated an alternative technique for limb isolation using an Omni-tract retractor instead of the traditional Steinmann pin, while comparing the two methods. METHODS: Forty patients, 28 with recurrent in-transit melanoma and 12 with locally advanced/recurrent sarcoma of the limbs, underwent HILP in a single institution and were included in the study. The Steinmann pin was applied in the first 23 cases, whereas the Omni-tract retractor was applied in the latter 17 patients. RESULTS: The median follow-up for the whole study group was 17.5 mo, whereas the overall response rate was 92.9% for melanoma and 75% for sarcoma patients. Both overall survival and local progression-free survival differed significantly between patients with complete response and those with partial response, stable disease or progressive disease. The use of the Omni-tract retractor was advantageous in every examined field, with the overall complication rate, duration of analgesic administration, and total opioid and paracetamol dose, being significantly less in the Omni-tract patient group. CONCLUSIONS: Although this study was not a randomized trial, we consider that the noninvasive application of the Omni-tract retractor will gain significant acceptance, by contributing to the reduction of HILP complications.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy with lobaplatin and docetaxel improves survival for patients with peritoneal carcinomatosis from abdominal and pelvic malignancies.

BACKGROUND: This work was to evaluate the perioperative safety and efficacy of cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) with lobaplatin and docetaxel in patients with peritoneal carcinomatosis (PC) from gastrointestinal and gynecological cancers. METHODS: Patients were treated by CRS + HIPEC with lobaplatin 50 mg/m(2) and docetaxel 60 mg/m(2) in 6000 mL of normal saline at 43 ± 0.5 °C for 60 min. Vital signs were recorded for 6 days after CRS + HIPEC procedures. Perioperative serious adverse events (SAE), hematological, hepatic, renal, and electrolytes parameters, the changes in serum tumor markers (TM) before and after operation, patient recovery, and overall survival (OS) were analyzed. RESULTS: One hundred consecutive PC patients underwent 105 CRS + HIPEC procedures and postoperative chemotherapy. The median CRS + HIPEC duration was 463 (range, 245-820) min, and the highest temperature and heart rate during six postoperative days were 38.6 °C (median 37.5 °C) and 124 bpm (median 100 bpm), respectively. The 30-day perioperative SAE occurred in 16 (15.2 %) and mortality occurred in 2 (1.9 %) patients. Most routine blood laboratory tests at 1 week after surgery turned normal. Among 82 cases with increased preoperative TM CEA, CA125, and CA199, 71 cases had TM levels reduced or turned normal. Median time to nasogastric tube removal was 5 (range, 3-23) days, to liquid food intake 6 (range, 4-24) days, and to abdominal suture removal 15 (range, 10-30) days. At the median follow-up of 19.7 (range, 7.5-89.2) months, the median OS was 24.2 (95 % CI, 15.0-33.4) months, and the 1-, 3-, and 5-year OS rates were 77.5, 32.5, and 19.8 %, respectively. Univariate analysis identified five independent prognostic factors on OS: the origin of PC, peritoneal cancer index, completeness of CRS, cycles of adjuvant chemotherapy, and SAE. CONCLUSIONS: CRS + HIPEC with lobaplatin and docetaxel to treat PC is a feasible procedure with acceptable safety and can prolong the survival in selected patients with PC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00454519.

[Experimental technology of chemoperfusion treatment for abdominal carcinomatosis in ovarian cancer].

An experimental technology of normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet has been elaborated to treat abdominal carcinomatosis in ovarian cancer. Antitumor effects of the treatment were evaluated for the duration of animal life. Normothermic intraperitoneal chemoperfusion and hyperthermic intraperitoneal chemoperfusion with cisplatin and dioxadet in comparison with the standard intraperitoneal administration significantly increased the median life expectancy by 75-92%. Hyperthermic intraperitoneal chemoperfusion with dioxadet demonstrated potentiation of antitumor effect of hyperthermia and dioxadet. Experimental technology is recommended for testing new drugs and methods of chemoperfusion for malignant tumors affecting the peritoneum.

Negative-balance isolated pelvic perfusion in patients with incurable symptomatic rectal cancer: results and drug dose correlation to adverse events.

BACKGROUND: Drug leakage and lack of a drug-removal system have prevented clinical application of isolated pelvic perfusion (IPP). These barriers were overcome with negative-balance IPP (NIPP) in experimental pig models. Here, a phase 1 clinical study of NIPP was performed in patients with incurable symptomatic rectal cancer. PURPOSE: To establish a safe regimen of high-dose regional chemotherapy with NIPP using cisplatin in patients with incurable rectal cancer. MATERIAL AND METHODS: Between June 2004 and January 2007, NIPP therapy was performed for 23 patients (11 women, 12 men; mean age, 58 years). NIPP was routinely performed twice over a 4-week interval. Dose-limiting toxicities (DLTs) were defined using a 5 + 3 design, and cisplatin doses were escalated from 170 mg/m(2), with a fixed 5-fluorouracil dose of 1000 mg/m(2). The grade of adverse events (AEs) at the first and second sessions of NIPP therapy, pharmacokinetics, and antitumor response were evaluated. RESULTS: No DLTs were observed during the first session of NIPP. However, at the second session, two patients experienced the DLT of neuropathy after administration of 200 mg/m(2) cisplatin. Therefore, 190 mg/m(2) cisplatin was indicated as the maximum tolerated dose (MTD). The plasma pelvic-to-systemic exposure ratio was 18.4 based on the maximum concentration and 19.0 based on the concentration-time curve. Solid tumor responses included complete response in two patients, partial response in five patients, stable disease in 15 patients, and progressive disease in one patient. CONCLUSION: NIPP may offer the safe delivery of high-dose regional chemotherapy (MTD of 190 mg/m(2) cisplatin) with negligible AEs and effective control of tumor growth in patients with incurable rectal cancer.

Closed hyperthermic intraperitoneal chemotherapy with open abdomen: a novel technique to reduce exposure of the surgical team to chemotherapy drugs.

BACKGROUND: Exposure of the surgical team to toxic drugs during hyperthermic intraperitoneal chemotherapy (HIPEC) remains a matter of great concern. During closed-abdomen HIPEC, operating room staff are not exposed to drugs, but the distribution of the heated liquid within the abdomen is not optimal. With open-abdomen HIPEC, the opposite is true. Although the open-abdomen method is potentially more effective, it has not become a standard procedure because of the risk of exposure of members of the team to drugs. METHODS: We present a new technique (closed HIPEC with open abdomen) which ensures protection against potentially contaminating exposure to liquids, vapours and aerosols, and allows permanent access to the whole abdominal cavity. Its principle is to extend the abdominal surgical wound upwards with a sort of "glove-box". The cutaneous edges of the laparotomy are stapled to a latex "wall expander". The expander is draped over a special L-section metal frame placed above the abdomen. A transparent cover containing a "hand-access" port, like those used in laparoscopic surgery, is fixed inside the frame. RESULTS: In 10 patients, this device proved to be hermetic for both liquids and vapours. Intra-abdominal temperature was maintained between 42 and 43 degrees C during most of the procedure. The whole abdominal cavity was accessible to the surgeon, allowing optimal exposure of all peritoneal surfaces. CONCLUSION: This technique allows optimal HIPEC, while limiting the potential toxic effects for the surgical, medical and paramedical teams.

Hyperthermic chemoperfusion for the treatment of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a uniformly fatal disease with a poor prognosis. Multimodality therapy, including macroscopic complete resection, chemotherapy and/or radiotherapy, has improved survival relative to historical controls, but local recurrence remains problematic. Novel strategies are needed to improve local control. Intracavitary chemotherapy (IC) can deliver higher doses of drug locally with less toxicity than corresponding systemic therapy. When combined with hyperthermia, there is also an increase in local drug absorption and cytotoxic effect. Several phase I and II clinical trials have shown IC to be safe and feasible. Our experience and technique of hyperthermic IC is described. The evolution of our experience has led to the use of pharmacologic renal cytoprotection, which has permitted the safe administration of higher doses of IC than previously described. Further trials are being performed with a multidrug combination following macroscopic complete resection.

Isolated lung perfusion for pulmonary metastases, a review and work in progress.

Pulmonary metastasectomy is a widely accepted treatment for many patients with pulmonary metastases from various solid tumors. Nevertheless, 5-year survival is disappointing, with rates of 25-40%, and many patients develop recurrences. Isolated lung perfusion (ILuP) is a promising new technique to deliver high-dose chemotherapy to the lungs, while minimising systemic toxicities. This procedure is technically safe and feasible; however, clinical value and efficacy remain unclear. The aim of this paper is to give a review of literature on ILuP in humans, and to describe the development of the perfusion procedure in our institute.

Limited survival in patients with carcinomatosis from foregut malignancies after cytoreduction and continuous hyperthermic peritoneal perfusion.

Peritoneal carcinomatosis is a frequent mode of metastasis in patients with gastric, duodenal, or pancreatic cancer. Survival in this setting is short and therapeutic options are limited. This analysis examines the outcomes of 18 patients treated with operative cytoreduction and continuous hyperthermic peritoneal perfusion. Eighteen patients (6 males and 12 females) with gastric (n = 9), pancreatic (n = 7), or duodenal (n = 2) cancer were treated on protocol. Patients underwent optimal cytoreduction (complete gross resection, 11; minimal residual disease, 7) and a 90-minute perfusion with cisplatin. Clinical parameters and tumor and treatment characteristics were analyzed. Survival curves were estimated using the Kaplan-Meier method. Procedures included gastrectomy (n = 8), pancreaticoduodenectomy (n = 3), and hemicolectomy (n = 2). After cytoreduction, patients had no evidence of residual disease (n = 11), fewer than 100 implants less than 5 mm (n = 1), more than 100 implants between 5-10 mm (n = 3), or multiple implants with greater than 1 cm (n = 3). Five patients received a postoperative intraperitoneal dwell with 5-fluorouracil and paclitaxel. There was one perioperative mortality, and complications occurred in 10 patients. The median progression-free survival was 8 months (mean, 10 months; range, 1-47 months) with a median overall survival of 8 months (mean, 18 months; range, 1-74 months). In this cohort, peritoneal perfusion with cisplatin used to treat foregut malignancies has a high incidence of complications and does not significantly alter the natural history of the disease. Investigation of novel therapeutic approaches should be considered.

Hemicolectomy with concomitant heated intraperitoneal chemotherapy: a case study.

The use of heated intraperitoneal chemotherapy is an emerging new adjunct in the treatment of adenocarcinoma of the colon. However, documentation regarding perfusion circuitry and techniques associated with this therapy remain largely undescribed. After consultation with the surgical service team, a custom designed circuit was constructed for this procedure. Institutional approval and informed consent were obtained for surgical debulking and heated intraperitoneal chemotherapy for a 58-year old female. After surgical resection, a right hemicolectomy was performed and pathological specimens obtained. A modified custom circuit using a roller pump was first primed with 3 liters of Dianeal PD-2 and recirculated until temperature of 41 degrees C was obtained. The circuit was then connected to the patient for infusion of perfusate via Blake drains placed in the deep pelvis. Two additional drains were placed in the subdiaphragmatic space for return. Perfusate containing 30 mg of Mitomycin-C was circulated at 600-800 mL/min for 60 min at 41 degrees C. An additional 10 mg of Mitomycin-C was then administered through the circuit for an additional hour under similar conditions. Upon completion, a washout procedure was performed with 2 additional liters of Dianeal PD-2. The patient tolerated the procedure well and was discharged postoperative day 7. We describe the successful use of a perfusion-administered heated intraperitoneal chemotherapy regimen as an integral part of successful treatment of adenocarcinoma of the colon.

[The Czech experience in peritonectomy and hyperthermic perioperative cytostatic lavage in the treatment of peritoneal malignancy]. / Die tschechische Erfahrung mit der Peritonektomie und hyperthermen perioperativen Zytostatikalavage in der Behandlung der Peritonealkarzinose.

UNLABELLED: Peritoneal tumor dissemination has been considered as an incurable condition with fatal outcome. However cytoreductive surgery followed immediately by hyperthermic chemoperfusion has been described both for the treatment and prevention of locoregional cancer spread from various origins. This paper summarizes our experience in this field. PATIENTS AND METHODS: 28 patients were operated on for peritoneal dissemination of malignant tumors between 1999 and 2002 in the Surgical Department of the University Hospital Bulovka. Total or limited peritonectomy was carried out in these patients. In addition intraperitoneal perioperative hyperthermic chemoperfusion was performed using an electrolyte solution containing Mitomycin C, Cisplatin or Carboplatin. The perfusion was performed for 90 minutes, reaching a real hyperthermia of 41 to 43 degrees C. RESULTS: The overall morbidity was high (85.7%), the perioperative mortality (30 days) was 10.7%. Only 3 (15.7%) of 19 patients in whom complete peritonectomy could be carried out died during the follow-up period of 3 months to 3.5 years. CONCLUSION: There is an increasing evidence of both experimental and clinical studies showing the therapeutic and prophylactic usefulness of peritonectomy and perioperative hyperthermic chemoperfusion in patients with peritoneal carcinomatosis. However, well designed randomised trials are necessary to establish the role of this promising technique.

[Laboratory investigation of flow characteristics during intraperitoneal hyperthermic perfusion chemotherapy]. / Laboratoryjne badania dynamiki przeplywu jako element dootrzewnowej perfuzyjnej chemioterapii w hipertermii.

OBJECTIVES: Intraperitoneal hyperthermic perfusion chemotherapy (IPCH) is a complex method used for the treatment of the ovarian cancer. During the procedure, chemotherapeutic agent is administrated into the peritoneal cavity using continuous perfusion and hyperthermic conditions. DESIGN: This experiment was performed to simulate the main features of IPCH and to determine the hydrodynamic characteristics of this method in the laboratory conditions. MATERIALS AND METHODS: The model was made in a natural scale, regarding the anatomical proportions. In order to establish the dispersive properties of the model we determined the distribution of the tracer as a function of the drains' location and intensity of flow. RESULTS AND CONCLUSIONS: The important practical conclusion of the study is that the most advantageous variant is 'slanted' location of inflow and outflow drains. It is also possible to confirm that the hydrodynamic features applied during IPCH enable adequate drug distribution in the peritoneal cavity. The employed location of drains could be reconsider including the possibility of introducing cyclic flow direction alteration (increasing the dispersive properties of the system). We would like thank the Department of Cardiacthoracic Surgery, Rigshospitalet, Copenhagen, Denmark for lending the peristaltic pump.

Isolated limb perfusion: a literature review.

Through patient education, biological research, and technological advances, the rate of many cancers in the United States of America is declining. However, the incidence of melanoma is rising steadily, as are the efforts and resources allocated to its treatment. Isolated limb perfusion, ILP, is a standard of care for treating recurrent malignant melanoma confined to a limb. Although an extracorporeal procedure, only a small percentage of perfusionists are experienced regarding ILP's indications and performance techniques. Use of ILP may increase as the incidence of melanoma increases. This two-part review is designed to familiarize the perfusionist with the procedure and the disease it treats. Part I reviews the history of isolated limb perfusion, the diagnosis and classification of malignant melanoma, and the applicability of ILP in its treatment. Part II details a procedural overview and technical considerations of the therapy from the perfusionist perspective. The review concludes with patient selection, outcomes, and the future of ILP as well as other applications for the hyperthermic regional delivery of chemotherapy using extracorporeal technology.

Isolation perfusion of the liver.

Thousands of patients die annually from unresectable metastatic or primary hepatic cancers confined to liver. Isolated hepatic perfusion (IHP) is a regional treatment strategy in which the vascular supply to the liver is isolated and perfused with a therapeutic regimen using an extracorporeal circuit consisting of a reservoir, heat exchanger, and oxygenator. Drug doses that would cause severe toxicities if delivered systemically can be confined to the liver by isolated hepatic perfusion, resulting in the ability to intensify treatment to the cancer-burdened region of the body. Agents and mechanisms commonly used in IHP include melphaIan, hyperthermia, and tumor necrosis factor. IHP appears to be efficacious for patients with advanced disease, as reflected by large tumor size, high number of lesions, or significant overall tumor burden in the liver. In addition, responses are observed for patients whose cancer is refractory to systemic and hepatic arterial infusion chemotherapy. Recent clinical trials have demonstrated that IHP has anti-tumor efficacy against primary hepatic neoplasms and metastases from various primary tumors, such as colorectal carcinoma, ocular melanoma, and neuroendocrine tumors. Current studies demonstrate that combining hepatic arterial infusion with floxuridine after IHP for patients with colorectal cancer metastases is associated with significant and durable response rates. Continued clinical evaluation is warranted for the use of IHP in the treatment of unresectable liver metastases.

Circuit and protocol for hypoxic hyperthermic isolated limb perfusion to treat malignant melanoma.

In the treatment of cancer, isolated limb perfusion (ILP) allows what would be a lethal systemic dose of cytotoxic drugs to be administered directly to a tumour site of an extremity. Unfortunately, ILP is a complex, expensive, time-consuming treatment that requires general anaesthesia, vascular surgery and expertise with extracorporeal circuits that may not be available outside a cardiac centre. By streamlining the traditional ILP protocols and eliminating the oxygenator from the circuit, an equally safe and effective technique of hypoxic hyperthermic isolated limb perfusion has been developed.

A porcine model for investigation of hyperthermic isolated liver perfusion.

Our study was aimed at developing a reliable method of hyperthermic isolated liver perfusion (HILP) in pigs and at assessing its local and systemic side effects. HILP was performed via the hepatic artery and portal vein in 15 animals. The perfusate consisted of blood (200 ml), oxypolygelatine (500 ml), Ringer's solution (1000 ml), and trapped intrahepatic blood. HILP was carried out for 45 min at a mean perfusate inflow temperature of 41.2 degrees C. The mean portal flow and pressure were adjusted to 500 ml/min and 20-25 mm Hg; the mean arterial flow and pressure were 130 ml/min and 40-60 mm Hg, respectively. After 20 min of perfusion the mean temperature in the right and the left liver lobe were 40.8 degrees C and 40.3 degrees C and remained almost constant over the whole perfusion period. Liver enzymes (alanine aminotransferase and aspartate aminotransferase) and serum lactate levels showed slight increases after perfusion but normalized within 1 week. Histology of liver parenchyma showed only mild pathological changes, which were also reversible within 7 days. The presented method of HILP is a safe and reproducible technique for isolated hyperthermic liver perfusion. Based on this animal model, experimental HILP with different chemotherapeutic agents can be investigated in order to assess hepatic and systemic toxicity of this therapy.

Continuous hyperthermic peritoneal perfusion for peritoneal dissemination of gastric cancer.

BACKGROUND/AIMS: We investigated the histological and clinical effectiveness of continuous hyperthermic peritoneal perfusion (CHPP) for treating peritoneal dissemination (therapeutic CHPP) and for the prevention of peritoneal recurrence (prophylactic CHPP). METHODOLOGY: In 5 patients with gastric cancer and peritoneal dissemination, the apoptosis index of the cancer cells on in situ end-labeling for detection of apoptotic cells was 3.0+/-1.2% before CHPP, and had increased to 52.9+/-8.3% after CHPP. The survival curve of the therapeutic CHPP group was significantly better than that of the control group. The therapeutic CHPP group was classified as miliary type or nodular type. The survival curve in the miliary type was significantly better than that in the nodular type. RESULTS: In prophylactic CHPP, there was no improvement in prognosis, but a prophylactic effect against peritoneal recurrence was demonstrated in the patients who were n4 negative when the mean intraperitoneal temperature during CHPP (MIT) was maintained above 42 degrees C. CONCLUSIONS: These results indicated that an improved prognosis can be expected after therapeutic CHPP in patients with peritoneal spread. The beneficial effects are especially marked in patients with the miliary type. Moreover, prophylactic CHPP exerts a prophylactic effect against peritoneal recurrence in patients with n4 negative, providing that the MIT can be maintained above 42 degrees C.

[Intraoperative (hyperthermic) intraperitoneal chemotherapy--considerations and aspects of safe intra- and postoperative treatment with cytostatic drugs]. / Intraoperative (hypertherme) intraperitoneale Chemotherapie-Uberlegungen und Aspekte zum sicheren intra- und postoperativen Umgang mit Zytostatika.

The application of open intraoperative intraperitoneal chemotherapy following cytoreductive surgery for the treatment of pseudomyxoma peritonei or peritoneal carcinomatosis requires safety precautions for the medical and non-medical personnel. In agreement with already existing rules, precautions were established which result in an optimum of safety. These concern the preparation of the cytostatic drugs, the application in the operating room as well as personal precautions intra- and postoperatively. After the establishment of theses recommendations, 22 patients were treated with open intraperitoneal chemotherapy in 1.5 years without any severe accidents. Therefore, a safe intraoperative use of cytotoxic drugs is possible. At the moment, the indication for such an approach may be given in peritoneal carcinomatosis from appendix, colon or ovarian cancer. In the future, an adjuvant application in other gastrointestinal malignancies (e.g. T3/T4 gastric carcinoma) may be considered.

Hyperthermic isolated limb perfusion with cis-diamminedichloro-platinum. II. An experimental study in dogs with a balloon-occlusion technique for repeated high-dose treatment.

Isolated organ perfusion is attractive for regional high-dose chemotherapy because of its advantage to reduce whole body toxicity. Intraoperative hyperthermic isolated perfusion procedures involving a heart-lung machine have been developed, but repeated treatments carry a high risk of vessel and tissue damage. Therefore, a study of isolated hyperthermic limb perfusion in four dogs was conducted using a balloon-occlusion technique including a hyperthermia unit, two low-flow rotary pumps, a bubble oxygenator, and two polyurethane balloon catheters. After 15 min infusion of cisplatinum the concentrations of serum platinum (Pt) in the isolated limb and in the whole body were measured by atomic absorption spectroscopy. Regional exposure to Pt was more than 10-fold higher than systemic exposure. After 60 min isolated limb perfusion, the area under the curve (AUC) of Pt concentrations in the isolated limb showed values between 767.4 and 1055.6 micrograms/l x 60 min, whereas in the whole body values between 59.8 and 75.9 micrograms/l x 60 min were obtained. Repeated isolated limb perfusions with the balloon-occlusion technique were performed in three dogs without systemic side effects. This model of regional chemotherapy may be useful for preoperative chemotherapy in malignant tumors of the limbs.