http://repub.eur.nl/res/aut/376/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/16563/ 2009-05-01T00:00:00Z Aim: Ocular melanoma prefers to metastasize to the liver and the liver is the sole site of metastatic disease in 80% of patients. Until now there has been no standard treatment available and these patients have a very poor prognosis (median survival 2-5 months). Isolated hepatic perfusion may be an option in patients with irresectable hepatic ocular melanoma metastases. The aim of this study was to evaluate applicability, toxicity and response in this selected group of ocular melanoma patients by treatment with isolated hypoxic hepatic perfusion with retrograde outflow (IHHP) with melphalan. Methods: From September 2002 until July 2006 eight consecutive patients were included in this study. IHHP was performed with inflow via the hepatic artery and retrograde outflow via the portal vein during 25 min with 1 mg/kg melphalan. The perfusion was followed by a complete wash-out procedure. Results: The median total operation time was 4 h with a median blood/fluid loss of 1100 ml. No postoperative mortality was observed. Median hospital stay was 9.5 days. Toxicity was moderate: WHO grade 3 leukocytopenia in 3 patients, grade 3 hepatic toxicity in 1 patient. In 37% of patients (3/8) a partial response could be demonstrated 3 months after IHHP. Stable disease was found in 3 patients and progressive disease in 2 patients. Median time to local progression was 6 months and the median survival was 11 months. Conclusion: Melphalan-based IHHP with retrograde outflow is a safe treatment option for patients with irresectable ocular melanoma metastases. Survival benefit seems to be comparable to classical IHHP. http://repub.eur.nl/res/pub/30052/ 2008-05-01T00:00:00Z Background: Isolated hepatic perfusion with high-dose chemotherapy is a treatment option for patients with irresectable metastases confined to the liver. Prolonged local control and impact on survival have been claimed. Major drawbacks are magnitude and costs of the procedure. We developed an isolated hypoxic hepatic perfusion (IHHP) with retrograde outflow without the need for a heart-lung machine. Patients and Methods: Twenty-four consecutive patients with irresectable metastases of various origins were treated. IHHP inflow was via the hepatic artery, outflow via the portal vein with occlusion of the retrohepatic caval vein. Radiolabeled albumine was used for leakage monitoring. Melphalan was used at 1-2 mg/kg. A 25-minute perfusion period was followed by a complete washout. Local and systemic melphalan concentrations were determined. Results: Compared with oxygenated classical IHP, the IHPP procedure reduced operation time from >8 h to 4 hours, blood loss from >4000 to 900 cc and saved material and personnel costs. Leakage was 0% with negligible systemic toxicity and 0% perioperative mortality. Tumor response: complete response (CR) in 4%, partial response (PR) in 58%, and stable disease (SD) in 13%. Median time to progression was 9 months (2-24 months); pharmacokinetics demonstrated intrahepatic melphalan concentrations more than 9 fold higher than postperfusion systemic concentrations. Conclusions: IHPP is a relatively simple procedure with reduced costs, reduced blood loss, no mortality, limited toxicity, and response rates comparable to classic IHP. The median duration of 9 months of tumor control should be improved. Hereto, vasoactive drugs, will be explored in further studies. http://repub.eur.nl/res/pub/36108/ 2007-04-01T00:00:00Z Histamine (Hi) combined to melphalan in a rat experimental model of isolated limb perfusion (ILP) for lower limb soft tissue sarcoma, resulted in overall response rates (OR) of 66%. Likewise, ILP with interleukin-2 (IL-2) resulted in OR of 67%, when combined to melphalan, in the same experimental model. In systemic immunotherapy, the combination of IL-2 and Hi has been used for solid tumor treatment based on immunomodulatory effects. In this study, we used our well-established ILP experimental model to evaluate whether the synergistic effect between the two drugs seen in the systemic setting, could further improve response rates in a loco-regional setting. Histological evaluation was done directly and 24 h after ILP. Melphalan uptake by tumor and muscle were measured. Hi and IL-2 together, combined to melphalan in the ILP led to OR of only 28%. Histology of tumors demonstrated partial loss of Hi-induced hemorrhagic effect when IL-2 was present. Melphalan accumulation in the tumor when both Hi and IL-2 were added (3.1-fold) was very similar to accumulation with Hi only (2.8-fold), or IL-2 only (3.5-fold) combined to melphalan. In vitro there was no synergy between the drugs. In conclusion there was a negative synergistic effect between IL-2 and Hi in the regional setting. http://repub.eur.nl/res/pub/36704/ 2007-02-01T00:00:00Z Background: Nonresectable primary and metastatic liver tumors remain an important clinical problem. Melphalan-based isolated hepatic perfusion (M-IHP) leads to more than 70% objective responses in selective groups of patients with nonresectable metastases confined to the liver. Complete responses are rare and progression-free survival is limited. Tumor necrosis factor (TNF), a very active agent in isolated limb perfusion, is linked to serious hepatotoxicity, restricting its use in IHP. Because of its vasoactive properties, histamine (Hi) is an alternative to TNF. In this article we evaluate its potential synergistic effect in M-IHP, improving response rates. Methods: Our experimental rat IHP model is used for the treatment of soft tissue sarcoma liver metastases. Blood samples are collected for monitoring liver enzymes. Livers are excised 72 h and 7 days after treatment for histologic evaluation. Results: After sham-IHP and Hi-IHP, tumor progression was observed in 100% of treated animals, while after M-IHP this number fell to 62% and after Hi + M-IHP it fell to only 22% (P = 0.006). Overall response rates were of 55% for Hi + M-IHP vs. 25% for M-IHP, and, more importantly, complete responses (CR) were observed only after Hi + M-IHP (22%) (P = 0.009). Hepatotoxicity peaked within 24 h after IHP, independent of the treatment administered, recovered in 48 h, and was related mainly to the elevation of transaminases (grade 3 ASAT and grade 1 ALAT for control group and grades 3 and 4, respectively, for all other treatments). No serious systemic toxicity was observed. Histology of the liver showed no serious damage. Conclusion: Hi + M-IHP has synergistic antitumor effects without any increase in regional or systemic toxicity. http://repub.eur.nl/res/pub/10500/ 2006-10-12T00:00:00Z Soft tissue sarcomas account for approximately 5000 new cases per year in Europe. 60% of them occur in the extremities and are often large at first diagnosis with a high propensity for hematogenic spread so that half of the patients die of disseminated disease. The use of aggressive approaches, such as amputation has no positive impact in survival rates, as compared to conservative approaches. In this sense, Isolated limb perfusion (ILP) plays a major role, consisting of the regional administration of high doses of drugs to an isolated limb. TNF/melphalan (TM-ILP) leads to overall response rates of circa 100% for melanoma patients and circa 70% for sarcoma patients, with a limb salvage index of approximately 75%. The mechanism of action of TNF is first a higher tumor drug uptake and secondarily the destruction of the tumor associated vasculature (TAV). Based on this success, there was a renewed interest in organ perfusion, unfortunately, the use of TNF in t! hese settings remains controversial with lack of confirmatory positive or synergistic responses in lung perfusion and with unacceptable hepatotoxicity in liver perfusion. In the Experimental Surgical Oncology experimental rat models of ILP and Isolated Hepatic Perfusion (IHP) were developed for a better understanding of the mechanism of action of these techniques and for the evaluation of new drugs. The aim of our study was to evaluate the potential use of Histamine, IL-2 and their combination, in the regional setting as an alternative to TNF. Hi showed a synergistic effect, when combined to doxorubicin in the experimental ILP, and when combined to melphalan in the experimental ILP and IHP. IL-2 also had a synergistic effect when combined to melphalan in the experimental ILP. Yet, the combination of Hi and IL-2 to melphalan in the ILP led to decreased response rates as compared to each agent alone combined to melphalan. The mechanism of action of Hi in the regional setting was very similar to the mechanism of action of TNF with a better tumor drug uptake, TAV destruction, and best responses seen with its combination to chemotherapeutic drugs.! Additionally, Hi had a direct cytotoxic effect against both tumor cells and TAV. http://repub.eur.nl/res/pub/13410/ 2004-12-01T00:00:00Z BACKGROUND: Isolated hepatic perfusion for irresectable metastases confined to the liver has reported response rates of 50% to 75%. Magnitude, costs, and nonrepeatability of the procedure are its major drawbacks. We developed a less invasive, less costly, and potentially repeatable balloon catheter-mediated isolated hypoxic hepatic perfusion (IHHP) technique. METHODS: In this phase I and II study, 18 consecutive patients with irresectable colorectal or ocular melanoma hepatic metastases were included. Two different perfusion methods were used, both with inflow via the hepatic artery, using melphalan 1 mg/kg. In the first eight patients, the portal vein was occluded, and outflow was via the hepatic veins into an intracaval double-balloon catheter. This orthograde IHHP had on average 56% leakage. In next 10 patients, we performed a retrograde outflow IHHP with a triple balloon blocking outflow into the caval vein and allowing outflow via the portal vein. The retrograde IHHP still had 35% leakage on average. RESULTS: Although local drug concentrations were high with retrograde IHHP, systemic toxicity was still moderate to severe. Partial responses were seen in 12% and stable disease in 81% of patients. The median time to local progression was 4.8 months. CONCLUSIONS: We have abandoned occlusion balloon methodology for IHHP because it failed to obtain leakage control. We are presently conducting a study using a simplified surgical retrograde IHHP method, in which leakage is fully controlled, which translates into high response rates. http://repub.eur.nl/res/pub/13544/ 2004-11-03T00:00:00Z BACKGROUND: We have previously shown how tumor response of isolated limb perfusion (ILP) with melphalan was improved when tumor necrosis factor alpha (TNF-alpha) was added. Taking into account that other vasoactive drugs could also improve tumor response to ILP, we evaluated histamine (Hi) as an alternative to TNF-alpha. METHODS: We used a rat ILP model to assess the combined effects of Hi and melphalan (n = 6) on tumor regression, melphalan uptake (n = 6), and tissue histology (n = 2) compared with Hi or melphalan alone. We also evaluated the growth of BN-175 tumor cells as well as apoptosis, necrosis, cell morphology, and paracellular permeability of human umbilical vein endothelial cells (HUVECs) after Hi treatment alone and in combination with melphalan. RESULTS: The antitumor effect of the combination of Hi and melphalan in vivo was synergistic, and Hi-dependent reduction in tumor volume was blocked by H1 and H2 receptor inhibitors. Tumor regression was observed in 66% of the animals treated with Hi and melphalan, compared with 17% after treatment with Hi or melphalan alone. Tumor melphalan uptake increased and vascular integrity in the surrounding tissue was reduced after ILP treatment with Hi and melphalan compared with melphalan alone. In vitro results paralleled in vivo results. BN-175 tumor cells were more sensitive to the cytotoxicity of combined treatment than HUVECs, and Hi treatment increased the permeability of HUVECs. CONCLUSIONS: Hi in combination with melphalan in ILP improved response to that of melphalan alone through direct and indirect mechanisms. These results warrant further evaluation in the clinical ILP setting and, importantly, in organ perfusion. http://repub.eur.nl/res/pub/10369/ 2004-01-01T00:00:00Z OBJECTIVE: The aim of this study is to describe the experience with 100 TNF-based ILP for locally advanced melanoma and to determine prognostic factors for response, time to local progression, and survival. METHODS: One hundred TNF-based ILPs were performed between 1991 and 2003 in 87 patients for whom local control by surgery of in-transit melanoma metastases was impossible. In total, 62 iliac, 33 femoral, and 5 axillary ILPs were performed in mild hyperthermic conditions with 2 to 4 mg of TNF and 10 to 13 mg of melphalan per liter of limb volume. RESULTS: Overall response was 95%, with 69% complete response, 26% partial response, and 5% no change. Complete response rate differed significantly for patients with IIIA disease versus IIIAB and IV. Local and systemic toxicity was mild to moderate in almost all cases, with no treatment-related death and one treatment-related amputation. Five-year overall survival was 32%; local progression occurred in 55% after a median of 16 months. In complete response patients, 5-year survival was 42% with local progression in 52% at a median of 22 months. Response rate and survival were significantly influenced by stage of disease; (local progression free) survival was influenced by response rate. CONCLUSIONS: TNF-based ILP results in excellent response rates in this patient population with unfavorable characteristics. Response on ILP predicts outcome in patients and reflects aggressiveness of the tumor.