Sander Romijn

Isolated lung perfusion with gemcitabine in a rat: pharmacokinetics and survival.

BACKGROUND Toxicity and pharmacokinetics of gemcitabine (GCB) were evaluated in a rat model of isolated lung perfusion (ILuP) and compared to intravenous (iv) infusion. MATERIALS AND METHODS CC531S adenocarcinoma cells were incubated in vitro for 24 h with GCB. Cell survival was determined 4 days after GCB treatment with the sulforhodamine B test. In a first in vivo experiment, Wag/Rij rats underwent left ILuP with 20 mg/kg (n = 3), 40 mg/kg (n = 6), 80 mg/kg (n = 6), 160 mg/kg (n = 6), or 320 mg/kg (n = 6) of GCB and a control group (n = 6) with buffered starch. After 3 weeks, right pneumonectomy was performed. Furthermore, survival was determined for rats treated with iv infusion of 40 mg/kg (n = 10), 80 mg/kg (n = 10), 160 mg/kg (n = 10), or 320 mg/kg (n = 6) of GCB and a control group (n = 6) treated with saline (0.9% NaCl). In a second experiment lung and serum GCB levels were determined for rats treated with iv infusion (160 mg/kg, n = 6) and rats which had ILuP (160 mg/kg, n = 6; 320 mg/kg, n = 6). RESULTS Incubation of the CC531S adenocarcinoma cells with GCB led to a 50% decrease (P < 0.05) in the number of cells compared to controls at a dose of 23.6 nM. After 90 days, the mortality for rats treated with 320 mg/kg iv GCB was 100% compared to 17% after ILuP for the same dose. ILuP with 160 and 320 mg/kg resulted in significantly higher lung levels of GCB compared to iv therapy without any systemic leakage. CONCLUSIONS GCB ILuP is well-tolerated to a maximum dose of 320 mg/kg and results in significantly higher GCB lung levels with undetectable serum levels compared to iv treatment.

Single-pass isolated lung perfusion versus recirculating isolated lung perfusion with melphalan in a rat model

BACKGROUND Isolated lung perfusion (ILuP) with melphalan (MN) is superior to intravenous infusion for the treatment of pulmonary carcinoma and sarcoma metastases. However, it is unknown whether a bolus injection of MN into the perfusion circuit or ILuP with a fixed concentration of MN will result in the highest lung levels. METHODS ILuP with 0.5 mg MN was performed in Wag-Rij rats for 30 minutes either by a single-pass system (SP) (fixed concentration) (n = 10) or by reperfusion (RP) (bolus injection) (n = 10). In a separate experiment, rats were perfused with blood as the perfusate. In a third experiment, tumor levels were compared between SP, RP, or intravenous therapy with a dose of 0.5 mg. For induction of pulmonary metastases, 0.5 x 10(6) single adenocarcinoma cells were injected intravenously and therapy was given on day 30. For comparison of drug concentrations, unpaired Students t test was applied. Statistical significance was accepted at p less than 0.05. RESULTS Lung perfusion studies were succesfully performed without systemic leakage. Temperature of perfusate and rats was 34 degrees C to 37 degrees C. A significantly higher hematocrit (mean 27.9) compared with buffered starch (mean 2.5) did not result in higher MN lung levels or lower wet-to-dry ratio. Tumor levels were significantly higher after ILuP compared with intravenous therapy. However, no difference in tumor and lung levels was seen between single-pass and reperfusion. CONCLUSIONS Both ILuP techniques resulted in significantly higher MN lung levels than after intravenous therapy. Because no difference was seen between single-pass and recirculating perfusion, MN can be injected as a bolus into the closed perfusion circuit.

Isolated lung perfusion for the treatment of pulmonary metastases current mini-review of work in progress

Surgical resection of lung metastases is a widely accepted procedure but long-term results are disappointing with a 5-year survival rate of approximately 40%. Pulmonary metastasectomy is only indicated when complete resection can be achieved. A better survival is reported in patients with a single metastasis or a disease-free survival of more than 3 years. Intravenous chemotherapy has no major impact on survival because high-dose therapy is limited by systemic side-effects. Isolated lung perfusion has the advantage of both selectively delivering an agent into the lung while diverting the venous effluent. This allows the drug to be given in a significantly higher dose compared to intravenous therapy, while drug levels in critical organs are kept low enough to avoid significant morbidity. Isolated lung perfusion has proven to be effective for the treatment of lung metastases in animal models while the procedure is technically safe in humans. However, the real clinical value and survival benefit remain to be determined in ongoing clinical trials.The aim of this paper was to update the literature on isolated lung perfusion for the treatment of lung metastases. Furthermore, some proposals are made in order to improve the ultimate prognosis of these patients.

Pharmacokinetics after pulmonary artery perfusion with gemcitabine

BACKGROUND Isolated lung perfusion (ILuP) proved to be superior for the treatment of lung metastases compared with intravenous (i.v.) injection. However its invasive character limits repetitive treatment. Blood flow occlusion (BFO) as a regional therapy with gemcitabine (GCB) was evaluated in a rat model. Lung levels of GCB were examined with different exposure times and flow rates and compared with ILuP and i.v.. Cell kill was studied in vitro. METHODS In vitro survival of CC531 adenocarcinoma cells was determined after 10, 20, and 40 minutes of exposure to GCB. In vivo 48 Wag/Rij rats underwent BFO with GCB at a rate of 0.2 mL/min and 0.5 mL/min during 10, 20, 30, and 40 minutes. Statistical analysis was performed using Students t test. RESULTS In vitro, the dose of GCB resulting in 50% growth inhibition was 9.1 microg/mL, 7.2 microg/mL, and 2.2 microg/mL after 10, 20, and 40 minutes exposure respectively. In vivo, no significant difference in lung levels of GCB was observed between a flow rate of 0.2 mL/min compared with 0.5 mL/min at any exposure time point (p < 0.05). Lung tissue was saturated after 20 minutes. Blood flow occlusion resulted in a lower plasma levels and higher lung levels of GCB compared with i.v. injection of the maximal tolerated dose of 40 mg. CONCLUSIONS Growth inhibition of CC531 cells in vitro increased with exposure time while lung tissue was saturated after 20 minutes of BFO. No difference in GCB lung levels were seen after BFO compared with ILuP. Systemic exposure after i.v. injection was higher compared with BFO but did not result in higher lung levels.

Isolated Lung Perfusion for the Treatment of Pulmonary Metastatic Disease: a Review

Abstract Isolated lung perfusion with chemotherapeutic agents is an experimental technique for the treatment of lung metastatic disease from certain solid tumours. The technique had already been developed in the late 1950s but underwent a revival in the early 1980s. By that time, experimental work in large and small animals induced extensive clinical work with different agents such as doxorubicin, tumour necrosis factor, melphalan and cisplatin for which safety profiles and maximal tolerated doses were defined. A review of current work is presented in this article.

Variations in flow, duration, and concentration do not change the final lung concentration of melphalan after isolated lung perfusion in rats.

Objective: The influences of flow, perfusion time, and concentration on melphalan (MN) lung levels in a rat model of isolated lung perfusion (ILuP) were studied. Methods: ILuP was performed in WAG/Rij rats by using a single-pass system with 0.5, 0.05, 0.01, and 0.005 mg of MN. Subsequently ILuP with 0.05 mg MN was performed during 30 min with a flow rate of 0.5 ml/min, during 60 min with a flow rate of 0.5 ml/min, and during 30 min with a flow rate of 1.0 ml/min. Results: The lung MN levels of 0.05 mg were significantly lower as compared with 0.5 mg (p = 0.02). In the second experiment, no significant differences were seen in lung levels of MN between the different groups. Conclusion: The final lung MN levels were only determined by the absolute amount administered.