Combination chemotherapy with gemcitabine with isolated lung perfusion for the treatment of pulmonary metastases.

OBJECTIVE: Isolated lung perfusion is an experimental technique for the treatment of lung metastases. Single-agent isolated lung perfusion does not result in complete remission. We studied the in vivo and in vitro efficacy of combinations of gemcitabine, cisplatin, and melphalan. METHODS: In vitro, using the sulforhodamine B assay, CC531s cells were incubated with cisplatin, gemcitabine, or melphalan or with a combination of these drugs. One drug was added at concentrations causing 25% growth inhibition, whereas the second drug was added at variable concentrations. In vivo, left pulmonary metastases were induced in Wag/Rij rats by means of intravenous injection of CC531s adenocarcinoma cells. At day 7, rats underwent left isolated lung perfusion with gemcitabine (n = 7), cisplatin (n = 9), melphalan (n = 7), gemcitabine-cisplatin (n = 6), melphalan-gemcitabine (n = 6), and cisplatin-melphalan (n = 7). Death by means of metastatic disease was the end point. Survival and differences in survival were assessed by using Kaplan-Meier and log-rank testing. RESULTS: In vitro synergistic activity was observed for melphalan-gemcitabine, whereas other combinations showed additive or antagonistic activity. In vivo treated rats lived longer compared with control animals ( P < .0001). In isolated lung perfusion melphalan resulted in longer survival compared with gemcitabine ( P = .0016) and cisplatin ( P = .046). Isolated lung perfusion with melphalan-gemcitabine resulted in 67% survival of the rats after 90 days versus 0% in other groups. CONCLUSIONS: Isolated lung perfusion monotherapy or combination therapy with gemcitabine, cisplatin, or melphalan resulted in significantly longer survival compared with that seen in control animals. Isolated lung perfusion combination therapy with melphalan-gemcitabine resulted in the best survival either in vitro or in vivo.

Anterograde versus retrograde isolated lung perfusion with melphalan in the WAG-Rij rat.

OBJECTIVE: Isolated lung perfusion (ILuP) is an experimental technique currently tested to increase the 5-year survival of 40% after surgical resection of pulmonary metastases from certain solid tumors. The standard technique of anterograde perfusion was compared with retrograde isolated lung perfusion in which the drug is introduced through the pulmonary veins while the effluent is collected from the pulmonary artery. Since the lung has a dual arterial circulation through the pulmonary artery and bronchial circulation, perfusion through the pulmonary veins can result in a more homogeneous distribution throughout the lung with subsequent higher melphalan concentration. METHODS: We randomized 20 rats into two groups. Group one underwent anterograde isolated left lung perfusion while group two underwent retrograde isolated left lung perfusion. A dose of 2 mg/kg melphalan (MN) was administered to the lung at a flow of 0.5 mL/min during 30 min, followed by a 5-min washout with buffered hetastarch (BHE). The final melphalan lung concentration (FMLC) was determined in the hilum, at the apex, the mid-periphery and the base of the lung. Statistical analysis was done with an unpaired student's t-test. RESULTS: Retrograde left ILuP resulted in a higher FMLC in the hilum (P<0.0001) and in the base of the lung (P=0.03), while anterograde ILuP induced a higher concentration at the apex of the lung (P=0.04). No difference was seen in the mid-peripheral area of the lung (P=0.92). CONCLUSIONS: In this experimental study, retrograde perfusion seems to increase final melphalan lung concentration in hilar and basal regions of the lung compared to anterograde perfusion.

Transphrenic fistulization of a subphrenic abscess to lung parenchyma.

A 53-year-old woman was admitted with respiratory distress. For several years, she had chronic alcoholic pancreatitis with ductal stones that were treated with a stent and with shockwave lithotripsy. Both treatments were unsuccessful, and the pancreatitis was complicated with an infected pseudocyst. The pancreatic head had to be resected, which was complicated with recurrent subphrenic abscesses. She then was admitted with respiratory distress and initially diagnosed with pneumonia of the right lower lobe. Further investigations showed supradiaphragmatic and subdiaphragmatic air-fluid levels. In both collections Streptococcus milleri was cultured, and subsequently the patient was diagnosed with a fistula connecting the subdiaphragmatic abscess with pulmonary tissue. This was treated with intravenous amoxicillin/clavulanate and drainage of the subdiaphragmatic collection. She did not develop a pulmonary empyema, because multiple adhesions, which were due to recurrent abscesses after pancreatic surgery, prevented breakthrough into the pleural cavity.

Regional differences of melphalan lung levels after isolated lung perfusion in the rat.

BACKGROUND: Efficacy studies of isolated lung perfusion (ILuP) with melphalan showed superior results compared to intravenous therapy. However, the influence of pharmacokinetic parameters on the final melphalan lung concentration (FMLC) is unknown. In this study, we studied the impact of three different perfusion parameters on the FMLC in different areas of the lung. MATERIAL AND METHODS: Fifty-four rats were randomized into nine groups. Each group underwent ILuP with variation of perfusion duration (15, 30, and 60 min), the flow (0.125, 0.25, and 0.5 ml/min), concentration (8.3, 16.7, 33.3, 66.7, and 133.3 microg/ml) and the resulting dose (maximum 4 mg/kg). Lung samples were taken from the hilum and at the periphery of the lung (apex, base). Additional samples were taken to evaluate wet-to-dry ratio (W/D-ratio). Multiple linear regression and Student's t test were used for analysis. Significance was defined as a P

Isolated lung perfusion with melphalan for resectable lung metastases: a phase I clinical trial.

BACKGROUND: Current 5-year survival after complete resection of pulmonary metastases is 20% to 40%, and many patients develop intrathoracic recurrences. Isolated lung perfusion is an experimental technique to deliver high-dose chemotherapy to the lung without systemic exposure. A phase I trial of isolated lung perfusion with melphalan (MN) combined with pulmonary metastasectomy for resectable lung metastases was conducted to define the dose-limiting toxicity and maximum tolerated dose. METHODS: From May 2001 to August 2003, 16 patients underwent isolated lung perfusion with MN, followed by surgical resection of lung metastases. Patients were treated with increasing MN doses (15, 30, 45, and 60 mg). For each dose level, normothermia (37 degrees C) and hyperthermia (42 degrees C) were evaluated (n = 3 per level). Serum samples were obtained during the procedure. Pulmonary, hematologic, and nonhematologic toxicities were recorded. The primary tumor was colorectal in 7 patients, renal in 5, sarcoma in 3, and salivary gland in 1. Isolated lung perfusion was performed unilaterally in 11 patients, and staged bilaterally in 5. RESULTS: In total, 21 procedures of isolated lung perfusion with complete metastasectomy were performed without technical difficulties. Operative mortality was 0%, and no systemic toxicity was encountered. Grade 3 pulmonary toxicity developed at a dose of 60 mg of MN at 37 degrees C in 2 of 3 patients at this dose, terminating the trial. CONCLUSIONS: Isolated lung perfusion with MN combined with pulmonary metastasectomy is feasible. Dose-limiting toxicity occurred at a dose of 60 mg of MN at 37 degrees C, and the maximum tolerated dose was set at 45 mg of MN at 42 degrees C.

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 Student's 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 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.

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 Student's 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.