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.     

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 with melphalan prolongs survival in a rat model of metastatic pulmonary adenocarcinoma.

INTRODUCTION: Survival after isolated lung perfusion (ILuP) with melphalan was tested in a model of unilateral pulmonary adenocarcinoma. METHODS: On day 0, rats were randomized into four groups: Group 1 (n = 9) received tumor cells intravenously for induction of bilateral lung metastases, whereas groups 2-4 (n = 21) underwent a 10-min occlusion of the right pulmonary artery during tumor cell injection for induction of unilateral left lung metastases. On day 7, groups 1 and 2 received no treatment. Group 3 underwent left ILuP with melphalan (2.0 mg/kg) while group 4 received melphalan intravenously (0.5 mg/kg). The end point of the study was death from metastatic disease. RESULTS: Median survival of ILuP-treated animals (81 +/- 12 days) was significantly longer compared to group 1 (18 +/- 1 days; p = 0.0001), group 2 (28 +/- 3 days; p = 0.0002) and group 4 (37 +/- 6; p = 0.0004). CONCLUSIONS: ILuP with melphalan prolongs survival in the treatment of experimental metastatic pulmonary carcinoma.     

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.     

Isolated lung perfusion for pulmonary metastases

Isolated lung perfusion is an experimental surgical technique evaluated for the delivery of high-dose chemotherapy to improve 5-year survival after pulmonary metastasectomy. Extensive experimental work in animal models has demonstrated superior pharmacokinetics and efficacy compared with systemic therapy. Phase I clinical trials of isolated lung perfusion found a maximum tolerated dose**** of TNF-alpha, doxorubicin, cisplatin, and melphalan, whereas the combination of isolated lung perfusion with a complete metastasectomy was feasible. The combination of isolated lung perfusion and regional lung perfusion techniques needs further investigation.     

Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion

BACKGROUND: The antitumor effect of isolated lung perfusion with cisplatin was limited because the intracellular platinum concentration did not increase sufficiently. To solve this problem, digitonin, a detergent, was chosen to increase cell permeability and enhance intracellular uptake and antitumor effect. This study was designed to investigate toxicity, pharmacokinetics, and efficacy of isolated lung perfusion with the combined use of digitonin and cisplatin in Fischer 344 rats. METHODS: Systemic and local toxicities of isolated lung perfusion treatment were evaluated on the basis of body weight change, survival rate, and histologic findings. The maximal tolerated dose of digitonin was determined by assessing survival on day 21 after contralateral pneumonectomy, body weight change, and histologic findings. Pharmacokinetics were observed in a solitary lung tumor nodule model by measuring platinum concentration in tumor and normal lung tissue. The antitumor effect was evaluated by the number of tumor nodules in the left lung 21 days after isolated lung perfusion. Isolated lung perfusion was performed 7 days after 1.0 x 10(6) methylcholanthrene sarcoma cells were injected into the external jugular vein. RESULTS: The maximal tolerated dose of digitonin was 20 micromol/L. Platinum concentration of tumor nodules in the digitonin-cisplatin-treated rats was 20% higher than in the cisplatin-only group (5.48 +/- 0.64 microg/g tissue versus 4.50 +/- 1.09 microg/g tissue; p = 0.067). The number of pulmonary nodules decreased significantly by digitonin use (1.3 +/- 1.5 versus 9.7 +/- 2; p < 0.0001). CONCLUSIONS: Isolated lung perfusion with digitonin and cisplatin in combination was performed safely and enhanced the antitumor effect. These drugs in combination show promise for enhancing the effect of clinical isolated lung perfusion.     

Toxicity and pharmacokinetics of isolated lung perfusion with cisplatin in rat

OBJECTIVE: This study was designed to evaluate the toxicity and the pharmacokinetics of cisplatin administered via isolated lung perfusion in Fischer 344 rat. METHODS: Toxicity study; Cisplatin dosages of 3.3, 5.0, 6.7, and 10.0 mg/kg were injected intravenously in four groups, respectively. Cisplatin dosages of 3.3, 5.0, and 6.7 mg/kg were perfused via isolated lung perfusion in a further three groups, respectively. The maximum tolerated dosage of cisplatin was determined by assessing the survival rate on day 21. Pharmacokinetics study; Animals received 6.7 mg/kg of cisplatin intravenously or 3.3 mg/kg of cisplatin via isolated lung perfusion. The cisplatin levels of the lung were measured by flameless atomic spectrometry. RESULTS: Toxicity study; The maximum tolerated dosage of cisplatin via intravenous injection was 6.7 mg/kg, and via isolated lung perfusion was 3.3 mg/kg. Pharmacokinetics study; The cisplatin level in the perfused lung was significantly higher than that in the lung of the animal treated intravenously (16.6 +/- 6.2 micrograms/g of tissue and 7.5 +/- 3.2 micrograms/g of tissue, respectively) (p = 0.0096). CONCLUSION: Isolated lung perfusion with 3.3 mg/kg of cisplatin was pharmacokinetically superior to the maximum tolerated intravenous injection of cisplatin.     

Evaluation of isolated lung perfusion as neoadjuvant therapy of lung metastases using a novel in vivo pig model: II. High-dose cisplatin is well tolerated by the native lung tissue.

OBJECTIVE: Efficacy of in vivo isolated lung perfusion (ILP) with cisplatin could be shown in different rodent tumor models. Despite the use of this alternative therapeutical strategy in very few patients with lung metastases, there are no systematic studies regarding the tolerance of the native lung tissue in large animal models or humans. METHODS: In a novel ILP pig model, groups with two different concentrations of cisplatin (group CP150: 150 mg/m(2) cisplatin, n=5; group CP300: 300 mg/m(2) cisplatin, n=5) were compared with a control group (n=5) and a Sham group (n=5) concerning the influence on hemodynamic, ventilatory and gas exchange parameters as well as on structural integrity of the lung. In the additional CP300-HT group the potentially cumulative effect of hyperthermia and high-dose cisplatin perfusion was evaluated (300 mg/m(2) cisplatin, 41.5 degrees C, n=5). Following the ILP of the left lung for 40 min, right main bronchus and right pulmonary arteries were clamped and survival as well as lung function parameters were dependent on the previously perfused lung for the 6-h-reperfusion period. Quantification of histological acute lung injury was performed using the score of Chiang. ANOVA, ANOVA with repeated measures and Pearson's correlation estimation were applied for statistical evaluation. RESULTS: All animals survived ILP and the entire reperfusion period. Platinum levels of the perfusate and lung tissue showed a significant correlation with the dose given (P<0.001) but no correlation with the very low plasma levels in all groups (P=0.825). ILP resulted in a slight deterioration of most functional parameters compared to the Sham group. Although there were no differences between the perfusion groups regarding hemodynamic and ventilatory parameters, gas exchange parameters (pO(2)/FiO(2)-index, pCO(2), AADO(2)) demonstrated a trend toward dose-related functional impairment. Histological evaluation confirmed a dose-depending damage of lung tissue (P<0.001, correlation coefficient 0.670). The hyperthermic ILP with high-dose cisplatin led to improved gas exchange parameters and a reduction of morphological lung damage. CONCLUSIONS: In vivo ILP with high-dose cisplatin represents a safe procedure in this pig model. Hyperthermic perfusion up to 41.5 degrees C was beneficial to reduce the acute lung injury. The promising results of this study might be used for initiation of clinical trials as an alternative treatment in patients with a very poor prognosis.     

Reversal of lethal, chemotherapeutically induced acute hepatic necrosis in rats by regenerating liver cytosol

In this report we further evaluate the role of regenerating liver cytosol (RLC) as a stimulator of hepatic regeneration by assessing its effect on survival, liver function, and hepatic regeneration in a model of in vivo isolated perfusion of the rat liver with high concentrations of cytotoxic drugs and regional hyperthermia. Isolated perfusion with 500 mg/kg of 5-fluorouracil (5-FU) and 2.5 mg/kg of mitomycin-C (Mit-C) resulted in 70% (n = 20) and 71% (n = 14) mortality, respectively, from 2 to 7 days after perfusion, with extensive, patchy necrosis and infarction seen on histologic examination and markedly elevated levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) at 6 and 24 hours after perfusion. The intraperitoneal administration of RLC (80 mg total protein/rat) at the time of hepatic perfusion resulted in 70% (5-FU, n = 20, P less than 0.05) and 80% (Mit-C, n = 20, P less than 0.01) survival at 21 days post perfusion. RLC-treated rats demonstrated significantly lower SGOT and SGPT levels at 6 and 24 hours after perfusion and normal liver histologic appearance by 14 days after perfusion in surviving rats. Hepatic regenerative capacity following partial hepatectomy was severely inhibited (P less than 0.001) following isolated hepatic perfusion with sublethal doses of 5-FU (125 mg/kg, 250 mg/kg), Mit-C (1.5 mg/kg) and hyperthermia (41 degrees C and 43 degrees C X 5 minutes). The administration of RLC at the time of partial hepatectomy restored the DNA synthetic response in perfused rats to that seen in normal control rats after partial hepatectomy (P less than 0.05). These results demonstrate that the liver is the source of a factor (s) (RLC) that significantly improves survival after lethal chemotherapeutic injury to the liver by stimulating endogenous hepatic regeneration. A potential clinical application for a stimulator of hepatic regeneration in situations of deliberate, therapeutic insult to the liver is suggested.     

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.     

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°C) and hyperthermia (42°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°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°C, and the maximum tolerated dose was set at 45 mg of MN at 42°C.     

In-transit melanoma: the role of alkylating-agent resistance in regional therapy

BACKGROUND: Regional perfusion treatments for melanoma, using the alkylating agent melphalan, show variable responses in magnitude and duration. Surprisingly, the potential contribution of alkylating-agent resistance mechanisms to diminish tumor responses, especially the crucial cellular detoxifying system formed by glutathione (GSH) and its associated enzyme glutathione-S-transferase (GST), has remained unexplored. Objectives of this study were to characterize GSH levels and GST activity in melanoma of patients undergoing regional perfusion and examine the effect of melphalan concentration in both an in vitro human melanoma cell line and in the extremity melanoma of an in vivo rodent limb infusion model. STUDY DESIGN: Human in-transit melanoma, muscle, subcutaneous tissue, and skin (n = 9) and metastatic regional lymph nodes (n = 7) were evaluated for GSH level and GST activity. Effects of increasing melphalan exposure on GSH and GST were studied in an in vitro human melanoma cell line. A survival human melanoma xenograft model of isolated limb infusion using increasing dosages of melphalan was used, with evaluation of GSH and GST in the recurrent tumor. RESULTS: GSH levels in human in-transit lesions and muscle were significantly higher than that of skin and subcutaneous tissue. Four of 9 patients had tumor-to-muscle GSH ratio > 1. A strong correlation was seen between in vitro melphalan dose and resultant GSH level and GST activity. In vivo recurrent tumor GSH levels correlated with increasing melphalan infusion dose. CONCLUSIONS: A GSH-based resistance pathway may play a role in effecting response and toxicity to regional melphalan perfusion.     

Chemotherapy by isolated liver perfusion with endovascular occlusion catheter: preliminary experience in pigs

Very high concentrations of cytotoxic drug may be obtained with chemotherapy performed with vascular exclusion. OBJECTIVE: To study the pharmacokinetics and toxicity of melphalan during in situ isolated liver perfusion, and to test an endovascular occlusion catheter. METHODS: Isolated liver perfusion with melphalan (15 mg bolus) was performed in 6 pigs (50-60 kg) for 30 min, with non-oxygenated Ringer's solution. Hepatic outflow, collected by a double balloon catheter inserted into the retrohepatic inferior vena cava, was pumped into the gastroduodenal artery, while the common hepatic artery and portal vein were clamped. RESULTS: A maximum concentration of 30,000 ng/mL was obtained in the circuit before an exponential decrease, while the concentration in systemic blood was less than 500 ng/mL (n = 3). Before closing the abdomen, melphalan concentrations were about 2,000 ng/mg in the liver, and undetectable in the muscle. Postoperative course (2 weeks, n = 2) was uneventful with minor alterations in blood tests and hepatic histology. CONCLUSION: This method of local chemotherapy with melphalan appears to be safe with minor leakage and minimal toxicity.     

Anti-beta1 integrin antibody reduces surgery-induced adhesion of colon carcinoma cells to traumatized peritoneal surfaces

OBJECTIVE: To study the mechanisms behind surgery-induced augmentation of tumor outgrowth. SUMMARY BACKGROUND DATA: Surgery provides the best chance of cure for most primary intra-abdominal carcinomas. Effective treatment is however relatively frequent complicated by peritoneal recurrences, which often originate from free-floating intraperitoneal tumor cells that implant on peritoneal surfaces. We previously reported that surgical trauma promotes development of peritoneal metastases. METHODS: Evaluation of adhesion of CC531s rat colon carcinoma cell line intraperitoneally after laparotomy using in vivo, ex vivo, and in vitro models. Also, human ex vivo models were used to study peritoneal tumor cell adhesion. RESULTS: Peritoneal imprints of operated rats showed that direct damaging of the peritoneum resulted in enhanced adhesion of rat CC531 colon carcinoma cells to submesothelial extracellular matrix (ECM) proteins in vivo, which was confirmed by electron microscopy. Additionally, the inflammatory reaction of the peritoneal cavity led to retraction of mesothelial cells, hereby also exposing ECM at peritoneal surfaces that had not been traumatized directly. Furthermore, we demonstrated that beta1 integrin subunits represented the primary mediators involved in adherence to either isolated ECM components or excised traumatized rat and human peritoneum. Importantly, incubation of CC531s cells with anti-beta1 integrin antibodies resulted in a significant decrease of tumor cell adhesion in vivo. CONCLUSIONS: Surgical trauma results in exposure of ECM at directly and nondirectly damaged peritoneal surfaces, leading to increased beta1 integrin-dependent tumor cell adhesion. Perioperative therapies, which aim to block beta1 integrin subunits, might therefore serve as new clinical tools for the prevention of peritoneal recurrences.     

CaSm/gemcitabine chemo-gene therapy leads to prolonged survival in a murine model of pancreatic cancer

BACKGROUND: CaSm, the cancer-associated Sm-like oncogene, is overexpressed in greater than 80% of pancreatic tumors. We previously reported that an adenovirus expressing antisense RNA to CaSm (Ad-alpha CaSm) can decrease pancreatic tumor growth in vivo but is not curative. In the current study we investigated the mechanism of Ad-alpha CaSm's antitumor effect to rationally approach combinatorial therapy for improved efficacy. METHODS: AsPC-1 and Panc-1 human pancreatic cancer cells were treated with Ad-alpha CaSm and examined by MTT assay for in vitro proliferation changes. Flow cytometry determined the effect of CaSm down-regulation on the cell cycle, and then cells treated with Ad-alpha CaSm in combination with cisplatin, etoposide, or gemcitabine chemotherapies were reexamined by MTT assay. SCID-Bg mice bearing subcutaneous AsPC-1 tumors were treated with Ad-alpha CaSm, gemcitabine, or the combination and monitored for tumor growth and survival. RESULTS: Treatment with Ad-alpha CaSm reduced the proliferation of AsPC-1 and Panc-1 cells (59% and 44%, respectively; P <.05). The cell cycle revealed a cytostatic block with decreased G(1) phase and increased DNA content in treated cells. The combination of Ad-alpha CaSm with gemcitabine significantly reduced in vitro proliferation (66% vs 39% and 48% for controls), decreased in vivo AsPC-1 tumor growth by 71% (n = 10), and extended survival time from 57 to 100 days. CONCLUSIONS: Down-regulation of CaSm reduces the growth of pancreatic cancer cells by altering the cell cycle in a cytostatic manner. The combination of Ad-alpha CaSm with gemcitabine is more effective than either agent used separately.     

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

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.     

Isolated lung perfusion for the treatment of pulmonary metastatic disease: a review

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.     

Results of induction chemotherapy followed by surgical resection in patients with stage IIIA (N2) non-small cell lung cancer: the importance of the nodal down-staging after chemotherapy

Objective: Chemotherapy of stage IIIA non-small cell lung cancer (NSCLC) using second generation, cisplatin-based combinations has shown to improve the results; however, the distant relapses remain the major problem. Encouraging results in the treatment of stage IV NSCLC with newer agents (gemcitabine, placlitaxel) has encouraged us to use them in stage III. The aim of this study was to assess feasibility and efficacy of induction chemotherapy with cisplatin and gemcitabine followed by surgery for patients with stage IIIA (N2) NSCLC. Methods: From February 1996 to December 1999, 36 consecutive patients with mediastinoscopically staged N2 NSCLC received three cycles of cisplatin (80 mg/m², day 2) and gemcitabine (1200 mg/m², day 1+8) followed by surgery in responding patients. Patients with stable disease or even local progression received radiotherapy. All patients had clinical N2 disease (mediastinal lymph nodes metastasis) observed on CT scan. Results: No major complications of the chemotherapy occurred. Twenty-five patients (70%) had a clinical partial response and were surgically explored, with 18 complete resections (70%). There were no in-hospital deaths, although four (16%) major complications: bronchopleural fistula (two), respiratory insufficiency (one), oesophagospleural fistula (one). In the total group of 36 patients, 3-year survival was 20%. So far, no patient without surgery has survived longer then 27 months; median survival was 8 months. In the group of the 25 patients who underwent surgery 3-year survival was 30%, with a median survival of 21 months. The difference is significant (P=0.0027). In the surgical group, the survival of patients with down staged disease (56%) was greater than that of patients with persistent N2 disease (44%) after chemotherapy (3-year survival of 59 and 0%, respectively; P=0.0013). Conclusion: induction chemotherapy with cisplatin and gemcitabine resulted in major tumour regression in a large percentage of patients with clinical N2 disease. In responding patients both the complete respectability rate and survival were higher when compared to historical controls. Survival was significantly better in patients down-staged to a mediastinal negative disease.     

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相似文献   

Isolated hyperthermic liver perfusion with cytostatic-containing perfusate activates the complement cascade.

Eight patients with advanced liver malignancy undergoing isolated hyperthermic liver perfusion with melphalan and cisplatin were studied with regard to complement activation and formation of anaphylatoxins (C3a and C5a) and terminal C5b-9 complement complexes (TCCs). Blood samples for complement variables (C1-INH, C3, C4, C5, C3a, C5a and TCCs) were taken before surgery, 1 min before the start of perfusion, 1, 2 and 3 h after the start of perfusion, and 24 h after operation. Samples were drawn from the perfusate 1 h after the start of perfusion. Activation of complement was observed during perfusion. Raised plasma concentrations of C3a and TCCs were recorded and high levels of C3a and TCCs were found in the perfusate. In vitro tests indicated that melphalan and cisplatin may activate complement. This activation occurred at 37 and 42 degrees C but was more pronounced at 42 degrees C.