Isolated Lung Perfusion With Melphalan for Resectable Lung Metastases: A Phase I Clinical Trial

Hendriks, Jeroen; Grootenboers, Marco J.J.H.; Schramel, Franz M.N.H.; Boven, Wim Jan van; Stockman, Bernard; Seldenrijk, Cornelis A.; Broecke, P. ten; Knibbe, Catherijne A. J.; Slee, P. H. Th. J.; Bruijn, Ernst de; Vlaeminck, R.; Heeren, Jos; Vermorken, Jan B.; Putte, Bart Van de; Romijn, Sander; Marck, Eric Van; Schil, Paul Van

doi:10.1016/j.athoracsur.2004.05.058

Cited by 67 publications

(62 citation statements)

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“…First, isolated lung perfusion results in significantly higher drug concentrations in both lung and tumor tissue compared with i.v. administration as shown by many experimental and human data (Pass et al, 1996;Ratto et al, 1996;Hendriks et al, 1998Hendriks et al, , 2004Burt et al, 2000;van Putte et al, 2002). High-dose drug administration during isolated lung perfusion using drugs like gemcitabine and cisplatin is well tolerated by healthy lung tissue (Ratto et al, 1996;van Putte et al, 2003avan Putte et al, , 2005.…”

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confidence: 99%

Pharmacokinetics of Gemcitabine when Delivered by Selective Pulmonary Artery Perfusion for the Treatment of Lung Cancer

Putte

Grootenboers²,

Boven

et al. 2008

Drug Metab Dispos

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ABSTRACT:Lung cancer represents a major health problem. Cytostatic and radiotherapeutic treatment is limited because of dose-limiting systemic toxicity and surgery as a result of its invasive nature. Therefore, we developed a catheterization model of selective pulmonary artery perfusion (SPAP) combining the properties of isolated lung perfusion and i.v. treatment to achieve higher local drug levels and equivalent systemic exposure. Sixteen pigs underwent SPAP using a clinically applied dose of gemcitabine (1 g/m 2 ). They furthermore underwent thoracotomy for tissue sampling. Three groups were treated with SPAP for 2 min with normal pulmonary blood flow, 50 and 90% flow reduction. Another group had SPAP for 10 min with normal blood flow. All the SPAP groups underwent catheterization of the left pulmonary artery. An additional group (n ‫؍‬ 4) was infused i.v. for 30 min using the same dose. Concentrations were analyzed with analysis of variance. Pulmonary peak concentrations (p ‫؍‬ 0.01) and areas under the curve (AUC) (p ‫؍‬ 0.001) of SPAP for 2 and 10 min were significantly higher compared with i.v., whereas SPAP for 10 min resulted in the highest AUC (p ‫؍‬ 0.045) compared with SPAP for 2 min. Flow reduction during SPAP resulted in inhomogeneous distribution. Liver levels, AUC (serum), and wet-to-dry ratios of all the SPAP groups were not significantly different compared with i.v. SPAP resulted in higher lung concentrations, whereas systemic exposure was comparable with i.v. Therefore, we advocate SPAP as a new method to be tested clinically to achieve down-staging of the tumor and lymph node status in lung cancer.Cancer is the leading cause of death before the age of 85 years, resulting in more than half a million deaths per year in the United States (Jemal et al., 2006). In 2005, primary lung cancer was the second leading cancer type in the United States with approximately 190,000 new cases to be estimated for 2006. Among all the cancer types, lung cancer has the highest death rate (Jemal et al., 2006).Non-small cell lung cancer (NSCLC) is usually treated by surgical resection, radiotherapy, and/or cytostatic drug administration, depending on the disease stage. Stage 1 (a and b) and 2 (a and b) NSCLCs are currently treated by surgical resection, whereas (adjuvant) cytostatic therapy is applied to stage 1b, 2, and 3 disease, resulting in a 5-year survival of 75, 60, 40, 20, and 15%, respectively (Spiro and Silvestri, 2005).An i.v. infusion is the desired route of cytostatic drug administration to achieve exposure of the primary lung tumor and distant disease, as well as resulting in a 5-year survival benefit of 4 to 14% compared with surgery alone (Betticher, 2005). However, this method is dose-limited by the occurrence of systemic toxicity like bone marrow suppression that limits exposure of the primary tumor and pulmonary (lymph node) metastases.In contrast, isolated lung perfusion with cytostatic drugs is an experimental surgical technique for the treatment of lung metastases that aims to destroy pulmonar...

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confidence: 99%

Pharmacokinetics of Gemcitabine when Delivered by Selective Pulmonary Artery Perfusion for the Treatment of Lung Cancer

Putte

Grootenboers²,

Boven

et al. 2008

Drug Metab Dispos

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“…Recently, a phase-I trial with melphalan in patients with resectable lung metastases was completed. The maximally tolerated dose (MTD) of melphalan was found to be 45 mg at 428C, higher doses resulted in pulmonary toxicity [25]. No animal model system will precisely define what the human tolerance to any drug will be, although physiologically, the pig model resembles best the human situation.…”

Section: Discussionmentioning

confidence: 97%

Isolated lung perfusion with melphalan: Pharmacokinetics and toxicity in a pig model

et al. 2006

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“…Currently, a phase I trial evaluating melphalan in ILuP has recently been completed in our cardiothoracic institutions determining the maximal tolerated dose of melphalan to be 45 mg at 42 8C in the setting of ILuP in humans [9]. Dose limiting toxicity occurred at 60 mg melphalan at 42 8C.…”

Section: Discussionmentioning

confidence: 98%

“…The experimental work resulted in several phase I trials [9][10][11][12][13]. Dose-escalating schedules were applied searching for acceptable toxicity levels.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary intravascular volume can be used for dose calculation in isolated lung perfusion

Putte

Huisman

Hendriks

et al. 2005

European Journal of Cardio-Thoracic Surgery

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Isolated Lung Perfusion With Melphalan for Resectable Lung Metastases: A Phase I Clinical Trial

Cited by 67 publications

References 22 publications

Pharmacokinetics of Gemcitabine when Delivered by Selective Pulmonary Artery Perfusion for the Treatment of Lung Cancer

Pharmacokinetics of Gemcitabine when Delivered by Selective Pulmonary Artery Perfusion for the Treatment of Lung Cancer

Isolated lung perfusion with melphalan: Pharmacokinetics and toxicity in a pig model

Pulmonary intravascular volume can be used for dose calculation in isolated lung perfusion

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