Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas

Ratto, G. B.; Toma, Salvatore; Civalleri, D; Passerone, Giancarlo; Esposito, Mauro; Zaccheo, D; Canepa, Marco; Romano, Paola; Palumbo, R.; Cian, Franco De; Scarano, F; Vannozzi, Maria Ornella; Spessa, Ezio; Fantino, G.

doi:10.1016/s0022-5223(96)70043-0

Cited by 81 publications

(61 citation statements)

References 26 publications

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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.…”

Section: Introductionmentioning

confidence: 99%

“…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. Furthermore, a recent phase I trial evaluating toxicity of isolated lung perfusion with melphalan showed a rapid pulmonary lymph drainage resulting in equivalent concentrations in either the lymph nodes and lung tissue, although this approach is applied only once or twice per patient because of its invasive nature (unpublished data).…”

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confidence: 99%

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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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Section: Introductionmentioning

confidence: 99%

mentioning

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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“…Significantly higher lung tissue concentrations were obtained compared to systemic treatment or pulmonary artery blood flow occlusion (147,148). Kaneda et al (149) showed that ILuP with cisplatin was pharmacokinetically superior to IV treatment in a rodent model.…”

Section: Cisplatinmentioning

confidence: 99%

“…For instance, Johnston's group only included unresectable metastases whereas Ratto and Schröder investigated two different patient groups: resectable lung metastases and patients without any other treatment option left. Ratto used 3 times greater cisplatin concentration compared to Schröder without any additional histological damage (128,148,160). These variations make it very hard to draw any conclusions, especially on the reported survival data.…”

Section: Cisplatinmentioning

confidence: 99%

Lung Metastatic Disease: Surgical Resection and Locoregional Chemotherapy

Hengst¹,

Hendriks²,

Schil³

2012

Toraks Cer Bult

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Currently, surgical resection remains the gold standard for resectable lung metastases. Prognostic factors are histology, complete resection, number of metastases and disease-free interval. However, there is a high rate of recurrent disease in the thorax, even if systemic chemotherapy is applied. Because the latter is limited in dose due to systemic toxicity, new treatment options are being developed to selectively deliver high-dose chemotherapy into the lung, reducing systemic toxicity. Isolated lung perfusion (ILuP), similar to isolated limb perfusion, is an experimental surgical technique to deliver highdose chemotherapy into the lung without systemic exposure. Biological response modifiers like tumour necrosis factor can also be administered. ILuP results in significantly higher concentration of chemotherapy in the target organ compared to systemic chemotherapy, together with a survival benefit in experimental models of pulmonary metastases. Several phase I studies have shown that ILuP is technically feasible with low morbidity and low impact on the patient's pulmonary function. However, the utility of this technique is limited because it is an invasive technique. Other techniques to selectively deliver high-dose locoregional chemotherapy are embolic trapping (chemo-embolization), selective pulmonary artery perfusion (SPAP) without control of the venous effluent and the minimally invasive lung suffusion technique. This review will discuss surgical resection of lung metastases and address several techniques developed to deliver high doses of chemotherapy into the lung, as well as the current progress in experimental and clinical studies.

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“…Isolated lung perfusion (ILP) has been explored in clinical and experimental settings for the management of lung metastasis and demonstrated efficient delivery of cytostatic agents to the perfused lung with excellent separation between systemic and pulmonary circulations [1,2,3,4,5,6,7,8,9,10,11,12,13,14]. In an experimental model of sarcoma tumors grown on rodent lungs [10], doxorubicin ILP resulted in high drug uptake in the perfused lung with minimal systemic leakage and toxicity [11].…”

Section: Introductionmentioning

confidence: 99%

Photodynamic Therapy Enhances Liposomal Doxorubicin Distribution in Tumors during Isolated Perfusion of Rodent Lungs

Cheng

Wang

Haouala³

et al. 2011

Eur Surg Res

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Background: Photodynamic therapy (PDT) at low drug-light conditions can enhance the transport of intravenously injected macromolecular therapeutics through the tumor vasculature. Here we determined the impact of PDT on the distribution of liposomal doxorubicin (Liporubicin™) administered by isolated lung perfusion (ILP) in sarcomas grown on rodent lungs. Methods: A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the left lung of Fischer rats. Treatment schemes consisted in ILP alone (400 µg of Liporubicin), low-dose (0.0625 mg/kg Visudyne®, 10 J/cm² and 35 mW/cm²) and high-dose left lung PDT (0.125 mg/kg Visudyne, 10 J/cm² and 35 mW/cm²) followed by ILP (400 µg of Liporubicin). The uptake and distribution of Liporubicin in tumor and lung tissues were determined by high-performance liquid chromatography and fluorescence microscopy in each group. Results: Low-dose PDT significantly improved the distribution of Liporubicin in tumors compared to high-dose PDT (p < 0.05) and ILP alone (p < 0.05). However, both PDT pretreatments did not result in a higher overall drug uptake in tumors or a higher tumor-to-lung drug ratio compared to ILP alone. Conclusions: Intraoperative low-dose Visudyne-mediated PDT enhances liposomal doxorubicin distribution administered by ILP in sarcomas grown on rodent lungs which is predicted to improve tumor control by ILP.

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Isolated lung perfusion with platinum in the treatment of pulmonary metastases from soft tissue sarcomas

Cited by 81 publications

References 26 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

Lung Metastatic Disease: Surgical Resection and Locoregional Chemotherapy

Photodynamic Therapy Enhances Liposomal Doxorubicin Distribution in Tumors during Isolated Perfusion of Rodent Lungs

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