Pedro Reck Dos Santos1, Jin Sakamoto1, Manyin Chen1, Virginia Linacre1, Chantel Arce1, Mingyao Liu1, Thomas K Waddell1, Shaf Keshavjee1, Marcelo Cypel2. 1. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada. 2. Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute; and Division of Thoracic Surgery, Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada. Electronic address: marcelo.cypel@uhn.ca.
Abstract
BACKGROUND: In vivo lung perfusion (IVLP) is a promising adjuvant treatment of lung metastases, allowing the localized delivery of drugs to the lungs without systemic exposure. Previous experimental and clinical data resulted in variable efficacy and frequent toxicity. Our objectives were to demonstrate the feasibility and safety of a novel protective IVLP technique coupled with the delivery of sarcoma-based chemotherapy to the lung. METHODS: The left pulmonary artery and veins in pigs were cannulated and clamped. Left lung IVLP was performed for 4 hours. Doxorubicin (Dox) at a standard clinical dose of 75 mg/m(2) was used, followed by 150 and 225 mg/m(2). Dox 75 mg/m(2) combined with ifosfamide (Ifos) 6 g/m(2) was also tested. After IVLP, blood reperfusion was allowed for 4 hours. Lung physiology was assessed and biopsy samples were obtained for histologic assessment of acute lung injury (ALI), inflammatory profile, and cell death. Lung tissue levels, perfusate, and plasma levels of Dox were measured during the procedure. RESULTS: Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p = 0.36, respectively). Tissue levels of Dox were 70.3 μg/g homogeneously distributed in the lung (p = 0.12). No drug was detected systemically. Dox 150 mg/m(2) and 225 mg/m(2) showed incremental ALI. CONCLUSIONS: IVLP for 4 hours with Dox 75 mg/m(2) alone or combined with Ifos was well tolerated, without measurable ALI. High drug levels in perfusate and lung tissue were found without systemic leakage. A dose-related toxicity was observed with increases in Dox doses.
BACKGROUND: In vivo lung perfusion (IVLP) is a promising adjuvant treatment of lung metastases, allowing the localized delivery of drugs to the lungs without systemic exposure. Previous experimental and clinical data resulted in variable efficacy and frequent toxicity. Our objectives were to demonstrate the feasibility and safety of a novel protective IVLP technique coupled with the delivery of sarcoma-based chemotherapy to the lung. METHODS: The left pulmonary artery and veins in pigs were cannulated and clamped. Left lung IVLP was performed for 4 hours. Doxorubicin (Dox) at a standard clinical dose of 75 mg/m(2) was used, followed by 150 and 225 mg/m(2). Dox 75 mg/m(2) combined with ifosfamide (Ifos) 6 g/m(2) was also tested. After IVLP, blood reperfusion was allowed for 4 hours. Lung physiology was assessed and biopsy samples were obtained for histologic assessment of acute lung injury (ALI), inflammatory profile, and cell death. Lung tissue levels, perfusate, and plasma levels of Dox were measured during the procedure. RESULTS: Lungs treated with Dox 75 mg/m(2) alone or combined with Ifos showed stable function throughout the procedure, without evidence of ALI (p = 0.12 and p = 0.36, respectively). Tissue levels of Dox were 70.3 μg/g homogeneously distributed in the lung (p = 0.12). No drug was detected systemically. Dox 150 mg/m(2) and 225 mg/m(2) showed incremental ALI. CONCLUSIONS: IVLP for 4 hours with Dox 75 mg/m(2) alone or combined with Ifos was well tolerated, without measurable ALI. High drug levels in perfusate and lung tissue were found without systemic leakage. A dose-related toxicity was observed with increases in Dox doses.
Authors: J Hunter Mehaffey; Eric J Charles; Sarah Schubert; Morgan Salmon; Ashish K Sharma; Dustin Money; Mark H Stoler; Victor E Laubach; Curtis G Tribble; Mark E Roeser; Irving L Kron Journal: J Thorac Cardiovasc Surg Date: 2017-09-14 Impact factor: 5.209
Authors: Barbara Bojko; Nikita Looby; Mariola Olkowicz; Anna Roszkowska; Bogumiła Kupcewicz; Pedro Reck Dos Santos; Khaled Ramadan; Shaf Keshavjee; Thomas K Waddell; German Gómez-Ríos; Marcos Tascon; Krzysztof Goryński; Marcelo Cypel; Janusz Pawliszyn Journal: J Pharm Anal Date: 2020-09-02