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

Putte, Bart P. van; Hendriks, Jeroen; Romijn, Sander; Pauwels, Bea; Vermorken, Jan B.; Schil, Paul Van

doi:10.1016/j.jtcvs.2004.07.045

Cited by 17 publications

(13 citation statements)

References 17 publications

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“…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nodes and lung tissue, although this approach is applied only once or twice per patient because of its invasive nature (unpublished data).…”

mentioning

confidence: 98%

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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mentioning

confidence: 98%

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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“…The combination of melphalan with gemcitabine resulted in a beneficial effect prolonging survival even more compared to single-therapy with gemcitabine in the same model (145).…”

Section: Gemcitabinementioning

confidence: 94%

“…The combination therapy of melphalan with TNF-α and with gemcitabine was also tested. As mentioned above, TNF-α had no additional benefit, but the combination of melphalan with gemcitabine resulted Mets: metastases, BSO: buthionine sulfoximine, ILuP: isolated lung perfusion, FUDR: 5-fluorodeoxyuridine, TNF-α: Tumour necrosis factor alpha in a superior result compared to single therapy with one of these two drugs in the treatment of colorectal carcinoma lung metastases (145). This is the first and only reported study showing the additional effects of two chemotherapeutic agents in the setting of ILuP and it is a promising tool for future phase I clinical studies.…”

Section: Melphalanmentioning

confidence: 98%

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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“…Median survival time of ILuP-treated animals was significantly longer compared to intravenous treatment. Combining several chemotherapeutic drugs was feasible in the same experimental setting with melphalan and gemcitabine yielding the best survival results [44].…”

Section: Melphalanmentioning

confidence: 99%

Isolated lung perfusion and related techniques for the treatment of pulmonary metastases☆

Schil

Hendriks

Putte

et al. 2008

European Journal of Cardio-Thoracic Surgery

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Surgical resection is a widely accepted treatment for pulmonary metastases on the condition that a complete resection can be obtained. However, many patients will develop recurrent disease in the thorax despite the use of systemic chemotherapy, dosage of which is limited because of systemic toxicity. Similar to the basic principles of isolated limb and liver perfusion, isolated lung perfusion is an attractive and promising surgical technique for the delivery of high-dose chemotherapy with minimal systemic toxicity. The use of biological response modifiers, like tumour necrosis factor, is also feasible. Other related methods of delivering high-dose locoregional chemotherapy include embolic trapping (chemo-embolisation) and pulmonary artery infusion without control of the venous effluent. Isolated lung perfusion has proven to be highly effective in experimental models of pulmonary metastases with a clear survival advantage. Lung levels of cytostatic drugs are significantly higher after isolated lung perfusion compared to intravenous therapy without systemic exposure. Phase I human studies have shown that isolated lung perfusion is technically feasible with low morbidity and without compromising the patient's pulmonary function. Further clinical studies are necessary to determine its definitive effect on local recurrence, long-term toxicity, pulmonary function and survival.

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

Cited by 17 publications

References 17 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

Isolated lung perfusion and related techniques for the treatment of pulmonary metastases☆

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