A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

Abstract

Purpose As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-Xow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). Experimental design Gemcitabine at 500, 750 and 1,125 mg/m 2 was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-Xow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2Ј,2Ј-diXuorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-Xow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-Xow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH · 7.2, pO 2 nadir ratio ·0.70 or pCO 2 peak ratio ¸1.35. The tolerability of this procedure was also assessed. Results Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-Xow perfusion, with C max levels in the abdominal circuit of 246 ( §37%), 2,039 ( §77%) and 4,780 ( §7.3%) g/ml for the three dose levels 500, 750 and 1,125 mg/m 2 , respectively. These C max were between 13 ( §51%) and 290 ( §12%) times higher than those measured in the peripheral plasma. 123Similarly, the abdominal exposure to gemcitabine, calculated as AUC t0-20 , was between 5.5 ( §43%) and 200 ( §66%)-fold higher than the systemic exposure. Locoregional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C max and AUC t0-20 , both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to diVerentiate the respective contributions of systemic and regional exposures. A signiWcant correlation (P < 0.05) was found between systemic C max of gemcitabine and the nadir of both leucocytes and neutrophils. Conclusions Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-Xow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m 2 . However, the activity of gemcitabine under hypoxic conditions is not as Wrmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted Wrst to evaluate the tolerance in a phase I study and later on to assess whether it does impr...

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“…Such localized chemotherapy regimens usually offer improved local disease control and reduced systemic toxicity, compared with conventional chemotherapy, therefore, they hold great promise for cancer patients. Other less widely used regional chemotherapies that are not reviewed in this article include administration of chemotherapeutics via pancreatic perfusion (pancreatic cancer) [112,113], celiac axis infusion (pancreatic cancer) [114,115], hypoxic abdominal stop-flow perfusion (gastric cancers) [116,117] and pelvic perfusion (advanced colorectal cancers) [118,119]. Nevertheless, the absolute superiority of some of the newer techniques relative to infusion chemotherapy remains controversial in terms of their improvement in patient survival rate.…”