Isolated Liver Perfusion for Liver Metastases: Pharmacokinetic Advantage?

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ISOLATED LIVER PERFUSION FOR LIVER METASTASES Pharmacokinetic Advantage? T. S. Ravikumar, MD, FACS, and Kim Dixon, MS

The rationale regarding the superiority of intrahepatic administration of chemotherapeutic agents over systemic therapy and the clinical experience suggesting a higher response rate in studies comparing intrahepatic with systemic chemotherapy for colorectal liver metastases provided impetus to expand the regional hepatic therapy options. Chronic low-dose intrahepatic chemotherapy was limited by hepatobiliary toxicity and perhaps the development of acquired tumor resistance. It is therefore reasonable to hypothesize that intermittent bolus administration of high-dose chemotherapy may satisfy the requirement of dose intensification but may obviate the regional toxicity and acquired drug resistance. As outlined earlier in this issue, for drugs with low first pass extraction, such highdose infusion results in systemic exposure that would limit the intrahepatic dose. In an effort to address some of these questions, we initiated a phase 1/11 clinical trial in April 1990 to explore the use of a percutaneous double balloon catheter for hepatic venous isolation and detoxification of the drugs after high-dose intrahepatic infusion. Curley and colleagues (see article elsewhere in this issue) have summarized their experience with the use of this double balloon device in the treatment of hepatocellular cancers. We have earlier reported on the safety and feasibility of using this system for liver tumor management.I8Our experience is largely in the treatment of liver metastases. For colorectal liver metastases, we used 5-fluorouracil (FU), whereas doxorubicin was used for treating noncolorectal liver metastases. A Fibonacci dose escalation schema was used in a phase 1/11 concept. Although the choice of 5-FU was based on its proven track record in colorectal tumors, we believe that the approach of isolated liver perfusion is best suited for non-cell cycle specific agents. In this article we analyze the pharmacokinetic data

From the Cancer Institute of New Jersey, and the Departments of Surgery, Molecular Genetics, and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, New Brunswick, New Jersey THE SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 5 NUMBER 2 APRIL 1996

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on doxorubicin, a non-cell cycle specific drug with a wide range of antitumor efficacy. PATIENTS, METHODS AND OVERALL RESULTS

A total of 25 isolated liver perfusion procedures were carried out in nine patients with either primary hepatocellular cancer or liver metastasis from sarcoma or melanoma during the period from 1990 to 1993. The procedures were accomplished under local anesthesia or intravenous sedation, with only an overnight hospital stay. Percutaneous selective catheterization of hepatic artery was accomplished in the angiography suite, and the patients were brought to the operating room for placement of inferior vena cava double balloon catheter (Delcath System, Stamford, CT) through the femoral vein to allow hepatic venous blood extraction. An internal jugular vein catheter was inserted for venous reinfusion. The Delcath catheter was positioned in retrohepatic vena cava under fluoroscopic control to isolate hepatic venous output. The hepatic venous blood was passed through a venovenous bypass circuit through activated charcoal filters to detoxify doxorubicin and reinfused into the jugular venous catheters. Doxorubicin (30minute infusion and 60-minute detoxification)dose escalation was as follows: 50, 75, 90, and 120 mg/m2. The patients received heparinization during venovenous bypass. The catheters were removed at the end of the procedure after reversal of heparinization, and pressure dressings were applied at catheter entry sites. This liver perfusion procedure was repeated at 3-week intervals. A detailed summary of this Delcath system and analysis of toxicities are reported elsewhere.18 Two of the nine patients achieved near-complete remission, with 95% reduction of tumor volume. One of the two patients had metastatic melanoma, and the other metastatic retroperitoneal sarcoma. The former patient with extensive melanoma survived 23 months, and the latter with sarcoma is alive 30 months after initiation of therapy.

In order to study the efficiency of the Delcath system to isolate and detoxify hepatic venous output, we performed serial pharmacokinetic estimations of the blood from extracorporeal circuit (before and after charcoal filtration) and peripheral circulation. Blood samples were obtained at the following time points: before drug infusion, mid-infusion, end infusion, and 2,5,10,15,30, and 60 minutes after infusion. The two major toxicities of doxorubicin are hematologic and cardiac. The hematologic toxicity is dose limiting and correlates with the values of doxorubicin "area under the concentration curve" (AUC). The cardiotoxicity correlates with peak concentrations of the drug and the total cumulative dose. We therefore estimated both the AUC and peak concentrations, both in hepatic venous output and systemic circulation. Furthermore, the efficiency of the filter was calculated by the differences in prefilter and postfilter doxorubicin levels. The extraction efficiency of the filters in the Delcath system was calculated as a differencebetween prefilter and postfilter blood concentrations at peak blood levels. This invariably occurred at the end infusion blood sampling time. The percentage extraction at various doses were as follows: 72.2%, 82.3%, 68.6%, and 70.6% at 50, 75, 90, and 120 mg/m2 of doses, respectively. These data imply that over the therapeutic range of doxorubicin concentrations investigated, the filters functioned efficiently. These

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data also may imply that because the percent extraction remained constant throughout this dose range, net concentration of doxorubicin entering the systemic circulation from the inflow of the venovenous bypass circuit would be directly proportional to the dose of hepatic arterial infusion. The peak concentrations of doxorubicin in the hepatic venous effluent (prefilter levels) and peripheral systemic circulation also were calculated in order to observe the correlation with hematologic toxicity. The peak concentrations of doxorubicin in the hepatic veins were 2.88, 1.65, 4.23, and 6.93 pmol/L, respectively, for 50, 75, 90, and 120 mg/m2 dose of doxorubicin. The corresponding systemic levels were 0.83,0.52,2.04, and 1.06, respectively, thereby demonstrating at least threefold to fourfold reduction in systemic peak levels when compared with hepatic venous peak levels. The AUC level for doxorubicin followed a similar trend when comparing prefilter and postfilter concentrations. The percent extraction by the filter ranged from 65% to 85% in the dose range of 50 to 120 mg/m2. The more significant finding, however, was in the AUC levels in systemic circulation. A comparison of postfilter AUC with systemic AUC demonstrated significant interpatient and intrapatient (between different treatments) variability. Because of these variations, significant increase in systemic AUC when compared with postfilter AUC could not be demonstrated. However, there was an 8% to 150% difference observed in various treatments. These pharmacokinetic data were corroborated by the pharmacodynamic evaluation in correlating the toxicity with the drug levels. We found grade 3 and grade 4 toxicities in some patients receiving 90 and 120 mg/m2 of doxorubicin. These pharmacokinetic and pharmacodynamic data suggest that there are other factors involved in systemic toxicity than can be explained by escape of the drug through the filters alone. Based on the previous findings, one can design a model of the perihepatic circulation as well as intrahepatic physiology that may retain doxorubicin for longer times than 1 hour. COMPARISON OF DOXORUBlClN PHARMACOKINETICS: INTRAVENOUS, INTRA-ARTERIAL INFUSIONS AND LIVER PERFUSION

In order to compare the pharmacokinetics of isolated liver perfusion using the Delcath system with the conventional administration of doxorubicin both intravenously as well as intra-arterially into the liver, our data were analyzed in the context of the published information in the literature. In a computer-based literature search using the standard key words of pharmacokinetics, doxorubicin, intra-arterial, intravenous, infusion, 20 studies were found to contain information relevant to our analysis; they are contained in Tables 1 through 3. The tables are arranged according to the method of administration of doxorubicin. These methods of administration are intravenous bolus administration, intravenous prolonged infusion, or intra-arterial bolus or infusion. In each table the studies are grouped according to the dose of administration of doxorubicin. We found tremendous variation in terms of the sampling times for drug pharmacokinetics, and the results also were expressed in several different formats (e.g., pmol, ng, AUC, peak concentration only, etc.). In order to make a valid comparison, the data are derivitized to conform to uniform nomenclature and are represented as AUC in ng, h/mL. These data are then collated to obtain mean values of the studies and are represented as histograms in Figures 1 and 2. As demonstrated in Tables 1 and 2 and Figures 1 and 2, there is linearity in terms of systemic AUC with increasing dose of doxorubicin ranging from 15 to

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Table 1. PHARMACOKINETICS OF BOLUS INTRAVENOUS ADMINISTRATION OF DOXORUBlClN Dose Systemic Author (mglm2) AUC (ng, hlmL) Erttmann7 15 519.5 Twelvesz1 25 1619 Erttmann,7Preiss,15Leca12 30 951-1 353 Mro~s,l~Erttmann,~ Ratain17 50 1413-2055 Camaggi5 60 1974 Preiss,lST~elves,~l Rossi20 75 2591-6867

150 mg/m2. Although there is no significant difference in the systemic AUC between intravenous bolus administration and intravenous prolonged infusion, the attenuation of peak concentrations obtainable by prolonged infusion may have a significant impact in minimizing the toxicities of doxorubicin relating to peak levels. In comparing the systemic AUC between intravenous administration and intra-arterial administration (Table 3), it is also obvious that without institution of detoxification filters into the hepatic venous segment, there was no advantage in minimizing systemic AUC by using the hepatic arterial route. In other words, due to the poor hepatic extraction of doxorubicin, the systemic AUC levels were comparable between intravenous and intra-arterial administration. The seminal comparisons to be made as a result of this pharmacokinetic analysis relate to the significance of hepatic venous drug detoxification by the use of Delcath system. The data represented in the tables and the histograms demonstrate that systemic drug exposure even at 15 mg/m2 of doxorubicin (520 ng, h/mL) is comparable to the systemic AUC for 90 to 120 mg/m2 of doxorubicin given by hepatic artery infusion with detoxification by Delcath system (252-715 ng, h/mL). This low systemic AUC is in the context of high hepatic venous AUC, which is considered to be reflective of liver AUC (1188-2090 ng, h/mL). Although there is significant variability among the studies reviewed here, one could estimate that for the systemic infusion of doxorubicin in the range of 75 to 100 mg/mz, systemic AUC is in the range of 2000 ng, h/mL. Based on our study of the Delcath system and the study of Ku et all0using a similar system of hepatic vein detoxification, the systemic AUC for the dose range 75 to 120 mg/m2 is in the range of 650 ng, h/mL. This range provides us with an estimate at least a threefold reduction in systemic drug exposure using the Delcath system in the therapeutic range of doxorubicin, when compared with either intravenous infusion or intra-arterial administration without detoxification. Further physiologic modeIing of the system indicates that an additional advantage of peak drug level in the liver and higher liver exposure to doxorubicin Table 2. PHARMACOKINETICS OF INTRAVENOUS INFUSION OF DOXORUBlClN Author Yoshidazz BressoIle3 Rodvoldlg Bronchud4 Bronchud4 Bronchud4 Bronchud4

Dose (mglm2) 50 28-72 50-70 75 100 125 150

Systemic AUC (ng, h1mL) 1160 2173 1618 1663 1864 2283 2430

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Table 3. PHARMACOKINETICS OF HEPATIC INTRA-ARTERIALADMINISTRATION OF DOXORUBlClN WITHOUT DETOXIFICATION Dose Systemic Author AUC (ng, hlmL) (mslm2)

does exist. Because we did not analyze hepatic parenchymal concentrations per se in the study, we could only indirectly estimate the liver exposure of doxorubicin by subtracting the value of hepatic venous drug levels from hepatic arterial concentration of doxorubicin administered. However, this model assumes that all the hepatic venous output is captured by the prefilter hepatic venous flow into the cartridge. We found that this assumption is probably incorrect based on two observations. First, while the hepatic venous output should be in the range of 1000 to 1400 mL/min, our venovenous bypass flow rate usually ranged between 500 and 700 mL/min. Second, the systemic AUC was, in general, higher than postfilter AUC, suggesting that some of hepatic venous output bypassed the filters, perhaps through venous collaterals. Therefore, liver exposure has to be calculated by another physiologic model. An alternative approach to overcoming this missing information on a ratio of hepatic venous output that is bypassing the filtration system is to use the information from the study of Garnick et Garnick and coworkers8 have calculated the hepatic extraction ratio of doxorubicin over wide concentrations of dose and duration of infusion into the hepatic artery. Their study suggests that the hepatic extraction ratio varied from 0.05 to 0.5, with an average estimate of 0.3. These data are in keeping with the other information from the literature of about 30% extraction of doxorubicin during first pass. We also observed that in our patients treated with the Delcath system using doxorubicin, the urinary metabolite excretion (reflected by orange discoloration of the urine) often increased after 1hour of liver perfusion and detoxification.This observation suggested that the liver may act as a temporary reservoir for doxorubicin, releasing both active and metabolized form of the drug during 1 to 4 hours after completion of liver perfusion. This latter observation is also in keeping with IV Bolus

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Dose Figure 2. A comparison of systemic AUC with hepatic venous AUC (ng, h/mL) following intraarterial administration of doxorubicin (dose mg/m2).The value for 30 mg/m2is without hepatic venous detoxification, whereas 50 to 120 mg/m2 are from studies using detoxification filters. Dark bar = systemic; light bar = hepatic.

o u r pharmacokinetic d a t a of grade 3 / 4 toxicity i n 90 t o 120 m g / m 2 d o s e of doxorubicin. If w e a s s u m e a 30% extraction of first pass of doxorubicin through the liver, t h e calculated hepatic exposure would b e 30% higher t h a n the hepatic vein AUC. This model gives us hepatic AUC of 1544 ng, h / m L (1188 ng, h / m L X 1.3), w i t h systemic AUC of 663 ng, h / m L for the s a m e dose. I n other words, t h e Delcath system using 90 m g / m 2 of doxorubicin provides systemic A U C comparable t o 15 t o 25 m g / m 2 of intravenous dose b u t a t the s a m e time achieves hepatic AUC comparable to 75 t o 100 m g / m 2 of doxorubicin. Acknowledgments We deeply appreciate the expert manuscript preparation by Ms. Linda Moriarty and the study support provided by Delcath Systems in Stamford, Connecticut.

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