Clinical and Preclinical Trials of Isolated Liver Perfusion for Advanced Liver Tumors: Primary Liver Tumors

MANAGEMENT OPTIONS IN PRIMARY AND SECONDARY LIVER CANCER

CLINICAL AND PRECLINICAL TRIALS OF ISOLATED LIVER PERFUSION FOR ADVANCED LIVER TUMORS Primary Liver Tumors Andrew M. Lowy, MD, and Steven A. Curley, MD

Drugs used for cancer chemotherapy generally have a narrow therapeutic index. Thus, systemic toxicity in non-neoplastic tissues is the principal impediment to achieving enhanced tumor cytotoxicity by increasing the dose intensity of chemotherapeutic agent^.^ Because primary and metastatic liver tumors derive their blood supply from the hepatic artery, regional treatment of liver malignancies with hepatic arterial infusion (HAI) of chemotherapeutic drugs has been used in an attempt to increase tumor exposure to the drugs and reduce systemic chemotherapy-related toxicity.I7However, even HA1 may fail to achieve drug levels sufficient to increase tumor cytotoxicity before systemic toxicity forces a reduction in treatment dosing. This is because chemotherapeutic agents with low rates of hepatic extraction produce significant systemic drug levels after HAI.

RATIONALE FOR REGIONAL CHEMOTHERAPY

The relative pharmacokinetic advantage (Rd) for arterial infusion of drug can be expressed as: Rd = Rt/Rs = 1 + CI,,/Q(l - E) where Rt is the increased target (organ or regional site) exposure to the drug, Rs is decreased systemic drug exposure, Cl,, is the total body clearance of the drug, Q is the blood flow through the infused artery, and E is the rate of regional drug extraction. Three variables (Q,E, and Cl,,) in this equation may be manipulated to effect a change in the From the Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas THE SURGICAL ONCOLOGY CLINICS OF NORTH AMERICA VOLUME 5 NUMBER 2 APRIL 1996

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L O W & CURLEY

pharmacokinetics of intra-arterial drug infusion and thereby improve drug exposure at the target site. For HAI, blood flow (Q) can be reduced by using vasoconstrictors such as angiotensin I1 or by combining arterial infusion with mechanical occlusion of the artery.6,18However, reduction of hepatic blood flow has allowed only negligible increases in chemotherapeutic dosage. Agents with a high first-pass hepatic extraction (E) rate are preferable for hepatic infusional therapy because this rate decreases systemic drug exposure. The fluoropyrimidines (floxuridine and 5-fluorouracil) have been used extensively for HA1 treatment of primary and metastatic liver tumors because of their high rate of hepatic e~traction.~," Although systemic drug exposure is limited after HA1 of fluoropyrimidines, hepatobiliary toxicity has prevented dose escalation, particularly with floxuridine, which has been associated with biliary s c l e r o ~ i s . ~ , ~ , ~ ~ The venous drainage of the human liver is isolated to a short segment of the inferior vena cava; thus, isolating the complete venous outflow of the liver is possible.14We have systematically studied a novel dual-balloon vena cava catheter to achieve complete hepatic venous isolation (CHVI). The isolated total hepatic venous return is pumped through an extracorporeal circuit containing carbon chemofilters. The system used for CHVI and extracorporeal chemofiltration (CHVI-CF)(Fig. 1)was designed to affect the last parameter (Cl,,) in the equation for pharmacokinetic advantage of regional chemotherapy infusion. We studied this system to determine if, by capturing the total hepatic venous outflow and filtering it prior to returning it to the systemic circulation, we could achieve a pharmacologic high first-pass drug clearance and effectively increase the Cl,,. If this system of CHVI-CF were effective, it would allow delivery of increased dosages of chemotherapeutic drugs by HA1 while reducing systemic exposure to the drug. This would permit dose escalation of chemotherapeutic agents with lower rates of hepatic extraction. FEASIBILITY STUDY

The initial study of the CHVI-CF system was designed to assess the feasibility of the technique. Adult domestic pigs were used for this study.2 The diameter of the vena cava and hepatic venous drainage pattern in pigs is similar to that in humans. This similarity permitted use of the identical dual-balloon vena cava catheter and extracorporeal circuit designed for treatment of human liver cancers. Unlike many systems designed to isolate hepatic venous return, an operation is not required with the CVHI-CF system because all catheters are placed percutaneously. Our initial studies with this CVHI-CF system produced two important results: (1) We gained a thorough understanding of the hemodynamic effects related to this system. When animals were placed on the CVHI circuit with the chemofilters excluded from the blood flow, no significant change in systolic or diastolic blood pressure or in cardiac output was seen. However, when the chemofilters were included in the circuit (CVHI-CF), a rapid 50% decrease in blood pressure and cardiac output occurred. Further evaluation of the filters revealed that they avidly bind circulating catecholamines. The chemofilter-related reduction in blood pressure and cardiac output was abrogated by initiating a systemic phenylephrine drip before opening the chemofilters to the bypass circuit. (2) We found that the CHVI-CF system successfully reduced systemic drug exposure to chemotherapeutic drugs administered by HAI. Three drugs were chosen for the feasibility trial: doxorubicin, mitomycin C, and cisplatin. These drugs have low to moderate rates of hepatic extraction and are known to have systemic dose-limiting toxicities when given by HAI.',12By measuring prefilter (hepatic venous), postfilter, and systemic

-POST-FILTER HEPATIC VEIN

CARBON FILTERS

PRE-FILTER

CAPACITANCE

CHEMOTHERAPV-

PUMP

Figure 1. The system used to deliver hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration. Demonstration of the placement of a transfemoral arterial catheter to administer doxorubicin, a transfemoral venous dual-balloon catheter to achieve complete hepatic venous isolation, and an internal jugular venous catheter to return blood after extracorporeal chemofiltration (left). Stopcocks placed in the tubing proximal and distal to the chemofilters are used to obtain prefilter (hepatic venous) and postfilter blood samples, respectively. Demonstration of the position of the tip of the hepatic arterial catheter into the distal proper hepatic artery to prevent infusion of doxorubicin to extrahepatic organs (right). The dual-balloon vena cava catheter is positioned under fluoroscopic guidance to isolate the total hepatic venous outflow. (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

levels of drug during the HA1 and for 1 hour after HAI, we demonstrated that systemic levels of doxorubicin and mitomycin C were at least 90% lower than hepatic venous levels of these drugs. The reduction in systemic exposure to cisplatin was less efficient, with a 65% reduction in systemic drug level compared with hepatic venous drug level. We predicted and confirmed that this reduction was related to the high fraction of cisplatin bound to serum proteins; the carbon chemofilters do not remove circulating proteins. However, the feasibility studies did not provide information on toxicity or survival. We learned how to counteract the hemodynamic effects caused by the CHVI-CF circuit and demonstrated its potential efficacy in reducing systemic exposure to chemotherapeutic drugs during high-dose chemotherapy HAI. Thus, the next step was to assess pharmacologic toxicity and survival after HA1 with the CVHI-CF circuit. PRECLlNlCAL PHARMACOLOGIC AND TOXICITY STUDY

Pigs were used again to perform experiments intended to assess hepatobiliary toxicity and survival after HA1 of doxorubicin with CHVI-CF.3During this study, we conducted detailed pharmacokinetic studies of HA1 of doxorubicin with CHVICF, while ascertaining if the increase in therapeutic index of doxorubicin using this system was associated with hepatobiliary toxicity. Animals were treated with a 10-minute HA1 of doxorubicin at a dose of 1 or 3 mg/kg. The first dose is equivalent to the maximum tolerated dose in humans for a bolus administration of doxorubicin. The serum doxorubicin levels after HA1 of doxorubicin (1 mg/kg) with CVHI-CF are shown in Figure 2, whereas the re-

W Prefilter El Postfilter Systemic

"

5

10

15

20

30

60

Time (in minutes) Figure 2. Mean plasma concentrations of doxorubicin (DOX) in prefilter (hepatic venous), postfilter, and systemic blood samples from four pigs that received 10-minute hepatic arterial infusion of 1 mglkg DOX, by means of complete hepatic venous isolation and dual-balloon vena cava catheter and extracorporeal chemofiltration. Time 0 = beginning of 10-minute doxorubicin infusion; time 10 = completion of doxorubicin infusion. Values represent mean +- SEM. (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

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sults for the 3 mg/kg dose are shown in Figure 3. An important reference value for doxorubicin administration is 1000 ng/mL. Previous studies have demonstrated that significant cardiac and bone marrow toxicity occurs when the systemic serum level of doxorubicin exceeds 1000 ng/mL.13 As seen in Figure 2, the peak prefilter (hepatic venous) level of doxorubicin exceeds 2000 ng/mL. However, the peak systemic level of doxorubicin was only 200 ng/mL, significantly below the 1000 ng/mL level associated with systemic doxorubicin toxicity. The more than 90% reduction in systemic doxorubicin levels compared with prefilter levels was noted again in animals treated with 3 mg/kg (Fig. 3).The peak prefilter level was 5800 ng/mL, whereas the peak systemic level was 210 ng/mL. All animals that underwent HA1 of doxorubicin with CVHI-CF survived the procedure and recovered uneventfully. Animal activity and eating patterns were normal within 24 hours of the procedure. Hepatocellular toxicity related to the HA1 of doxorubicin was assessed for 14 days after drug administration. Animals treated at a dose of 1 mg/kg had no significant change in serum liver tests (alkaline phosphatase, total and direct bilirubin, aspartate aminotransferase, and alanine aminotransferase) in the 14 days after HA1 of doxorubicin, compared with pretreatment values. In animals treated with the 3 mg/kg dose, the only abnormality was a transient elevation in aspartate aminotransferase 3 days after treatment, which had returned to normal by the seventh day. All animals were sacrificed after the CVHI-CF procedure, and pathologic evaluation revealed that 50% of the animals treated at each dose had minimal periportal inflammation without other changes in liver architecture. The remaining animals in each group had entirely normal livers. This study in a non-

W

Prefilter

El Postfilter I3 Systemic

Time (in minutes) Figure 3. Mean plasma concentrations of doxorubicin (DOX) in prefilter (hepatic venous), postfilter, and systemic blood samples from four pigs that received 10-minute hepatic arterial infusion of 3 mglkg DOX by means of complete hepatic venous isolation and dual-balloon vena cava catheter and extracorporeal chemofiltration. Time 0 = beginning of 10-minute doxorubicin infusion; time 10 = completion of doxorubicin infusion. Values represent mean SEM. (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

tumor-bearing animal model thus demonstrated that high-dose HA1 of doxorubicin with CVHI-CF was well tolerated without significant acute hepatobiliary toxicity. PRECLlNlCAL LIVER TUMOR MODEL

Increased serum drug concentrations do not necessarily reflect target tissue drug levels. Although the prior animal studies showed it was possible to administer higher doses of chemotherapeutic drug by HA1 with CHVI-CF, we had no evidence that this correlated with increased tissue or tumor levels of drug. To examine this question, we chose to use VX-2 tumors in a rabbit animal model. The VX-2 tumor is a hypervascular stromal cell tumor that resembles hepatocellular carcinoma (HCC) in its clinical behavior. Therefore, it proved a useful model to study tissue levels of drug after regional infusion of doxor~bicin.~ The first experiments in this rabbit study were performed to determine the maximal tolerated dose of doxorubicin administered by a 5-minute HA1 or portal venous infusion (PVI) without CHVI-CF. The maximum tolerated dose in both the HA1 and PVI animals was 1.5 mg/kg of doxorubicin. All animals receiving doses of more than 1.5 mg/kg died as a result of chemotherapy-related systemic toxicities. To confirm that HA1 of doxorubicin produced higher intratumoral levels of drug than did PVI, the next groups of animals received a 5-minute HA1 or PVI of doxorubicin (3 mg/kg) with CVHI-CF. Prefilter, postfilter, and systemic serum samples were obtained and again demonstrated a 90%reduction in systemic levels of doxorubicin compared with prefilter drug levels. As seen in Table 1, HA1 of doxorubicin produced significantly higher intratumoral levels of drug than did PVI of an identical dose of doxorubicin. Two other key points are illustrated by the table: (1)tissue levels in both the heart and kidney were reduced significantly in animals treated with CHVI-CF compared with animals treated with HA1 or PVI alone, and (2) the intratumoral level of doxorubicin in animals treated with HA1 of 3 mg/kg with CVHI-CF was almost twofold greater than the intratumoral levels after treatment with the maximum tolerated HA1 dose of 1.5 mg/kg (without CVHI-CF) (40.9 k 7.4 ng of doxorubicin per gram of tumor versus 22.1 k 5.6 ng/ g; P < 0.01). Hepatic arterial infusion of doxorubicin (5 mg/kg) produced further increases in intratumoral levels of the drug (Table 2). Again, at the 5 mg/kg dose, the serum pharmacology data confirmed a marked reduction in systemic doxorubicin levels with CVHI-CF, which correlates with the reduced drug levels in the heart and kidneys as noted in Table 2. The final set of experiments in this study were performed to assess tumor response. At various time intervals after treatment, animals were sacrificed and a pathologic evaluation of the treated VX-2 tumor and the liver was performed.

Table 1. TISSUE DOXORUBlClN CONTENT 30 MINUTES AFTER HA1 OR PVI OF 3 MGlKG DOXORUBlClN WITH OR WITHOUT CHVI-CF HAIwithCHVI-CF HA1 alone (control) PVI with CHVI-CF PVl alone (control)

Liver

Tumor

Heart

38.1t6.6* 44.7 +. 9.0 28.7 t 2.2 23.6 t 4.0

40.9t7.4 40.2 t 5.5 9.9 a 2.0 9.8 t 2.3

2 . 6 t 1.2t 33.2 t 3.1 8.3 ? 1.7$ 48.3 t 13.6

'Data are ng doxorubicin/g of tissue and are presented as mean ISEM (n ( P < 0.001 CHVI-CF versus control by Student's paired, two-tailed t tcst. * P < 0.01 CHVI-CF versJs control by Student's paired, two-tailed t test.

Kidney

=

5.6-c 81.7 t 7.2 t 65.4 ? 5).

1.lt 17.2 2.lt 7.4

435

CLINICAL AND PRECLINICAL TRIALS OF ISOLATED LIVER PERFUSION

Table 2. TISSUE DOXORUBlClN CONTENT 30 MINUTES AFTER HA1 OF 5 MG/KG DOXORUBlClN WITH OR WITHOUT CHVI-CF

HA1 with CHVI-CF HA1 alone (control)

Liver

Tumor

Heart

Kidney

56.6 k 7.1* 64.4 2 9.2

61.1 ? 6.0 70.6 10.5

5.9 2 2.9t 71.4 ? 10.5

6.4 2 1.6t 136.2 14.1

+

+

*Data are ng doxorubicinlg of tissue and are presented as mean ? SEM (n = 5) t P < 0.001 CHVI-CF versus control by Student's paired, two-tailed ttest.

Control animals treated with HA1 of doxorubicin (1.5 mg/kg) without CHVI-CF showed progression of the VX-2 tumors 7 and 14 days after treatment. However, animals treated with 3 mg/kg with CVHI-CF showed significant necrosis of the tumors at 7 and 14 days and had no progression of the tumor within the liver. Areas of the liver not involved by tumor showed no evidence of inflammation or alteration in normal hepatic architecture. Thus, the third preclinical study established that CHVI-CF significantly reduced systemic serum and tissue levels of doxorubicin after HA1 while increasing the intratumoral level of drug and enhancing tumor cytotoxicity. HUMAN PHASE 1 TRIAL

Based on hemodynamic, pharmacologic, and tumor response data obtained in the preclinical trials of this CHVI-CF system, we initiated a phase 1 trial of this .~ adminsystem in patients with unresectable hepatocellular ~ a n c e rDoxorubicin istered by systemic intravenous infusion or HA1 has produced antitumor response in 20% to 40% of patients with hepatocellular cancer.',15The doxorubicin dose that can be administered by HA1 is not significantly greater than intravenous doses because of the relatively low hepatic extraction and dose-limiting systemic toxicities. Ten patients received a 20-minute HA1 of doxorubicin with CHVI-CF, including 6 men and 4 women with a mean age of 56 years (range, 39 to 71 years). Patient characteristics are summarized in Table 3. Seven of the 10 patients had positive serologic results for hepatitis B surface antigen, and 8 had elevated serum alphafetoprotein levels. The mean maximum diameter of the tumors before treatment was 9.5 cm (range, 6-14 cm). The 10 patients who received HA1 of doxorubicin underwent a total of 17 treatments on protocol (range: one to three treatments per patient). All catheters were placed percutaneously using local anesthesia and light intravenous sedation. In no case was general anesthesia required. The complications associated with treatment also are listed in Table 3. We noted that 9 of 10 patients who underwent treatment on this protocol had a reduction in systolic and diastolic blood pressure when blood flow in the bypass pump circuit was directed through the carbon chemofilters (Table 4). The transient hypotension was treated successfully by continuous intravenous infusion of phenylephrine in the 9 patients. Six patients had a treatment-related complication. Two weeks after his first treatment, patient 4 developed a femoral deep venous thrombosis and swelling of the leg on the side of the femoral vein access site. Although this problem required hospitalization for anticoagulation, the patient successfully underwent a second treatment with no further sequelae. Patient 5 developed severe nausea and vomiting 2 days after treatment and was successfully treated as an outpatient with antiemetic medication and intravenous fluids. Re-evaluation of his pretreatment angiogram revealed an arterial-portal venous shunt with reversal of flow in the

w

Table 3. PATIENT CHARACTERISTICS, COMPLICATIONS, TREATMENT RESPONSE, AND OUTCOME Patient Number 1

Sex

Age (years)

Tumor Diameter (cm)*

Hepatitis B Positive

Elevated Serum AFP

Prior Systemic Chemotherapy

HA1 DOX Dose (mglmz)

Male

66

10

Yes

No

No

60

Number of CompliTreatments cations 3

None

Treatment Response

Status

> 25% tumor

DOD 20 m o t

reduction

2

Male

39

8

Yes

Yes

No

60

3

None

> 50% tumor reduction

Resected; alive NED 17 mo

3

Female

69

12

No

Yes

Yes

90

2

None

No response

DOD 6 mo

4

Male

71

10

No

Yes

No

90

2

Femoral DVT

> 50% tumor

Resected; alive NED 13 mo

Missed AV shunt

> 25% tumor

AWD 13 mo

Balloon failure

> 25% tumor reduction

AWD 7 mo

5 6

Male Female

65 52

14 9

Yes Yes

No

No

Yes

No

90 120

1 2

reduction

reduction

7

Female

40

8

Yes

Yes

Yes

120

1

None

Tumor progression

DOD 2 mo

8

Male

52

9

No

Yes

Yes

120

1

Grade 3 liver toxicity

No response

AWD 3 mo

9

Female

52

8

Yes

Yes

Yes

120

1

Grade 3 liver toxicity

> 25% tumor reduction

AWD 2 mo

Grade 3 liver toxicity

> 25% tumor reduction

AWD 2 mo

10

Male

43

11

Yes

Yes

AFP = alpha-fetoprotein, DVT = deep venous thrombosis, AV shunt AWD = alive with disease *Maximum diameter on CT scan prior to first treatment on protocol tTime period in months measured from first treatment on protocol

No

=

arteriovenous shunt, DOX

120

=

1

doxorubicin, DOD

=

dead of disease, NED

=

no evidence of disease,

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CLINICAL AND PRECLINICAL TRIALS OF ISOLATED LIVER PERFUSION

Table 4. HEMODYNAMIC PARAMETERS BEFORE, DURING, AND AFTER COMPLETE HEPATIC VENOUS ISOLATION AND EXTRACORPOREAL CHEMOFILTRATION IN 10 PATIENTS

Pretreatment CHVI; filters excluded CHVI-CF (filters in circuit) End of 20-min DOX infusion End of 60-min CHVI-CF 1 hour after completion of CHVI-CF

BP svst

BP dias

HR

CVP

+4

65 t- 3

76 t- 4

7.5 t- 0.8

117 t- 5

66 ? 2

80 t- 4

7.3 t- 0.7

104 t- 5*

55

+ 3*

77

+5

6.1 t 0.8

+5

62

+3

72 t 4

8.5 ? 0.8

119

116

+

Numbers are mean SEM (n = 17) BP syst = systolic blood pressure in mm Hg, BP dias = diastolic blood pressure in mm Hg, HR heart rate in beats per minute, CVP = central venous pressure in mm Hg, DOX = doxorubicin * P < 0.05 compared with pretreatment values by Student's two-tailed t test

=

Prefilter Postfilter Systemic

Time in minutes Figure 4. Serum levels of doxorubicin (DOX) with a 20-minute hepatic arterial infusion of DOX (60 mg/m2) with complete hepatic venous isolation and chemofiltration (20-minute time point represents completion of the doxorubicin infusion). The data represent the mean i SEM for six treatments. Prefilter levels of DOX are measured from the hepatic venous effluent prior to passage across the carbon chemofilters. The reduction in peak postfilter and systemic DOX levels compared with peak prefilter levels was 77.8% and 85.3%, respectively (P < 0.01). (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

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portal vein. This flow reversal had led to high systemic levels of doxorubicin after the HAI. In patient 6, the cephalad balloon on the vena cava catheter spontaneously deflated 10 minutes into the HA1 of doxorubicin. Because the inflation of the two balloons and the position of the catheter were routinely checked every 45 to 60 seconds during the 20-minute drug infusion, this deflation was immediately noted, and the HA1 of doxorubicin was stopped. The patient remained on the chemofiltration circuit for the full 60 minutes and had no complications or toxic effects related to this technical problem. The final complications occurred in patients 8, 9, and 10, who developed hepatobiliary toxicity (aminotransferases elevated greater than threefold from baseline) within 2 weeks of their treatment. This toxicity was reversible in all three patients, with a return to baseline liver function tests within 6 weeks of treatment. However, because of the development of liver toxicity in three consecutive patients, the trial was closed and the maximum tolerated dose for doxorubicin by 20-minute infusion with CHVI-CF in patients with hepatocellular cancer was defined at 120 mg/m2. The plasma pharmacokinetic data from patients treated at the 60 mg/m2 dose is illustrated in Figure 4. The mean peak prefilter (hepatic venous outflow) doxorubicin level exceeded 1600 ng/mL. The mean peak systemic doxorubicin level was less than 300 ng/mL, a significant reduction from the peak prefilter level (P < 0.01). When compared with the peak prefilter doxorubicin level, a 77.8% reduction in the postfilter drug level and an 85.3%reduction in the systemic drug level was seen ( P < 0.01). Hepatic arterial infusion of doxorubicin (90 mg/m2) produced peak hepatic

t Z

Prefilter Postfilter Systemic

Time in minutes Figure 5. Serum levels of doxorubicin (DOX) with a 20-minute hepatic arterial infusion of DOX (90 mg/m2) with complete hepatic venous isolation and chemofiltration (20-minute time point represents completion of the doxorubicin infusion). The data represents the mean SEM for four treatments. Prefilter levels of DOX are measured from the hepatic venous effluent prior to passage across the carbon chemofilters. The reduction in peak postfilter and systemic DOX levels compared with peak prefilter levels was 85.6% and 87.2%, respectively (P < 0.01). (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33,1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

*

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439

venous levels of more than 2500 ng/mL at 20 minutes (patients 3 and 4) (Fig. 5). In contrast, the peak systemic drug level was less than 400 ng/mL (P < 0.01), or 87.2% lower than prefilter levels. Peak postfilter doxorubicin levels were 85.6% lower than prefilter levels ( P < 0.01). Figure 6 clearly illustrates that this system was not effective in reducing systemic exposure to the drug in the patient with venous drainage from the liver occurring through a route (portal-systemic shunt) other than the hepatic veins. The most striking prefilter doxorubicin levels were seen in patients treated with 120 mg/m2 (Fig. 7). The mean peak systemic level in these patients exceeded 9000 ng/mL, but peak postfilter and systemic drug levels (1650 ng/mL and 1450 ng/mL, respectively) were significantly lower than peak prefilter levels (P < 0.01). This represents an 81.8% reduction in the peak postfilter level and an 84.0% reduction in the peak systemic drug level. Because the CHVI-CF effectively limited systemic exposure to doxorubicin, patients generally felt well after the procedure, and in 16 of 17 treatments, patients were discharged from the hospital the day after treatment. Patient 7 was not discharged until 3 days after treatment because of right-upper-quadrant abdominal pain and nausea. Patients treated with the 60 and 90 mg/m2 doses developed no liver or hematologic toxicities as documented by posttreatment blood tests. However, patients treated with the 120 mg/m2 dose developed transient neutropenia, and as noted previously, three patients developed reversible liver toxicities. The final parameter used to assess doxorubicinrelated toxicity on this protocol was alopecia. Patients treated with 60 or 90

E Prefilter La Postfilter I3 Systemic

Time in minutes Figure 6. Serum levels of doxorubicin (DOX) with a 20-minute hepatic arterial infusion of DOX 90 mglm2 with complete hepatic venous isolation and chemofiltration (20-minutetime point represents completion of the doxorubicin infusion). This patient had an intratumoral arteriovenous shunt and reversal of flow through the portal vein that was missed on pretreatment angiography. As a result, high systemic DOX levels developed, and the patient received no further treatments with this system. (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

440

LOWY & CURLEY

Time in minutes Figure 7. Serum levels of doxorubicin (DOX) with a 20-minute hepatic arterial infusion of DOX 120 mg/m2 with complete hepatic venous isolation and chemofiltration (20-minute time point SEM represents completion of the doxorubicin infusion). The data represents the mean for five treatments. Prefilter levels of DOX are measured from the hepatic venous effluent prior to passage across the carbon chemofilters. The reduction in peak postfilter and systemic DOX levels compared with peak prefilter levels was 81.8% and 84.0% respectively (P< 0.01). (Adapted from Curley SA, Newman RA: From preclinical feasibility study to phase I clinical trial: Pharmacologic evaluation during the development of a novel treatment system for liver tumors. Cancer Bulletin 46:26-33, 1994; with permission from The Cancer Bulletin. Copyright 1994. The University of Texas M.D. Anderson Cancer Center, Houston, Texas.)

+

mg/m2 had minimal or no alopecia after treatment, but all patients treated with 120 mg/m2 developed significant hair loss. Although this was a phase 1 study to determine the hepatic maximum tolerated dose of this treatment system, antitumor response was monitored with CT scans of the abdomen. The treatment results are listed in Table 3. Seven of the 10 patients treated with this protocol had at least a 25% reduction in tumor volume. Two of those 7 patients had a marked antitumor response, with a tumor volume reduction of more than 50%,which allowed segmental resection of the remaining tumor. The median survival of the 7 responding patients was 16 months, compared with a median survival of 2 months for the 3 nonresponding patients.

SUMMARY Preclinical serum and tissue pharmacology studies have played a key role in the development and testing of this novel system designed to treat liver tumors. Pharmacologic evaluation confirmed that the CVHI-CF system significantly limited systemic serum and tissue exposure to chemotherapy drugs given by HAI. By reducing systemic drug exposure and, thus, limiting systemic toxicity, higher doses of antitumor agents can be administered to enhance intratumoral drug levels and increase tumor cell kill. The CVHI-CF system will likely prove increasingly valuable as more active chemotherapeutic agents are developed to treat hepatic malignancies.

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References 1. Bern MM, McDermott W, Cady B, et al: Intra-arterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma. Cancer 42:399405,1978 2. Curley SA, Byrd DR, Newman RA, et al: Hepatic arterial infusion chemotherapy with complete hepatic venous isolation and extracorporeal chemofiltration:A feasibility study of a novel system. Anticancer Drugs 2:175-183,1991 3. Curley SA, Byrd DR, Newman RA, et al: Reduction of systemic drug exposure following hepatic arterial infusion of doxorubicin with complete hepatic venous isolation and extracorporeal chemofiltration. Surgery 114:579-585,1993 4. Curley SA, Newman RA, Dougherty RA, et al: A novel system to treat human hepatocellular carcinoma: A phase I study. Ann Surg Oncol1:389-399, 1994 5. Curley SA, Stone DL, Fuhrman GM, et al: Increased doxorubicin levels in hepatic tumors with reduced systemic drug exposure achieved with complete hepatic venous isolation and extracorporeal chemofiltration. Cancer Chemother Pharmacol33:251-257, 1993 6. Frei E, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69:585594,1980 7. Hohn DC, Melnick J, Stagg RJ, et al: Biliary sclerosis in patients receiving hepatic arterial infusions of floxuridine. J Clin Oncol3:98-102,1985 8. Hohn DC, Stagg RJ, Friedman MA, et al: A randomized trial of continuous intravenous versus hepatic intra-arterial floxuridine in patients with colorectal cancer metastatic to the liver: The Northern California Oncology Group trial. J Clin Oncol7:1646-1654,1989 9. Kemeny MM, Battiforah, Blayney DW, et al: Sclerosing cholangitis after continuous hepatic artery infusion of FUDR. Ann Surg 202:176-181, 1985 10. Kemeny N, Daly J, Olderman P, et al: Hepatic artery pump infusion: Toxicity and results in patients with metastatic colorectal carcinoma. J Clin Oncol2:595-600, 1984 11. Kemeny N, Daly J, Reichman B, et al: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. Ann Intern Med 107:459465,1987 12. Khayat D, Le Cesne A, Weil M, et al: Intra-arterial treatment of hepatic metastases using 5-fluorouracil, Adriamycin, mitomycin C (FAM) chemotherapeutic regimen. Regional Cancer Treatment 1:62-64, 1988 13. Legha SS, Benjamin RS, Mackay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96:133-139,1982 14. Nakamura S, Tsuzuki T: Surgical anatomy of the hepatic veins and the inferior vena cava. Surg Gynecol Obstet 152:43-50,1981 15. O'Connell MJ, Hahn RG, Rubin J, et al: Chemotherapy of malignant hepatomas with sequential intra-arterial doxorubicin and systemic 5-fluorouracil and semustine. Cancer 62:1041-1043,1988 16. Sasaki Y, Imaoka S, Hasegawa Y, et al: Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin I1 in human hepatic cancer. Cancer 55:311-316,1985 17. Schwartz SI: Primary malignant tumors. I n Wanebo JH (ed):Hepatic and Biliary Cancer. New York, Marcel Dekker, 1987, pp. 3-15 18. Wright KC, Wallace S, Benjamin RS, et al: Experimental comparison between hepatic artery infusion and occlusion of Adriamycin. Cancer Drug Delivery 4:3341, 1987

Address vepvint vequests to Steven A. Curley, MD Department of Surgical Oncology The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Boulevard, Box 106 Houston, TX 77030