John W. Gyves

Regional chemotherapy of colorectal cancer metastatic to the liver.

Ninety‐three patients with biopsy‐proven colorectal cancer metastatic to the liver were treated with hepatic arterial infusion of 5‐fluorodeoxyuridine (FUDR). There were 52 men and 41 women (median age, 60 years). Forty‐two patients (45%) had failed prior systemic chemotherapy. Catheters were operatively placed and multiple catheters were used if dictated by hepatic arterial anatomy in order to obtain perfusion of the entire liver. The drug was delivered by a totally implanted INFUSAID model 400 pump and patients received cyclic therapy consisting of 2 weeks of 0.3 mg/kg/d FUDR alternating with 2 weeks of saline. Patients with extrahepatic tumor or patients whose hepatic tumor failed to respond to FUDR were given a 30 minute intraarterial infusion of mitomycin C, 15 mg/m2, every 6 to 8 weeks in addition to FUDR. Fifty of the 93 evaluable patients presented with metastatic tumor confined to the liver. Of these 50 patients, 83% demonstrated a significant reduction in tumor size with a median duration of response of 13 months and a median survival of 25 months from diagnosis of liver metastases. Twenty‐four of these 50 patients remain alive. Forty‐three patients presented with extrahepatic metastases in addition to their liver tumor, and 74% had a response with a median duration of 6 months and a median survival of 14 months. Only six patients of those presenting with extrahepatic tumor remain alive. None of the 93 patients died solely of uncontrolled liver tumor, and only 9 died as a result of uncontrolled liver metastases and disseminated extrahepatic tumor. The duration of survival for both groups was determined by the uncontrolled progression of extrahepatic tumor. In patients with metastatic colorectal cancer involving only the liver, hepatic arterial FUDR alone and with the addition of mitomycin C provided excellent control of hepatic tumor. Survival appeared to be prolonged in this uncontrolled study. Cancer 53:1336‐1343, 1984.

Totally implanted system for intravenous chemotherapy in patients with cancer.

A totally implanted system for improved central venous access has been investigated in 20 patients with cancer (six with solid tumors, four with leukemia, and 10 with lymphomas) who were treated with aggressive chemotherapy regimens and who lacked peripheral venous sites. The system is implanted using local anesthesia and consists of a subcutaneous injection port connected to a Silastic catheter threaded through the subclavian vein into the superior vena cava. Injections and continuous infusions (for up to three weeks) of virtually all classes of antineoplastic agents, antibiotics, blood components, and intravenous solutions were administered through the system. The system was filled with heparinized saline and not otherwise flushed between uses. The system has remained functional for periods exceeding 450 days (mean 235 days). There was no significant local irritation and no system became infected. None of 18 large-bore catheters (0.63 mm lumen) became occluded (seven to 300 days), whereas five of six small-bore catheters (0.38 mm lumen) became occluded (90 to 420 days). Three of the occluded systems were replaced. Acceptance has been excellent, and patients have had no impediment to normal activities. This system appears to be an alternate means of safe and reliable central venous access with improved convenience and cosmetic acceptability.

Improved regional selectivity of hepatic arterial mitomycin by starch microspheres

Biodegradable starch microspheres, 40 μm in diameter, were administered through hepatic arterial catheters in 16 subjects with primary and metastatic liver tumors. These microspheres temporarily obstruct blood flow at the precapillary arteriole (microcirculation) level. Our study was undertaken to determine whether such occlusion would enhance hepatic deposition of, and thereby decrease systemic exposure to, simultaneously administered hepatic arterial mitomycin C (mito). When mito (10 mg/m2 over 1 min) was given with 90 × 106 microspheres (10 subjects), there was a 17% to 70% reduction in systemic mito exposure. When mito (10 mg/m2 over 1 min) was given with 36 × 106 microspheres (six subjects), there was a 15% to 60% reduction in systemic exposure, which may correlate with dose‐dependent shunting (8% to 29%) through the liver to the lung (and hence to the systemic circulation), attributed to the starch microspheres. No life‐threatening myelosuppression was noted; hepatic toxicity consisted of transient pain and elevation of liver enzymes.

REGIONAL CHEMOTHERAPY OF NEOPLASTIC DISEASES

Recent developments have made regional chemotherapy a more rational endeavour. The important pharmacokinetic principles have been defined. The increase in regional exposure achieved is a direct function of a drugs total body clearance and is an inverse function of the permeability-area product (defining ease of egress) for third spaces or of the regional arterial blood flow for intraarterial infusion. Agents having appropriate properties are available. For new agents with appropriate pharmacokinetic parameters, regional chemotherapy may provide a means to examine the dose response against measurable tumors in the regions in question. The observation that most tumors are hypervascular may be crucial to the development of selective treatments using microspheres to deliver therapy in direct proportion to the density of the microvasculature. Regionally infused vasoconstrictors (epinephrine, angiotensin) may allow shunting of flow away from normal tissue toward tumor without potentially serious systemic cardiovascular effects. Investigations and applications of regional chemotherapy have been fostered immensely by the reliably and convenience of the Infusaid implantable pump and by implantable injection ports. The problem of systemic failure with regional approaches still remains but is approachable using pharmacologically rational programs aimed at delivering maximal systemic chemotherapy along with regional treatment. In hepatic arterial therapy, in particular, a randomized prospective study is being considered to examine the impact of such combined treatment versus regional therapy alone and versus systemic chemotherapy alone for metastatic colorectal cancer to liver. Thus, the future for regional chemotherapy appears exciting. There are many opportunities to apply therapeutic principles rationally with the potential of significant benefit to many patients.

New implantable continuous administration and bolus dose intracarotid drug delivery system for the treatment of malignant gliomas

A totally implantable system for the continuous and bolus delivery of intra-arterial chemotherapeutic agents to patients with malignant gliomas is described. The system utilizes an Infusaid pump (Infusaid Corp., Sharon, Massachusetts), which discharges the drug directly into the internal carotid artery and is percutaneously refillable. This system has been utilized experimentally in primates and in the treatment of six patients with malignant gliomas. It seems that this system can be utilized safely as an experimental technique in the treatment of malignant gliomas.

Constant intraperitoneal 5-fluorouracil infusion through a totally implanted system.

Five‐day continuous intraperitoneal (ip) infusions of 5‐fluorouracil (FU) were injected into five patients as part of a phase 1 clinical pharmacology study. They received 20 courses through a totally implanted catheter/injection port system. Six courses are evaluable for kinetic parameters and all courses are evaluable for toxicity. In each course a 2 to 3 log FU concentration differential in favor of the peritoneal cavity was achieved and maintained. Steady‐state venous plasma FU concentrations averaged 0.34 µM, whereas steady‐state ip FU concentrations averaged 697 µM. Mean total body clearance (TBC) in these patients was 18.4 l/min and mean permeability‐area (PA) product for diffusion from the peritoneum was 13.7 ml/min. Mean TBC of 20 l/min with ip FU infusion was observed in one patient who also received a 24‐hr IV FU infusion for comparison. The TBC during the later infusion was 5.9 l/min. In this patient, calculations indicate 75% extraction of drug during the passage from the peritoneum to the systemic circulation, presumably representing in large part hepatic extraction of FU taken into the portal venous circulation. Ip constant infusion and bolus kinetics were compared in one patient. TBC for the ip bolus was 14.3 l/min, which was approximately half of the TBC of 29.5 l/min determined during the 5‐day constant ip infusion. Thus constant ip infusion of FU (1 gm/day) can provide an improved regional advantage over bolus ip FU because of an increased TBC. Toxicity was acceptable in all courses. Dose limiting toxicity was regional, namely moderate chemical peritonitis seen in two of the five patients on repeated courses. There was no myelosuppression, alopecia, nausea, or vomiting. There were no infectious complications. The only patient with measurable disease had an objective response in hepatic metastases from gastric cancer. The implanted device was well tolerated and facilitated peritoneal fluid sampling.

Evaluation of focal hepatic masses: a comparative study of MRI and CT

We evaluated suspected hepatic lesions in 30 patients using both nongated spin-echo magnetic resonance imaging (MRI) on a 0.35 T superconducting magnet and contrast-enhanced dynamic incremental computed tomography (CT). In the 27 patients with focal lesions, both modalities detected abnormalities in 26 patients. Liver lesions were equally well demonstrated using MRI and CT in 15 patients, better demonstrated by CT in 11 patients, and better demonstrated by MRI in 1 patient. Small lesions (<2 cm) were much better demonstrated using CT than MRI; this was significant when knowledge of the precise extent of disease was necessary for planning surgical therapy or for evaluating response to chemotherapy. Five patients had significant extrahepatic disease detected by CT; MRI identified extrahepatic abnormalities in only 2 of these 5 patients. We conclude that at the current time CT is more useful than nongated spin-echo MRI in the evaluation of suspected hepatic masses.

Local thrombolytic therapy for hepatic artery thrombosis following chemotherapy infusion catheter placement

Nine patients with hepatic artery thrombosis subsequent to catheter placement (four surgical and five percutaneous) for hepatic arterial infusion chemotherapy were treated with local thrombolytic therapy. The thromboses were located in the common hepatic, proper hepatic and hepatic arteries. Thrombolytic therapy was instituted within seven days of catheter placement, at a rate of 5,000 to 20,000 units/hour (streptokinase) or 5,000 to 15,000 units/hour (urokinase) for 15 to 64 hours. All patients had repeat angiography and 99mTc-MAA hepatic artery perfusion scintigraphy after the infusion. In eight of the patients, thrombolytic therapy resulted in dissolution of the thrombus and recanalization of the hepatic artery. In three of these patients, rethrombosis occurred within a few days, and was attributed to underlying arterial abnormalities. The other five had documented continued hepatic arterial patency allowing completion of the chemotherapy course. The patient who did not respond to the lytic therapy had developed extensive collateral flow through the gastroduodenal artery to the liver.

A Dog Model Using an implanted System for Protracted Hepatic Arterial Chemotherapy

A model for hepatic arterial chemotherapy studies using large dogs and an implantable infusion pump has been developed. Using this technique near complete perfusion (greater than 90%) of the liver can be achieved in vivo as determined by hepatic arterial perfusion scintigraphy with technitium 99m macroaggregated albumin. The system is reliable and has been in use for a total of 1353 days (mean of 104 days, range 52-239) in 13 dogs. Pump implantation causes no apparent acute liver damage based on pre- and post-operative alkaline phosphatase and serum glutamic-pyruvic transaminase determinations and does not affect the general mobility or behavior of the animals. Careful placement of the catheter and attention to the physicochemical properties of the solutions loaded are factors contributing to the success of the model. The model permits comprehensive preclinical pharmacokinetic and toxicologic studies of new or preexistent chemotherapeutic agents in the same device that will be used for later administration in human subjects. By providing the means to examine and develop new treatment modalities, it enables the design of even more potent cytotoxic therapy directed into the tumor vascular bed.

Atlas of Hepatic Arterial Perfusion Scintigraphy

Tc-99m MAA intra-arterial perfusion studies are necessary to determine blood flow distribution for hepatic arterial chemotherapy. In this mini-atlas, examples selected from over 900 cases to illustrate important points to aid in a better understanding and interpretation of these studies with particular emphasis on diagnostic and therapeutic interventions are presented.