Isolated hepatic perfusion for unresectable hepatic metastases

Each year, isolated hepatic metastases from a variety of primary malignancies pose a significant clinical dilemma for tens of thousands of patients (see Chapters 90 , 91 , and 92 ). For a small percentage of patients, surgical resection or ablation is effective in controlling clinically apparent disease, but for many patients with colorectal, gastrointestinal neuroendocrine tumors, and ocular melanoma, the number of tumors and volume of affected liver render resection and/or ablation incapable of meaningful disease control. In more selected circumstances, metastases arising from tumors of the breast, skin, and soft tissue can be present solely as hepatic disease, with patient quality of life and survival dictated by the ability to control intrahepatic disease. Since the 1950s, strategies designed to focus chemotherapy solely upon liver metastases have been investigated by many researchers at a limited number of institutions around the world, with sequential improvements in safety and efficacy observed with advances in surgical and catheter-based technology. Isolated hepatic perfusion (IHP) has been developed under a series of clinical trials within institutions with experience in regional therapies to the liver, limb, and lung; approaches share a common goal of focused high-dose treatment to the cancer bearing region of the body, while minimizing systemic drug exposure and toxicity. Regional isolation of drug delivery ensures that unaffected tissue avoids drug exposure and potential associated toxicity via complete separation of the regional and systemic circulation, allowing dose escalation of therapeutic agents, limited largely by the tissue tolerance of the perfused organ or limb. For agents with a sharp dose response curve such as melphalan, improved efficacy manifested via increased tumor response can be observed as the absence of bone marrow and gastrointestinal visceral exposure to a drug, allowing dose escalation into more clinically relevant dose levels. For chemotherapeutic agents more traditionally used in the treatment of metastatic colorectal cancer, IHP with oxaliplatin with or without 5-FU, has demonstrated early-stage clinical activity. Based on its unique vascular anatomy (see Chapter 2 ), the liver is a favorable site for delivery of regional therapy, as complete control of circulatory inflow and outflow can be readily obtained. Additionally, established tumors in liver derive the majority of blood flow from the arterial tree, while the portal vein is maintained as the primary source of nutrient flow to the hepatic parenchyma, allowing intra-arterial delivery to effectively concentrate drug within tumor bearing areas of the liver. Animal models described by Ridge ^, demonstrate nearly 100% of blood delivered to tumors arises from the arterial circulation versus 25% to normal liver. The ability to obtain complete vascular isolation also permits the manipulation of acid-base status of the circuit and the delivery of clinically relevant levels of hyperthermia and/or biologic agents, which would otherwise be too toxic or technically impractical to deliver. Additionally, drugs such as melphalan have greater tumor absorption and efficacy in an acidotic environment, conditions easily obtained within a closed perfusion circuit. For patients with multiple hepatic metastases, the likelihood of additional subclinical disease being present within the liver increases with greater tumor volume, and thus treating the entire diseased organ through regional perfusion strategies allows the targeting of micrometastatic disease within the treated organ.

The initial report detailing the clinical use of IHP was published in 1961 by Robert Ausman from the Roswell Park Cancer Center, describing his experience with both a porcine treatment model along with 5 treated patients. In this brief report, evidence of antitumor efficacy was seen in 2 patients after a 60-minutes perfusion with melphalan. Over the ensuing 2 decades, additional small series examining the utility of prolonged hyperthermic perfusions without drug as well as normothermic perfusions utilizing melphalan or mitomycin-C and 5-FU were described by Skibba (Medical College of Wisconsin) and multiple European groups, respectively. The absence of long-term follow-up and the presence of significant toxicity prevented wide-spread adoption of this approach until interest in the field of regional therapy was reignited in 1992 by Lienhard and Lejeune et al. who reported the successful delivery of a combination of melphalan, tumor necrosis factor (TNF), and interferon-α via hyperthermic isolated limb perfusion in a group of 29 patients with advanced extremity sarcoma or melanoma. Clinical results demonstrated a 90% complete response rate in patients with advanced melanoma along with an 80% limb salvage rate in patients with advanced sarcoma. Of equal or greater significance was the demonstration that meticulous surgical technique could result in effective, near complete vascular isolation, with resultant decrease in out of field drug exposure and associated toxicity. When this increased attention to circuit integrity and leak monitoring was applied to the patients undergoing IHP, a similar decrease in systemic toxicity permitted the more widespread investigation of this clinical approach.

In the United States, a significant effort in the development and refinement of vascular isolation-perfusion techniques was initiated by Fraker and Alexander in the Surgery Branch of the National Cancer Institute. Two initial studies examined the utility of TNF alone and TNF plus melphalan regimens for unresectable hepatic metastases in separate phase I, dose escalation trials. TNF alone was associated with coagulopathy at a maximally tolerated dose of 1.5 mg, with minimal antitumor effects. A subsequent trial included alternating dose escalation of TNF and melphalan, establishing maximum tolerated doses of 1.0 mg and 1.5 mg/kg, respectively. This regimen also demonstrated an overall response rate of 75% in patients with unresectable hepatic metastases. Ultimately, TNF was dropped from the treatment regimen when its lack of clear clinical benefit led to its removal from the US market, but the encouraging early results led to IRB approved protocols examining the clinical benefit of melphalan as a single agent administered over a 60-minutes hyperthermic, acidotic perfusion. Subsequently, two sequential studies completed at the University of Pittsburgh have detailed the safe utilization and maximally tolerated doses of oxaliplatin alone and in combination with 5-FU within the 60-minutes IHP circuit.

Surgical technique

Preoperative evaluation of patients thought suitable for IHP should include an assessment of the patients overall cardiovascular risk factors, the extent of both intra and extrahepatic tumor malignancy, and an assessment of the liver functional status. Standard preoperative cardiac clearance should include a treadmill stress test, as the induction of veno-venous bypass can lead to the induction of atrial fibrillation in patients so disposed. Hepatic reserve is important to assess (see Chapter 4 ), as the dose limiting toxicity observed in phase I trials was liver based, and more frequent in patients with greater than 50% of hepatic replacement with tumor or a serum bilirubin over 3 mg/dL. For patients with colorectal cancer and a significant chemotherapy history including either oxaliplatin and/or irinotecan, extensive portal inflammation, hepatic congestion or steatohepatitis must be ruled out via biopsy assessment of the uninvolved hepatic parenchyma. In such patients, it is our practice to obtain a preoperative biopsy of the liver to assess for significant steatohepatitis, periportal fibrosis, and/or hepatic venous sinusoidal congestion. Patients who have had extensive portal or hepatic venous dissection associated with major hepatectomy should be approached with caution.

IHP is performed under general anesthesia via an upper midline incision, with a right subcostal extension once extrahepatic disease is ruled out. In patients whose primary tumor remains in situ, a full midline incision is indicated to facilitate the resection of the primary colon tumor, with a diverting loop ileostomy created for all patients with left colon or rectal cancer. The presence of extrahepatic disease other than periportal lymphadenopathy or primary tumor amenable to complete resection is a contraindication to perfusion.

Preparation of the liver for perfusion includes completion of cholecystectomy, and full mobilization the liver. ^, All lateral attachments are taken down so that the vena cava is fully visualized and all retroperitoneal venous tributaries are taken to ensure there will be no leak of chemotherapy from the isolated segment of the retrohepatic IVC. The duodenum is mobilized, and the vena cava is mobilized from the renal veins to the hepatic veins. The right adrenal vein is ligated and divided, but both phrenic veins are preserved. The common hepatic artery is identified and the gastroduodenal artery (GDA) is mobilized from its origin for a length of 2 cm and will serve as the arterial inflow catheterization site. Nodal tissue in the porta hepatis is dissected to allow clamping of the portal structures, with the hepatic artery clamp proximal to the takeoff of the GDA. Minor accessory right and left hepatic vessels may be ligated, but replaced or accessory arteries of a significant size prepared for cannulation along with the GDA. The extent of vascular dissection and liver mobilization is pictured in Fig. 100.1 . After completion of dissection, the patient is heparinized to an ACT above 400 seconds. An external venovenous bypass circuit is established by placing a cannula into the left femoral vein and advancing it into the infrarenal IVC and then advancing a second cannula through the internal jugular vein into the superior vena cava. This allowed maintenance of the systemic circulation by actively shunting IVC blood during treatment. Once the venous bypass had been established, the IHP circuit is constructed. The GDA is ligated distally. The inflow perfusion cannula for perfusion is positioned in the proximal GDA, and, once secured, a cross clamp was placed across the entire porta hepatis, including the common hepatic artery, bile duct, and portal vein. The perfusion outflow cannula is inserted into the retrohepatic IVC via a percutaneous cannulation of the right femoral vein and a tourniquet is placed around the cannula at the level of the suprarenal infrahepatic IVC. The suprahepatic IVC is then crossclamped, completing the vascular isolation of the liver, and perfusion is initiated. The perfusate consists of approximately 500 mL Ringer’s lactate to which 2 units of packed red blood cells are added. Once perfusion is initiated, flow through the isolated circuit is maintained between 400 and 600 mL/min. The routine use of leak monitors has been abandoned as detectable leak is rare in the presence of a stable circuit reservoir, with labile systemic blood pressure or gain/loss in reservoir greater than 100 cc an indication of incomplete liver isolation. Temperature probes are placed into the anatomic right and left lobes of the liver, and the perfusate is heated to maintain hepatic hyperthermia of 40°C. Once hyperthermia is obtained and perfusion parameters are stable, Melphalan (1.5 mg/kg, Ideal Body Weight) is administered into arterial limb of the isolated perfusion circuit over 5 min. The liver is perfused for 1 hour, after which time the circuit is flushed with 2000 cc saline, and 500 cc colloid to flush all chemotherapy from the hepatic vasculature. The portal and suprahepatic IVC clamps are removed allowing native blood-flow to be restored. The GDA is either suture ligated or a hepatic arterial infusion pump is placed. The veno-venous bypass circuit is halted and anticoagulation is reversed with protamine and 2 units of fresh frozen plasma. Once the circuit has been removed, placement of hepatic artery infusion pumps is completed in a standard fashion for patients with colorectal cancer and cholangiocarcinoma. When significant accessory or replaced hepatic vessels are present (see Chapter 2 ), flow is preserved in the postoperative setting, as the potential ischemia associated with intraoperative ligation is a significant increase in hepatic toxicity. Embolization of accessory or replaced vessels in the interventional radiology suite is performed before discharge, once postperfusion hepatic toxicity has resolved. Postoperative care focuses on the maintenance of normal coagulation profiles and standard fluid resuscitation. Heparin is contra-indicated in the postoperative period as high levels of heparin induced antibodies are common at this time and additional heparin exposure can create an activated thrombotic state. This phenomenon is rare but can lead to devastating consequences if heparin is administered in the early postoperative setting.

FIGURE. 100.1, Isolated hepatic perfusion (IHP).

Pharmacokinetic analyses performed during early phase IHP trials have demonstrated that complete vascular isolation is routinely achieved, with no detectable levels of melphalan detected in the systemic circulation. A transient significant elevation of aspartate and alanine transaminases was routinely observed but was self-limited and resolved within 7 days. Biliary congestion and cholestatic jaundice are rare when proper patient selection with regard to underlying liver disease and tumor volume is maintained. Overall operative mortality is 4% across single institution experiences. Operative times and blood loss have decreased with the implementation of less invasive catheterization techniques, with operative times of less than 5 hours and mean operative blood loss less than 500 cc and a length of stay of 4 days.

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