Bland Embolization for Hepatic Malignancies

Karen T. Brown

Although surgery remains the best hope for cure in patients with most primary and metastatic liver cancers, many patients are not candidates for resection at presentation. This may be due to extent or distribution of disease, underlying liver function, or general medical condition of the patient. The basic physiologic principle that makes hepatic intraarterial therapy feasible is the dual blood supply to the liver. The portal vein provides more than 75% of blood flow to the normal hepatic parenchyma and is the primary trophic blood supply. Conversely, studies performed in the early 1950s established that the primary blood supply to liver tumors was from the hepatic artery.¹ Malignant tumors may be targeted by delivering treatment intraarterially, sparing normal hepatic parenchyma and diminishing or eliminating systemic effects of treatment.

In the last 30 years, many papers have been published describing myriad different techniques for performing hepatic embolotherapy. Many of the studies used chemotherapeutic agents and Lipiodol, despite the lack of convincing pharmacokinetic data. Studies clearly demonstrating an increased concentration of the chemotherapeutic agent(s) used for embolization within the embolized tumor(s) were performed with mitomycin C, doxorubicin, and aclarubicin dissolved in hydrocarbon solvents and then in Lipiodol ² or with a lipophilic agent,³ methods that are not used clinically. When the chemotherapeutic agent was dissolved in water and then mixed with Lipiodol and administered as an emulsion, the concentration of drug in the tumor was high immediately but low at 6 hours, 1 day, and 7 days.² In a study by Raoul and colleagues,⁴ doxorubicin was given to patients intraarterially, either alone as an infusion, emulsified with Lipiodol, or with Lipiodol and gelatin sponge. There was no significant difference in total amount of doxorubicin released into circulating blood, but patients in whom gelatin sponge was used had less released within the first hour of treatment. In a prospective randomized clinical study evaluating the effect of Lipiodol added to intraarterial cisplatin and doxorubicin, no difference in response was noted between the groups given only intraarterial chemotherapy and those who received chemotherapy emulsified with Lipiodol.⁵ Another study of intraarterial doxorubicin versus doxorubicin with Lipiodol found no difference in the area under the concentration time curve (AUC) or the terminal half-life, and no difference in pharmacokinetic or systemic toxicity in the same dose schedule as in patients who received intravenous doxorubicin.⁶ It seems that the pharmacokinetic data supporting the use of intraarterial chemotherapy or chemotherapy plus Lipiodol, at least when given with the hydrophilic chemotherapeutic agents commonly used today and administered as an emulsion, are not robust.

What has been demonstrated in both pharmacokinetic and clinical studies 4,7,8 is the benefit derived from addition of an embolic agent, even Gelfoam, to the transarterial chemoembolization (TACE) cocktail. Some authors even postulate that the primary effect of embolotherapy is derived from the embolic agent and not the chemotherapy or Lipiodol.⁸ If indeed the primary effect of TACE results from ischemia-induced cell death, the goal must be to induce terminal vessel blockade, inasmuch as we know that more proximal vessel occlusion within the liver leads to the almost immediate development of flow distal to the occlusion via myriad collateral vessels, as demonstrated by Michels in 1953.⁹ Bland embolization with small particles is an effective method of intraarterial treatment of hypervascular primary and metastatic tumors to the liver that can be used instead of TACE, thereby avoiding the added expense and systemic toxicity of chemotherapy.

Indications

Bland embolization is indicated for treatment of unresectable “hypervascular” hepatic neoplasms and can be used to treat both benign ¹⁰ and malignant¹¹ processes, but malignant lesions are most commonly treated. It is important to define “hypervascular” hepatic tumors. Malignant tumors in the liver derive primary blood supply from the hepatic artery, whereas normal hepatic parenchyma is primarily supplied by the portal vein. The term hypervascular does not simply mean the tumor has arterial blood supply, but rather that the tumor is more “arterialized” than normal liver. This encompasses tumors that demonstrate enhancement on the arterial phase of a triple-phase computed tomography (CT) scan even if these same tumors appear to be low density on the equilibrium phase.

The most common indication is for treatment of unresectable primary hepatocellular cancer (HCC), based on anatomic distribution of disease, vascular invasion, underlying hepatic function, or a combination of these factors. The majority of patients with HCC have underlying liver disease with resultant cirrhosis. Patients with normal liver function and, presumably, normal hepatic parenchyma may undergo resection of 75% to 80% of their liver without developing postoperative hepatic failure. Patients with underlying liver disease require a greater volume of liver remnant to maintain hepatic function, so tumors that might be resectable in patients with normal liver parenchyma may not be resectable in the presence of cirrhosis. In addition, patients with Child class C cirrhosis may be more likely to die of their underlying liver disease than of their HCC and are unlikely to tolerate arterial embolization well. For this reason, embolotherapy is indicated in patients with Child A or B cirrhosis.

Patients with hepatic metastatic disease from neuroendocrine tumors, gastrointestinal stromal tumors, other sarcomas, ocular melanoma, and a variety of other “hypervascular” metastases (e.g., from breast or renal cell cancer) may also be candidates for bland embolization, assuming the liver is the only site of disease, or when the procedure is being performed for palliation of symptoms. In the case of typically indolent neuroendocrine tumors metastatic to the liver, the diagnosis may first be established when patients present with symptoms related to hepatic metastases because the primary tumors are often small and whatever vasoactive or hormonal peptides they produce are excreted into the portal vein and then deactivated by the liver. It is only when the hormonally active tumor metastasizes to the liver and hormone is secreted directly into the systemic circulation that symptoms occur. Similarly, nonfunctional neuroendocrine tumors may first be diagnosed when hepatic metastatic disease results in abnormal liver function test results picked up on routine screening or cause “bulk-related” symptomatology. Hypervascular metastases from other primary tumors such as breast, renal cell, or even prostate cancer are not uncommon, and these tumors also respond to bland embolization. Given the pattern of metastatic dissemination of disease with these cancers, isolated hepatic metastases are less common, and liver-directed therapy is less often indicated.

Since the purpose of hepatic embolization is to either treat symptoms or extend survival, patients who are asymptomatic from their secondary hepatic disease and who have disease elsewhere should probably not be considered candidates. Intraarterial therapy based on ischemia induced by terminal vessel blockade should not be expected to be efficacious in patients with hypovascular tumors and has no proven role in the treatment of typical metastatic adenocarcinoma from most gastrointestinal malignancies.