Regional Strategies for Managing Hepatocellular Carcinoma

Introduction

Since hepatocellular carcinoma almost always develops in patients with underlying hepatitis or cirrhosis of the liver, it cannot be viewed as a single disease. Not only does the biology of the cancer vary depending on the underlying etiology of the liver disease—hepatitis B, hepatitis C, or cirrhosis of another etiology—but also patient outcomes are determined by the interplay between tumor growth and

adequate hepatic reserve. For these reasons, nearly every patient with hepatocellular carcinoma dies from hepatic failure, making efforts to control local tumor progression appropriate. Given the disappointing results of most therapies for hepatocellular carcinoma, except orthotopic liver transplantation,[1] regional strategies have been pursued aggressively.

The greatest emphasis has been placed on tumor ablative techniques. Because conventional resection is often impossible due to patients’ inadequate hepatic reserve, substitutions for extirpation are often performed. These include cryosurgery,[2] percutaneous ethanol injection,[3] radiofrequency ablation, and other intratumoral therapies. Although each of these therapies appears to be safe and feasible and seems to be able induce tumor necrosis, their utility has not been verified in any randomized trial. Orthotopic liver transplantation, the other surgical option for patients with technically unresectable disease, is appropriate for selected patients[4] but is limited by organ availability and rigorous criteria.

Regional hepatic drug delivery is theoretically applicable to many more patients with hepatocellular carcinoma, including those with multifocal tumors or comorbidities that preclude surgical interventions. Hepatic intraarterial chemotherapy (HIA), chemoembolization (with or without the lipid contrast medium, Lipiodol), and internal radiotherapy have all been attempted in patients with hepatocellular carcinoma. This review will analyze these regional therapies, while attempting to place their roles in patient management into perspective.

Rationale for Regional Chemotherapy

The pharmacologic principles behind regional drug delivery have been well described.[5] Given the features of chemotherapeutic drugs, certain agents may be selectively delivered to the liver via the hepatic artery, conferring a substantial regional advantage for the drug compared to that achieved with systemic administration. This may be especially valuable in patients in whom systemic toxicities may be less acceptable or where a dose-response curve may predict greater efficacy when a higher concentration of the agent can be delivered. Based on these considerations, the fluoropyrimidines, especially floxuridine (fluorodeoxyuridine [FUDR]), appear to be the ideal agents for regional administration.

This rational approach has been studied most extensively in patients with colorectal liver metastases. Numerous phase II and III trials have addressed the relative utility of the fluoropyrimidines administered systemically or regionally.[6] Regional fluoropyrimidine therapy is often used clinically, despite the fact that it has not clearly been shown to be superior to systemic therapies, although recent data suggest an improvement in patients receiving HIA adjuvant chemotherapy following metastasectomy for colorectal liver tumors.[7] The ongoing Cancer and Leukemia Group B (CALGB) trial #9481 is comparing HIA chemotherapy to systemic chemotherapy in patients with liver-only colorectal metastases.

Although hepatocellular carcinoma may be a more regional disease than hepatic metastases from colorectal cancer, the typical coexistence of underlying liver disease or cirrhosis complicates the local delivery of agents. First, baseline abnormalities in liver function tests may confuse the dose-reduction schema that are critical to the safe and ongoing delivery of HIA therapy.[8] Second, patients with severe underlying liver disease and cancer may be prone to substantial arteriovenous shunting,[9] causing much of the regional hepatic therapy to become systemic pulmonary therapy. Nonetheless, the theoretical regional advantage may translate into improved therapeutic efficacy in hepatocellular carcinoma.

HIA Chemotherapy for Hepatocellular Carcinoma

At least three small phase II trials have published results on HIA chemotherapy for hepatocellular carcinoma. In one study, floxuridine and mitomycin(Drug information on mitomycin) (Mutamycin) were delivered via an implanted pump into the hepatic artery of patients with hepatocellular carcinoma or cholangiocarcinoma.[10] Four of the eight patients with hepatocellular carcinoma achieved partial responses, and only one patient developed biliary toxicity. The median survival of all patients in the study was 14.5 months.

Other investigators have explored the combination of the fluoropyrimidines and anthracyclines in the same patient population. In one study, patients were treated with either EAP (etoposide, Adriamycin, and Platinol) or EDF (etoposide, Platinol, and fluorouracil(Drug information on fluorouracil) [5-FU]) administered via a percutaneous catheter into the common or proper hepatic artery.[11] This study reported a 50% objective partial response rate; however, both hepatic and systemic toxicities were substantial.

The largest series—involving 31 patients—reported on the HIA administration of floxuridine, leucovorin, Adriamycin, and Platinol (FLAP),[12] delivered through either a percutaneous catheter or an implanted pump over 4 days/cycle. The objective response rate was 41%, but toxicity was substantial. Interestingly, while response did not appear to be correlated with underlying hepatitis status, survival did, with patients who were positive for hepatitis B or hepatitis C surviving a median of 7.5 months, in contrast to the median survival of 15 months for all patients. Toxicity was also far greater in the hepatitis-positive patients.

This last series employed a therapy that has since spawned the systemic combination chemotherapy approach recently reported to be extremely active in hepatitis B surface antigen–positive patients with hepatocellular carcinoma.[13] Using systemic Platinol, interferon-alfa, Adriamycin, and 5-FU (PIAF), the investigators reported a 26% response rate, with pathologic complete responses confirmed at surgery. These same investigators did not observe any antitumor activity in patients who did not have hepatitis B.

The results of these studies need to be interpreted with caution, however. It is curious that the patients with hepatitis who received HIA FLAP therapy fared poorly, while the patients with hepatitis B who received systemic PIAF therapy appeared to derive the most benefit. Although patients in these HIA series achieved excellent response rates, it is important to keep in mind that these patients represented the healthiest group of patients with hepatocellular carcinoma.

Surgery to place the implanted pumps is technically complicated, even in patients without cirrhosis.[14] When used in patients with cirrhosis, HIA therapy is often associated with severe hepatic toxicity and decompensation.[15] Furthermore, at the University of California at San Francisco (UCSF), for example, fewer than 10% of all patients with hepatocellular carcinoma are deemed candidates for surgical placement of regional chemotherapy infusion devices.

Some investigators have utilized such data to justify the use of preoperative HIA chemotherapy to identify good surgical candidates. To some extent, this approach assesses the underlying biology of the disease and physiology of the patient; however, in no way has it been shown to improve patient outcome.

Adjuvant Setting

The use of HIA chemotherapy has also been explored in the adjuvant setting, following resection of primary hepatocellular carcinoma. Adjuvant HIA chemotherapy appears to improve survival in patients with completely resected hepatic metastases from colorectal cancer,[7] and this approach has been tested in hepatocellular cancer.

Retrospective data assessing the HIA combination of mitomycin, 5-FU, and doxorubicin(Drug information on doxorubicin) plus Lipiodol suggested that patients with risk factors for adverse outcomes—such as minimal margins or portal vein involvement—had a higher survival rate when given adjuvant treatment,[16] compared to untreated patients. This analysis was done after the fact, however, and to date, its findings have not been validated.

In fact, one prospective study from China tested this hypothesis by randomizing patients with fully resected hepatocellular carcinoma either to systemic epirubicin(Drug information on epirubicin) (Ellence) and HIA cisplatin(Drug information on cisplatin) with Lipiodol or to observation alone.[17] In this small study of 66 patients, the patients who received therapy actually experienced more frequent extrahepatic recurrences and worse outcomes.