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Regional Strategies for Managing Hepatocellular Carcinoma

Regional Strategies for Managing Hepatocellular Carcinoma

ABSTRACT: Hepatocellular carcinoma is a common, difficult-to-treat cancer that has a variable natural history depending on patient demographics and the etiology and extent of underlying liver disease. Resection is the preferred treatment option but is only possible in the rare patient who has adequate hepatic reserve and limited-stage cancer. Systemic chemotherapy is mostly inactive. Because most patients with hepatocellular cancer succumb to hepatic failure, this is a disease that appears to be amenable to regional treatments. For this reason, numerous intratumoral, ablative techniques are available. Other routinely used regional treatment modalities include intraarterial chemotherapy, chemoembolization, Lipiodol chemoembolization, and internal radiation. However, the benefits of these interventions have been difficult to ascertain given the variable clinical course of the disease. Regional delivery may prove to be most valuable as a route for administering newer agents. [ONCOLOGY 14(3):347-354, 2000]

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 (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 [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 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 (Ellence) and HIA 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.

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