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Update on Hepatic Intra-Arterial Chemotherapy

Update on Hepatic Intra-Arterial Chemotherapy

ABSTRACT: The use of hepatic intra-arterial (HIA) chemotherapy is based on the pharmacologic principle that the regional administration of certain drugs can lead to higher drug concentrations at the site of a tumor. This has been studied most extensively in patients with liver-only colorectal metastases. Four large randomized studies have failed to demonstrate a survival advantage of regional treatment over systemic chemotherapy, although two meta-analyses confirmed an improvement in response rate and suggest a trend toward improvement in survival. Two randomized studies have shown improved survival in patients treated with HIA chemotherapy, as compared with those given supportive care, and quality of life also appears to be superior in HIA chemotherapy recipients. The treatment employed in all of the randomized studies was hindered by substantial hepatobiliary toxicity and many surgical complications. Improved surgical techniques and newer chemotherapy combinations appear to have improved phase II results with HIA therapy, leading to a randomized trial now being conducted by the Cancer and Leukemia Group B (CALGB). The role of HIA chemotherapy in adjuvant settings and in other diseases has not been as well-studied, and such uses remain appropriate only for very selected patients. Ultimately, the regional advantage gained by the HIA route may prove to be most advantageous for the delivery of newer biologic agents. [ONCOLOGY 11(7):947-957, 1997]

Introduction

About 140,000 people in the United States were diagnosed with colon
or rectal cancer in 1996, and 40% of those patients will ultimately die
of metastasis from that disease.[1] The liver is the dominant metastatic
site in the majority of these patients, and more than 80% of patients with
hepatic metastases succumb to liver failure.[2]

Despite the fact that metastatic colorectal cancer is usually a systemic
disease, in some patients, the liver is the only site of metastasis. This
is evidenced by the fact that, with careful patient selection, resection
of isolated hepatic metastases can result in long-term disease-free survival.
For example, resection of up to three colorectal cancer lesions in patients
without evidence of extrahepatic colorectal tumor leads to a 5-year survival
of approximately 25%.[3,4]

The incorporation of intraoperative ultrasound of the liver into the
staging evaluation, as well as the application of prognostic factors, such
as carcinoembryonic antigen (CEA), lesion size, and stage of the primary
tumor, may permit the identification of a group of patients who would enjoy
an even better survival.[5] Unfortunately, although about one-third of
patients with hepatic metastases appear to have liver-only tumor, in no
more than 10% of these patients is the tumor amenable to curative hepatic
resection.

The regional delivery of chemotherapy to patients with liver tumors
is not a new concept. Even though colorectal metastases appear to migrate
to the liver via the portal vein, macrometastases in the liver derive more
than 80% of their blood supply from the hepatic arterial circulation; in
contrast, normal hepatocytes are supplied primarily by the portal circulation.
Therefore, the administration of chemotherapy into the hepatic artery allows
for the selective delivery of drug to the tumor with relative sparing of
normal hepatocytes.[6] The pharmacology behind this strategy is well-defined[7]:
depending on a drug's clearance and toxicity profile, a marked increase
in the area under the curve (AUC) may be achieved. If a dose-response relationship
for that drug and that disease exists, this could then translate into proportionally
greater efficacy.

The regional behavior of colorectal cancer metastatic to the liver and
favorable drug pharmacokinetics led to extensive clinical investigation
of hepatic intra-arterial (HIA) chemotherapy in the 1970s and '80s, initially
via percutaneously placed catheters. The introduction of a totally implantable
pump system made this an ambulatory treatment. Encouraging, if not inflated,
response rates ranging from 29%[8] to 88%[9] were reported and engendered
numerous randomized protocols comparing systemic vs HIA chemotherapy. Despite
these studies, the optimal dosing and role of HIA therapy in the management
of colorectal liver metastases remain unclear.

This review will summarize and critique the randomized studies and will
address the technologic and surgical advances that have now better defined
the technique necessary for the safe, successful administration of HIA
chemotherapy. A series of phase II trials will be reviewed, and the design
of a Cancer and Leukemia Group B (CALGB) randomized study assessing this
modality will be described. Although the focus of this review is on liver
metastases from colorectal cancer, a brief description of HIA therapy in
other malignancies will also be presented.

HIA Chemotherapy
in Untreated Patients

Results of Randomized Trials

Four major prospective trials comparing systemic fluoropyrimidine chemotherapy
vs HIA floxuridine (FUDR) chemotherapy delivered via the implanted pump
in untreated patients with liver-only colorectal metastases were completed
in the early 1980s (Table 1).[10-13]
In all, 375 patients were enrolled in these randomized studies. In each
study, the response rate to HIA chemotherapy was superior to the systemic
counterpart. However, in none of the studies did this translate into a
survival improvement for the HIA approach.

Two European trials conducted during the late 1980s randomly assigned
patients to either best supportive care or HIA FUDR. The studies of Rougier
et al[14] and Allen-Mersh et al[15] both demonstrated a survival advantage
of HIA therapy, but most of the control patients did not receive systemic
chemotherapy, raising the concern that these patients, at least by American
standards, received suboptimal treatment.

The latter study,[15] done in the United Kingdom, was conducted with
particularly rigorous quality control: Every pump was implanted by the
same surgeon (Allen-Mersh). A thorough quality-of-life analysis, administered
by dedicated nurses, demonstrated a prolongation of normal-quality survival,
with respect to physical symptoms, anxiety, and depression, in patients
treated with HIA chemotherapy, as compared with those given best supportive
care.

The data of all of these trials have been subjected to two different
meta-analyses. Each meta-analysis confirmed the trends that were apparent
in the individual studies; namely, that response rates were greater with
HIA therapy. However, although there was a trend toward an improvement
in survival, only when the patients enrolled on the no-treatment control
arms were included did the difference reach statistical significance.[16,17]

Why would the substantial improvement in response rate not translate
into a survival advantage? There are numerous possible explanations for
this:

  • Colorectal cancer is a systemic disease, and thus, even effective
    regional chemotherapy to liver metastases does not alter patient survival.

Although colorectal cancer metastatic to the liver is usually a systemic
disease, as noted above, selected patients with isolated liver metastases
from colorectal cancer can be cured with hepatic resection.[3]

Also, most patients with unresectable liver metastases die of progressive
liver dysfunction,[2] and even with effective management of liver metastases,
most patients treated with HIA chemotherapy in these studies die from advancing
liver involvement.[17] Therefore, the argument that systemic therapy is
needed is not necessarily supported by the facts.

  • Hepatobiliary toxicity, including biliary sclerosis, led to the
    cessation of therapy in many patients.

Without question, the dose of FUDR in most of the studies--.3 mg/kg/d
for 14 days--was too high. This was not appreciated until many patients
suffered permanent biliary damage.[18] Therefore, the HIA therapy was overly
toxic, and nearly half of the patients stopped treatment for that reason
rather than for treatment failure.

  • Surgical complications, including catheter dislodgment and gastrointestinal
    misperfusion (ie, inadvertent administration of chemotherapy to the stomach
    or duodenum), made this a very difficult therapy to deliver safely.

Reflecting the experience of the operating surgeon[19] and the infancy
of the technique,[20] surgical complications in these studies were prohibitive.
For example, of 33 patients randomized to HIA therapy in the Mayo Clinic
study,[13] HIA treatment was never begun in 5 patients because of surgical
complications, was prematurely discontinued in another 5 because of later
problems, and was abrogated in 4 others because of gastrointestinal misperfusion.

  • Crossover of patients from systemic to HIA therapy may have masked
    a survival advantage.

This may have confounded the findings of the two largest studies,[10,11]
since there is evidence that fluoropyrimidine-based HIA chemotherapy produces
a response rate better than 30% in previously treated patients.[17,21]

The results of these trials led to one of two interpretations: either
the therapy was not worth pursuing or needed to be improved markedly to
make it worthwhile. Focusing on potential areas of improvement, investigators
concentrated on patients without radiographic evidence of extrahepatic
tumor and pursued two avenues: (1) standardizing the surgical technique
of pump placement and (2) optimizing the delivery of chemotherapy from
the standpoint of toxicity and response.

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