Theoretically, effective regional cancer chemotherapy should afford
the opportunity to deliver a significantly higher concentration of a cytotoxic
agent than is possible with systemic administration of the same agent.
Furthermore, regional chemotherapy should cause its greatest stress on
the site of administration, producing a lesser burden of toxicity on the
Although intraperitoneal chemotherapy for advanced ovarian cancer has
only recently been found to improve recurrence and survival rates, regional
chemotherapy has a long, if somewhat checkered, record in the treatment
of sarcomas, melanomas, and early-stage bladder cancer. Nevertheless,
we believe that regional chemotherapy for cancer remains quite relevant,
as the next generation of trials will be conducted in association with
gene therapy techniques.
Hepatic intra-arterial (HIA) chemotherapy with floxuridine (FUDR) for
the treatment of colorectal liver metastases meets the criteria of an excellent
regional therapy. Hepatic intra-arterial therapy with FUDR, the deoxyribonucleoside
derivative of fluorouracil (5-FU), exposes the systemic circulation to
a small fraction of the dose administered to the liver: When administered
via the hepatic artery, almost 95% of FUDR is extracted on its first pass
through the liver. Hepatic intra-arterial therapy with FUDR virtually
eliminates the systemic toxicity of chemotherapy, but hepatic toxicity
is almost universal and, at times, may be irreversible. Even with the least
toxic HIA FUDR programs, some hepatotoxicity may be unavoidable.
Dr. Venook presents a comprehensive, well-balanced summary of the history
of HIA and future directions for its use. The article outlines the impact
of newer HIA FUDR schedules, as well the modulation of FUDR efficacy by
adding leucovorin or alternating FUDR with 5-FU and the modulation of FUDR-induced
hepatotoxicity by administering steroids.
Dr. Venook describes and impartially annotates the randomized trials
that have been completed, describing the design pitfalls of trials that
allowed crossover from one therapy to another and the social and medical
pitfalls of trials that compared relatively effective HIA against palliative
treatment. His description of the ongoing Cancer and Leukemia Group B (CALGB)
trial #9481 is especially noteworthy, as this trial has a noncrossover
design and utilizes the most effective, least toxic HIA therapy to date.
A companion study to CALGB #9481 will prospectively gather data on the
impact of p53 mutational status and thymidylate synthase quantitation on
responses of colorectal metastases to treatment with HIA FUDR vs systemic
5-FU. The unique translational component adds to the import of the timely
completion of this trial.
Dr. Venook's descriptions of the processes by which a patient is found
eligible for therapy, is anatomically evaluated, and has the pump placed
are valuable for those who do not participate in this procedure on a regular
basis. We would add that our group routinely uses heparinized saline instead
of heparinized water to avoid the possibility of hemolysis. Also, in the
absence of a separate left hepatic artery, we skeletonize the lesser curvature
of the stomach by ligation of the gastrohepatic ligament so as to prevent
Is a Trial Comparing HIA to Systemic Therapy Still Relevant?
A more global consideration is whether the efforts of clinical investigators
and the ever-shrinking dollars from funding agencies are best spent in
a prospective comparison of HIA to systemic therapy in appropriately evaluated
colorectal cancer patients with liver metastases. Treatment of this patient
population with either HIA FUDR or systemic 5-FU results in very few patients
surviving 5 years; the best results from trials of HIA therapy discussed
by Dr. Venook report median survivals of approximately 24 months.
Moreover, even as HIA pump technology and safety have improved, experienced
liver surgeons have noted the safety of major liver resections. With
improved operative morbidity and mortality statistics, surgical investigators
have expanded the eligibility criteria for hepatic resections after the
detection of colorectal metastases. A recent report cites curative results
for patients who undergo liver resection of four or more metastases or
metastatic disease spanning both the right and left lobes of the liver.
Surgical series published in the past year have noted median survivals
of 35 and 46 months with 5-year survival rates of 24% and 38%.[8,9] As
surgical indications for metastatic liver resections have been augmented,
a current comparison of liver-directed treatment with HIA FUDR to treatment
with systemic 5-FU may not be as relevant as a comparison of HIA FUDR to
Gaining a Better Understanding of the Biology of Metastasis
More importantly, as Dr. Venook suggests, if we are designing surgical
protocols for patients with metastatic solid tumors to the liver (for HIA
pump placement or resection), we should take advantage of these valuable
patients and their tumors to foster a better understanding of the biology
of the metastatic process. As our therapeutic options remain relatively
limited, it is important to associate the outcomes of specific therapeutic
efforts with the molecular biology of the tumors being treated. If therapeutic
outcome can be ascribed to molecular parameters within a metastatic tumor(s),
therapy will become less empiric and more rational.
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