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Update on Hepatic Intra-Arterial Chemotherapy

Update on Hepatic Intra-Arterial Chemotherapy

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 whole body.

Although intraperitoneal chemotherapy for advanced ovarian cancer has only recently been found to improve recurrence and survival rates,[1] regional chemotherapy has a long, if somewhat checkered, record in the treatment of sarcomas,[2] melanomas,[3] and early-stage bladder cancer.[4] 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.[5]

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.[6] 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 misperfusion.

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.[7] 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.[8] 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 surgery alone.

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.

References

1. Alberts DS, Liu PY, Hannigan EV et al: Intraperitoneal cisplatin plus intravenous cyclophosamide vs intravenous cisplatin plus cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950, 1996.

2. Wanebo HJ, Temple WJ, Popp MB et al: Combination regional therapy for extremity sarcoma: a tricenter study. Arch Surg 125:355, 1990.

3. Fraker DL, Alexander HR, Andrich M et al: Treatment of extremity melanoma with hyperthermic isolated limb perfusion with melphalan, tumor necrosis factor and interferon-gama: results of TNF dose escalation study. J Clin Oncol 14:479, 1996.

4. Herr HW, Schwalb DM, Zhang ZF et al: Intravesical BCG therapy prevents tumor progression and death from superficial bladder cancer: ten year follow-up of prospective randomized trial. J Clin Oncol 13:1404, 1995.

5. Rosenberg SA, Anderson WF, Blaese M et al: The development of gene therapy for treatment of cancer. Ann Surg 218:455, 1993.

6. Ensminger WD, Rosowsky A, Raso VO et al: A clinical pharmacological evaluation of hepatic arterial infusion of 5-fluoro-2¢-deoxyuridine and 5-fluorouracil. Cancer Res 40:3784, 1978.

7. Nordlinger B, Guiguet M, Vaillant JC et al: Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Cancer 77:1254, 1996.

8. Fong Y, Cohen AM, Fortner JG et al: Liver resection for colorectal metastases. J Clin Oncol 15:938-936, 1997.

9. Wanebo HJ, Chu QD, Vezeridis MP, Soderberg C: Patient selection for hepatic resection of colorectal metastases. Arch Surg 131:322, 1996.

 
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