PREVENTION OF 2ND PRIMARY TUMORS BY AN ACYCLIC RETINOID, POLYPRENOIC ACID, IN PATIENTS WITH HEPATOCELLULAR-CARCINOMA

Background. In patients with hepatocellular carcinoma (hepatoma), the rate of recurrent and second primary hepatomas is high despite surgica l resection and percutaneous ethanol-injection therapy. We developed a n acyclic retinoid, polyprenoic acid, that inhibits hepatocarcinogenes is in the laboratory and induces differentiation and apoptosis in cell lines derived from human hepatoma. In a randomized, controlled study, we tested whether the compound reduced the incidence of recurrent and second primary hepatomas after curative treatment. Methods. We prospe ctively studied 89 patients who were free of disease after surgical re section of a primary hepatoma or the percutaneous injection of ethanol . We randomly assigned the patients to receive either polyprenoic acid (600 mg daily) or placebo for 12 months. We studied the remnant liver by ultrasonography every three months after randomization. The primar y end point of the study was the appearance of a histologically confir med recurrent or new hepatoma.Results. Treatment with polyprenoic acid significantly reduced the incidence of recurrent or new hepatomas. Af ter a median follow-up of 38 months, 12 patients in the polyprenoic ac id group (27 percent) had recurrent or new hepatomas as compared with 22 patients in the placebo group (49 percent, P = 0.04). The most stri king difference was in the groups that had second primary hepatomas 7 in the group receiving polyprenoic acid as compared with 20 in the pla cebo group (P = 0.04 by the log-rank test). Cox proportional-hazards a nalysis demonstrated that as an independent factor, polyprenoic acid r educed the occurrence of second primary hepatomas (adjusted relative r isk, 0.31; 95 percent confidence interval, 0.12 to 0.78). Conclusions. Oral polyprenoic acid prevents second primary hepatomas after surgica l resection of the original tumor or the percutaneous injection of eth anol. (C) 1996, Massachusetts Medical Society.