Background In patients with hepatocellular carcinoma (hepatoma),the rate of recurrent and second primary hepatomas is high despitesurgical resection and percutaneous ethanol-injection therapy.We developed an acyclic retinoid, polyprenoic acid, that inhibitshepatocarcinogenesis in the laboratory and induces differentiationand apoptosis in cell lines derived from human hepatoma. Ina randomized, controlled study, we tested whether the compoundreduced the incidence of recurrent and second primary hepatomasafter curative treatment.
Methods We prospectively studied 89 patients who were free ofdisease after surgical resection of a primary hepatoma or thepercutaneous injection of ethanol. We randomly assigned thepatients to receive either polyprenoic acid (600 mg daily) orplacebo for 12 months. We studied the remnant liver by ultrasonographyevery three months after randomization. The primary end pointof the study was the appearance of a histologically confirmedrecurrent or new hepatoma.
Results Treatment with polyprenoic acid significantly reducedthe incidence of recurrent or new hepatomas. After a medianfollow-up of 38 months, 12 patients in the polyprenoic acidgroup (27 percent) had recurrent or new hepatomas as comparedwith 22 patients in the placebo group (49 percent, P = 0.04).The most striking difference was in the groups that had secondprimary hepatomas — 7 in the group receiving polyprenoicacid as compared with 20 in the placebo group (P = 0.04 by thelog-rank test). Cox proportional-hazards analysis demonstratedthat as an independent factor, polyprenoic acid reduced theoccurrence of second primary hepatomas (adjusted relative risk,0.31; 95 percent confidence interval, 0.12 to 0.78).
Conclusions Oral polyprenoic acid prevents second primary hepatomasafter surgical resection of the original tumor or the percutaneousinjection of ethanol.
Source Information
From the First Department of Internal Medicine (Y.M., H.M., S.A., M.O.) and the Departments of Pathology (T.T.) and Pharmacology (K.T.), Gifu University School of Medicine, Gifu; the Institute of Gastroenterology, Tokyo Women's Medical College, Tokyo (A.S., K.T.T.); the Gastrointestinal Disease Center, Gifu Municipal Hospital, Gifu (E.T.); Gihoku Hospital, Takatomi (M.N.); Gifu Red Cross Hospital, Gifu (T.N.); and Murakami Memorial Hospital, Asahi University, Gifu (T.K.) — all in Japan.
Address reprint requests to Dr. Muto at the First Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500, Japan.
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