Correspondence

Prevention of Second Primary Tumors by an Acyclic Retinoid in Patients with Hepatocellular Carcinoma

N Engl J Med 1999; 340:1046-1047April 1, 1999

Article

To the Editor:

Chemoprevention can prevent second primary cancers in patients with cancer,1 but the effect of secondary cancer prevention on absolute survival has not been established. In 1996 we reported in the Journal that oral administration of an acyclic retinoid for 12 months significantly reduced the incidence of second primary cancers in patients who had received curative treatment for hepatocellular carcinomas,2 but the effect on survival did not reach statistical significance after a median follow-up period of 38 months.

We have subsequently reexamined the patients every three months. Patients in whom a second primary hepatocellular carcinoma developed received mainly ultrasonographically guided ethanol ablation therapy. As of August 1998, the effect of the acyclic retinoid in preventing second primary hepatocellular carcinomas was even more evident (P=0.002 by the log-rank test) than it was in 1996 (P=0.04).2 Moreover, we found a significant difference in the survival rate between the acyclic-retinoid group and the placebo group after a median follow-up of 62 months (P=0.04) (Figure 1Figure 1Kaplan–Meier Estimates of Survival in Patients with Previously Treated Hepatocellular Carcinoma Who Were Given Acyclic Retinoid or Placebo.); the estimated 6-year survival was 74 percent in the acyclic-retinoid group and 46 percent in the placebo group. Proportional-hazards analysis of selected base-line variables (i.e., at the time of randomization), including treatment-group assignment, age and sex, the cause of the underlying liver disease, the method of treatment, and the number, stage, and size of earlier hepatocellular carcinomas, revealed that the administration of acyclic retinoid was the only independent factor that significantly improved survival. The estimated relative risk of death was 0.3 (95 percent confidence interval, 0.1 to 0.8) in the acyclic-retinoid group as compared with the placebo group.

Acyclic retinoid induces clonal deletion of premalignant and latent malignant cells in the remnant liver.3 There are now three proved strategies to prevent liver carcinogenesis: vaccination against hepatitis B virus to reduce the number of carriers of hepatitis B virus,4 eradication of hepatitis C virus by treatment with interferon alfa in patients with chronic active hepatitis,5 and deletion of premalignant and latent malignant clones by acyclic retinoid in patients with hepatocellular carcinoma.

Yasutoshi Muto, M.D.
Hisataka Moriwaki, M.D.
Gifu University School of Medicine, Gifu 500-8705, Japan

Akiko Saito, M.D.
Tokyo Women's Medical College, Tokyo 162-8666, Japan

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