Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma

Authors: Muto Y, Moriwaki H, Ninomiya M, Adachi S, Saito A, et al.
Source: New England Journal of Medicine. 334:1561-7. June 13, 1996.
Institution: Gifu University School of Medicine, Japan.
Financial support: Princess Takamatsu Cancer Research Fund and Governmental grants, Japan.



Antioxidants, including vitamin A and its analogues (retinoids) are hypothesized to prevent cancer, but results of randomized trials have not been very encouraging. A synthetic compound, polyprenoic acid, binds to the cellular retinoic acid-binding protein and has been shown to inhibit hepatocarcinoma in rats and mice. In this trial from Japan, polyprenoic acid was administered to patients with surgically or "chemically" resected hepatoma, who are at particularly high risk for recurrent or second primary hepatoma.


Results Author's Discussion

The authors speculate that, since retinoids are considered chemopreventive rather than chemotherapeutic, their effectiveness against new, second hepatomas rather than against disease recurrence is logical. They estimate that a real survival benefit will become apparent in about 48 months, if current trends continue. They note that the mechanism of action of polyprenoic acid is not known, but that hepatocarcinogenesis is linked to impaired retinoid metabolism.


David Shafritz, from the Albert Einstein College of Medicine, points out that distinguishing new primary tumors from tumor recurrence based on clinical criteria alone, as was done in this study, is not an ideal method. Some recurrences were probably counted as new primary hepatomas. He notes that this distinction can be made reliably, using viral DNA analysis, for example, when the hepatoma is caused by chronic viral hepatitis.


This is an important paper, since it seems to represent a (rare) success of chemoprevention, as opposed to chemotherapy. I have one caveat about the way the results are presented, however.

The authors first present the results comparing the recurrence rates in both groups, one against the other, and then present them using Kaplan-Meier survival curves.

The problem with directly comparing the data from the placebo and treatment groups is that patients with very different follow-up times are included and compared. This is particularly problematic when data are examined shortly after termination of a relatively long study, since there will be a wide disparity in lengths of follow-up under these circumstances: some patients will have just completed the trial whereas others will be several years out. This can be problematic if the effect of a therapy is just to delay the onset of disease by a short time, rather than to prevent it. In such a case, including patients with only short follow-up will inflate the calculated therapeutic effect.

Using the Kaplan-Meier survival curve method eliminates this problem by explicitly looking at development of disease over time. Patients with short follow-up are appropriately "placed" on the curve, and not compared with patients with longer follow-up. In the current study, I'm not sure the direct comparison should have been presented at all, but I would be interested to hear what others with more epidemiologic/biostatistics knowledge have to say.

The effect of polyprenoic acid on development of a second primary hepatoma was more pronounced when the authors compared the two groups directly, than when the (appropriate) Kaplan-Meyer analysis was presented. This makes me wonder whether some of the effect on hepatoma development wasn't due to a delay in appearance rather than actual prevention. Presumably, longer term follow-up will clarify this matter.

June 19, 1996

Reader comments

Date: Mon, 01 Jul 1996
From: Howard Homler MD <>

It was an intriguing study, primarily as it dealt with an unusual aspect of altering the natural history of cancer. I would have been interested in knowing if this compound has activity in other cancers. I was also troubled by the way recurrent cancers were distinguished from second primaries.

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