Japanese Journal of Clinical Oncology 31:357-358 (2001)
© 2001 Foundation for Promotion of Cancer Research
Editorial |
Cancer Chemoprevention as Adjuvant Therapy for Hepatocellular Carcinoma
Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors around the world. In Japan, the number of patients who die from HCC has been increasing annually and reached about 33 000 in 1998. At present, HCC is the third most common cause of cancer death among males and the fourth among females. Imaging diagnosis and assessment of tumor markers indicating small mass lesions in the liver have progressed in recent years. As a result, screening programs that use such diagnostic modalities have facilitated the early detection of HCC in patients with chronic liver disease and has increased the number of candidates for effective local treatments such as hepatic resection and percutaneous ablation therapy. However, very few patients undergoing such local treatments can be cured and the overall results of these treatments are still unsatisfactory, mostly because of post-therapeutic recurrence.
The recurrence rate of HCC is extremely high even after potentially curative treatments with surgical resection or ablation therapy; more than 70% of patients have tumor recurrences, mainly in the liver, after 5 years of post-therapeutic follow-up (1). Recurrent nodules have two possible origins: (a) they may be microscopic metastases from the primary tumor or (b) they may be other HCCs induced by multicentric carcinogenesis (second primary HCC). Although multiple recurrences detected shortly after treatment have been presumed to be the result of microscopic metastases, tumor recurrences that appeared after considerable periods of time (more than 2 years), particularly well-differentiated HCC, would more likely be multicentric HCC.
Adjuvant therapy to suppress recurrences, which is of great importance for improving the prognosis of HCC patients, can be divided into two different therapeutic methods based on the origins of recurrent nodules; anti-cancer treatments for microscopic metastases and chemoprevention of second primary HCC. The role of adjuvant anti-cancer treatments is still to be established in HCC, owing to both the limited activity and the adverse effects of these treatments. Moreover, the presence of chronic liver disease limits the ability of the liver remnant to tolerate adjuvant anti-cancer treatments. To improve the prognosis of HCC further, particularly the long-term prognosis after curative treatments for HCC, a new strategy to prevent second primary HCC may be required. Some agents, such as interferon 
, a Japanese herbal medicine and a retinoid analog, have been reported to suppress hepatocarcinogenesis in clinical trials (2–4).
Cancer chemoprevention, which can be defined as the use of specific natural or synthetic chemical agents to reverse, suppress or prevent carcinogenic progression to invasive cancer, is gaining prominence as a new approach for cancer control. The objective of cancer chemoprevention trials is to reduce the incidence of disease (and thus, ultimately, to reduce mortality) and double-blind randomized controlled trials (RCTs) have become a predominant tool to test agents aimed at preventing cancer. The most appropriate end-point of cancer chemoprevention trials is cancer incidence, but enormous sample sizes are needed over long periods of time to study the effects of chemopreventive agents on the incidence. Therefore, the development of intermediate (i.e. surrogate) end-point biomarkers (to indicate agent activity) holds great promise for cancer chemoprevention by allowing shorter, smaller and less expensive chemopreventive trials.
There have been several RCTs of adjuvant therapy for HCC reported in the English language literature. To date, four positive trials, in which various adjuvant treatments were compared with no adjuvant, are available (4–7). Lau et al. demonstrated that one 1850 MBq dose of [131I]lipiodol given intra-arterially after resection for HCC (mainly hepatitis B virus-related HCC) significantly reduced tumor recurrence and improved disease-free and overall survival (5). In a trial by Takayama et al., adoptive immunotherapy lowered recurrence and improved recurrence-free survival after resection for HCC (6). In addition, the interim analysis of a trial by Ikeda et al. demonstrated that interferon ß suppressed tumor recurrence after potentially curative treatments in patients with hepatitis C virus-related HCC (7). All of these three treatments were performed as an adjuvant to eradicate microscopic metastases and the treated patients remained at risk of multicentric HCC even if residual tumor was eliminated.
In the fourth positive trial, by Muto et al., patients were treated with an acyclic retinoid, polyprenoic acid, based on a concept (cancer chemoprevention) differing from that of the first three adjuvant treatments (4,8). This compound inhibits experimental hepatocarcinogenesis and induces differentiation and apoptosis of human HCC-derived cell lines (9,10). Oral administration of polyprenoic acid for 12 months significantly reduced the incidence of second primary HCC as compared with oral placebo (adjusted relative risk, 0.31). Moreover, the survival rate was also significantly improved by polyprenoic acid; the 6 year survival was 74% in the polyprenoic acid group and 46% in the placebo group (adjusted relative risk, 0.3). Thus, in adjuvant therapy with polyprenoic acid, the prevention of second primary HCC was translated into an overall survival advantage. Adverse effects of polyprenoic acid were generally mild and no typical toxicities of retinoids, such as dry skin, cheilitis or conjunctivitis, were observed in this trial.
Serum lectin-reactive -fetoprotein (AFP-L3) is a tumor marker that indicates the presence of latent HCC cells even when they are not detectable as a tumor by diagnostic images (11). AFP-L3 also indicates the grade of differentiation of premalignant hepatic cells (12). In the RCT of polyprenoic acid, this compound decreased the number of AFP-L3-positive patients by abolishing serum AFP-L3 in initially positive patients and by preventing the appearance of new AFP-L3-positive patients (13). This observation suggests that polyprenoic acid may have deleted the clone of premalignant or latent HCC cells producing AFP-L3 from the remnant liver and thereby contributed to reducing the incidence of second primary HCC. Thus, AFP-L3 is causally related to HCC and there is some evidence that it will be affected by intervention under study. Therefore, AFP-L3 can be used as an intermediate end-point biomarker in cancer chemoprevention against HCC.
This is the background of the Special Article by Okuno et al. that appears in this issue (14). They propose a new concept of ‘clonal deletion’ therapy (a deletion of a clone of premalignant or latent HCC cells from the liver) with polyprenoic acid for cancer chemoprevention against HCC. This article provides information for understanding the molecular mechanism of ‘clonal deletion’. Two possible mechanisms are suggested for this ‘clonal deletion’: cell death (or apoptosis) and differentiation induction. Differentiation of HCC cells by polyprenoic acid still requires further investigation, but apoptosis induction of HCC cells by polyprenoic acid has been clearly shown. Okuno et al. found a novel molecular mechanism of apoptosis induction by the compound. In addition to retinoid depletion, the phosphorylation of retinoid X receptor , which interferes with its signaling and metabolism, may be involved in the development of HCC. Polyprenoic acid restores the function of this phosphorylated retinoid X receptor and thereby induces apoptosis via the tissue transglutaminase pathway.
Do the positive results in the four trials cited above qualify these adjuvant treatments for standard of care? Not yet. Such adjuvant use may be precluded by the necessity for radiation protection, the complexity of treatment or a limited effect on overall survival. Among these adjuvant treatments, oral administration of polyprenoic acid may be the most promising approach because of its simplicity, ready availability, non-invasiveness and the lack of the necessity for radiation protection. However, several open questions remain concerning this agent in the prevention of HCC. What is the optimal dose and duration of polyprenoic acid therapy that will prevent HCC recurrence? Who are the appropriate patients to be treated with this agent? Does adjuvant therapy with polyprenoic acid really reduce the incidence of second primary cancer and improve survival? Would polyprenoic acid therapy also successfully prevent the occurrence of primary HCC in patients with chronic liver disease? To answer these questions and to define the role of polyprenoic acid therapy as an adjuvant to local treatments for HCC, a fair number of diligent trials, such as dose finding trials and double-blind RCTs, are mandatory. In such trials, risk–benefit and cost effectiveness would be other important end-points, since an efficient but invasive and expensive therapy has little chance of becoming generalized. Moreover, the advances in the molecular biology of hepatocarcinogenesis and chemopreventive agent mechanisms may facilitate the identification of a suitable patient population for this therapy.
FOOTNOTES
+ Abbreviations: AFP-L3, lectin-reactive -fetoprotein; HCC, hepatocellular carcinoma; RCT, randomized controlled trials 
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