• 4/6/2005
  • Bethesda, MD
  • Edward S. Kim, Waun Ki Hong
  • Journal of the National Cancer Institute, Vol. 97, No. 7, 468-470, April 6, 2005

The use of natural agents as medicinal treatments has a long history. The Greek physician Hippocrates (circa 400 BCE) was one of the earliest proponents of nutritional healing. His favorite remedies were apples, dates, and barley mush (1). The term “chemoprevention,” which was coined in 1976 (2), describes the use of specific natural, synthetic, or biologic agents to reverse, suppress, or prevent the development of disease.

Chemoprevention is an appealing approach to treating patients with a variety of medical conditions. For instance, cardiac patients who take low-dose aspirin do so in hopes of preventing a future ischemic event. Cancer chemoprevention’s best model is early-stage breast cancer, for which hormonal agents are used to prevent recurrence and contralateral disease in patients with the appropriate hormone receptor status.

Both basic biologic research and clinical chemical intervention are the underpinnings of chemoprevention aimed at delaying or halting the process of carcinogenesis. The principles of chemoprevention are based on the concepts of multifocal field carcinogenesis and multistep carcinogenesis. In field carcinogenesis (3), diffuse epithelial injury results from carcinogen exposure; genetic changes and premalignant and malignant lesions in one region of the field translate to an increased risk of cancer developing in the entire field. Multistep carcinogenesis occurs through the stepwise accumulation of alterations, both genotypic and phenotypic (4–7). Arresting one or several of the steps may impede or delay the development of cancer. For example, 13-cis retinoic acid (13cRA) has been shown to reverse oral premalignant lesions (leukoplakia and erythroplakia) that may progress to cancer (8). In addition to histologic assessment, evaluations of biomarkers that accurately predict risk or response are needed to assess these chemopreventive therapies in a timely and cost-efficient manner.

Second primary tumors (SPTs), the leading cause of mortality in head and neck cancer, provide a good illustration of the concept of field carcinogenesis. The annual rate of SPTs in cured head and neck cancer patients is approximately 5% per year. Warren and Gates (9) defined SPTs in 1932 as lesions that can arise from the same genetically altered “field” from which the first tumor developed. SPTs can also be independent and arise from a different clone (10–13). Tobacco-induced multifocal field carcinogenesis effects, which include multiple genetic abnormalities, have been detected in normal and premalignant epithelium of the head and neck, lung, esophagus, cervix, and bladder in high-risk patients (10,14–21). Further analysis of molecular characteristics of primary and second primary cancers, which is already in progress, will better define their origins (i.e., synchronous or metachronous).

In a quest to reduce the mortality of SPTs that plague the head and neck cancer patient population, investigators have applied chemoprevention strategies with specific natural and synthetic agents. In this issue of the Journal, Bairati et al. (22) report the results of a multicenter, double-blind, placebo-controlled, randomized chemoprevention trial that included 540 patients with stage I or II head and neck cancer treated by radiation therapy. Their aim was to assess whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer. Treatment with -tocopherol (400 IU/day) and -carotene (30 mg/day) or placebo began on the first day of radiation therapy and continued for 3 years after the end of radiation therapy. After 156 patients had been enrolled, -carotene supplementation was discontinued because of ethical concerns that arose from another trial (23) in which -carotene supplementation showed adverse effects or no difference (24) in smokers.

In the Bairati et al. study, compared with patients receiving placebo, patients receiving -tocopherol supplements had a higher rate of second primary cancers during the supplementation period (hazard ratio [HR] = 2.88, 95% confidence interval [CI] = 1.56 to 5.31) but a lower rate after supplementation was discontinued (HR = 0.41, 95% CI = 0.16 to 1.03) (median follow-up of 52 months). Analyses of cancer-free survival yielded similar results, with the rate of all second events (recurrence, distant metastasis, or SPT) higher during -tocopherol supplementation (HR = 1.86, 95% CI = 1.27 to 2.72) and lower afterward (HR = 0.71, 95% CI = 0.33 to 1.53). The proportion of participants free of second primary cancer overall after 8 years of follow-up was similar in both arms. Thus, -tocopherol supplementation produced unexpected adverse effects on the occurrence of second primary cancers and on cancer-free survival.

Previous trials have also been performed in chemoprevention of SPTs. Hong et al. performed a randomized placebo-controlled chemoprevention trial of high-dose 13cRA (50 to 100 mg · m–2 · day for 1 year) in 103 patients with a prior head and neck squamous cell cancer (larynx, pharynx, or oral cavity) (25). At a median follow-up of 32 months, fewer SPTs were seen in patients treated with high-dose 13cRA than in patients treated with placebo (4% versus 24%; P=.005). The efficacy of high-dose 13cRA was observed through 3 years even though treatment lasted only 1 year. After the 3-year period, the efficacy of the retinoid dissipated and the rates of SPTs in the 13cRA and placebo arms were identical (26). Despite these encouraging results, patients who received high-dose 13cRA experienced substantial toxicity. Therefore, in a subsequent trial of 1218 patients with prior head and neck squamous cell cancer, subjects were randomly assigned to low-dose 13cRA (30 mg/day) for 3 years or to placebo. Although the interim analysis was promising, the final report (27) indicated that low-dose 13cRA did not have an impact on SPT rates but may have delayed recurrence. A possible explanation for these divergent results may be that, in the first trial, patients not only had a higher drug dose but were started on the drug soon after their definitive treatment, whereas in the second trial, patients were enrolled up to 3 years after completing their cancer treatment. As with adjuvant chemotherapy, therapy may work best when initiated earlier.

Additional trials have studied retinoids alone and in combination with other agents for chemoprevention of head and neck cancer and other cancers. The EUROSCAN trial enrolled 2592 patients definitively treated for their primary tumors (60% head and neck cancer, 40% lung cancer) and randomly assigned them to receive retinyl palmitate, N-acetylcysteine, both agents, or placebo for 2 years (28). This study did not show any survival benefit or decrease in SPT with the agents in either disease type. Bolla et al. compared etretinate with placebo in 316 patients with prior early-stage squamous cell cancers of the oral cavity or oropharynx and reported no difference in 5-year survival, disease-free survival, or SPT rates (29). Shin et al. tested the combination of interferon-alfa, 13cRA, and -tocopherol in patients treated with locally advanced head and neck cancer in a bioadjuvant approach (30). Treatment continued for 1 year. Eighty-six percent of the patients completed the planned therapy. Median 1- and 2-year overall survival rates were 98% and 91%. This combination is currently being studied in a phase III comparative study.

Together, therefore, a number of large-scale chemoprevention trials have failed to show adequate benefit, at least using the agents that were currently available. Studies such as the one by Bairati et al. tested agents that seemed promising at the time the trial was initiated but for which enthusiasm has subsequently declined based on the results of the other trials. What becomes of the field of chemoprevention after the reporting of yet another negative trial? Several important aspects of chemoprevention must be addressed before we move forward with other chemoprevention trials.

Are chemoprevention strategies worth pursuing? The answer is yes. For certain tumors, adjuvant therapy with chemotherapy as well as biologic therapy improves survival. However, chemoprevention trials, especially in head and neck cancer, must be more selective in their definition of the patient population to be studied and in the specific agents tested to answer important questions of efficacy. The most important challenges to designing chemoprevention trials to reduce SPTs in head and neck cancer patients are the selection of safe and effective agents for long-term treatment and the identification of patients who are at highest risk of developing SPTs through a biologic risk model. Although the Bairati et al. study began treatment in a timely manner, the agents chosen seemed safe for use in this particular population of patients but were not very tailored to a specific risk-based population.

Which agent is appropriate for testing? This is a critical but difficult question. Chemoprevention trials are large, time-consuming, and expensive. The agents must be mature enough to ensure safety but demonstrate enough early efficacy to have promise in inhibiting carcinogenic pathways. The effects and theories behind the use of -carotene as a chemoprevention agent have been outlined extensively [e.g., see Duffield-Lillico and Begg (31)]. Fortunately, more agents are being studied in both preclinical models and more focused clinical trials of aerodigestive tract cancers, and more novel drugs should soon be available for future chemoprevention studies. The agents used in the Bairati et al. study did not carry much biomarker-based data that would predict that this therapy would be effective against this patient population.

Which patient population is appropriate to study? Risk stratification in chemoprevention studies has been limited to smoking history and history of prior cancers. More detailed classifications (e.g., according to marker gene expression) of cancers are needed to define appropriate populations to study; thus, development of a risk model is essential. A standard risk model does not exist for head and neck cancer, but several that are based on tissue arrays (32) or molecular epidemiologic evidence (33) have been proposed. We have attempted to study characteristics of tobacco intake as a risk model, but the specific genetic changes have been shown to have greater prognostic value. Lee et al. successfully analyzed multiple biomarkers and have been able to predict cancer development in patients with oral premalignancies (34). Among these patients, premalignant histology, prior cancer history, and three biomarkers (chromosomal polysomy, p53 protein expression, and LOH (loss of heterozygosity) at chromosome 3p or 9p) predicted those at high risk for cancer development. Although Bairati et al. treated patients who seemed at high risk to develop SPTs, we believe that future trials must require tissue testing for specific biomarkers, which may influence what type of therapy a particular patient receives.

What type of chemoprevention approach? Interest in chemoprevention is high. The next generation of trials will be focused more heavily than previous trials on the identification and integration of biomarkers to influence treatment (35). Once patients are found to have a poor prognostic genotype, then specific agents can be used to target these genetic abnormalities. This type of approach would maximize the potential benefit and minimize the risk. Once agents in appropriate populations are identified in these smaller phase II trials, there will then be stronger evidence to definitively test the agents in phase III trials using important health outcomes as the end points. The importance of beginning therapy early enough after the completion of definitive treatment may be important, especially when assessing the value of adjuvant therapy. Several trials are open or planned in aerodigestive tract cancers to study the effect of longer-term adjuvant use of biologic agents in early-stage cancers.

Does an apple a day keep the doctor away? The field of chemoprevention still remains an exciting area of research, yet many challenges are ahead. Risk stratification factors must become more specific and scientific. This, in turn, will allow us to treat the patient in a more biomarker-integrated approach. Only then will we be able to discover that elusive “golden apple” of chemoprevention.

Authors’ Affiliation:
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

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