Chemoprevention for the Treatment of Head and Neck Cancers

US Pharm. 2006;31(1)(Oncology suppl):16-21.

Chemoprevention, the use of agents to delay or reverse carcinogenic progression, is an innovative research area for head and neck cancer. Although the malignancy can be eradicated if diagnosed in early stages, the incidence of second primary tumors (SPTs) can threaten the long-term survival of patients with head and neck cancer. High doses of retinoids have been studied to reverse premalignant lesions and prevent SPTs. While it is hoped that chemopreventive research will decrease the rate of head and neck cancer, further research is still needed to identify agents that can prevent head and neck malignancies with minimal toxicity.

Head and neck cancer affects approximately 3% of Americans every year. An estimated 39,250 new cases of the disease were diagnosed in 2005, resulting in approximately 11,090 deaths.¹ Head and neck cancer is more common in men and in patients older than 50 years. Several of the associated risk factors linked with head and neck cancer include alcohol and tobacco use, betel nut consumption, frequent mouthwashing, and exposure to human papillomavirus. The most common head and neck cancers originate in the nasopharynx, pharyngeal wall, soft palate, tonsillar, pyriform sinus, base of tongue, and suppraglottic larynx. When head and neck cancer is diagnosed in early stages, patients have a better chance of eradicating the cancer. However, in patients who present with metastatic or recurrent disease, curative treatment is not possible, and median survival for these patients is about six to eight months.^2-4

SPTs are lesions that occur in the genetically altered areas where the first head or neck malignancy arose. SPTs can also be genetically independent from the initial tumor. SPTs can threaten the long-term survival of patients who initially were cured of their head or neck malignancy. SPTs arise at an annual incidence of 3% to 10%. In an effort to decrease the incidence of SPTs annually, many clinicians have pursued the arena of chemoprevention.^1,2 

Cancer Chemoprevention
Cancer chemoprevention is defined as the use of pharmacologic intervention with specific chemicals or nutrients to suppress, revert, or prevent carcinogenic progression to invasive cancer. This cancer control strategy is supported by the concepts of field and multistep
carcinogenesis. Carcinogenesis is a multistep progressive pathway that results from the collection of phenotypic and genetic variations that develop over a period of 10 to 20 years after the initial insult (i.e., the development of SPTs). Chemoprevention is the human intervention that halts the various steps of the carcinogenic process over several years; preventing one or several steps involved in carcinogenesis may delay the development of cancer.

The concept of field carcinogenesis, initially demonstrated in the 1950s in the head and neck areas as field cancerization, has been found to correlate to numerous epithelial sites. Field cancerization is described as disseminated epithelial damage as a result of exposure to inhaled carcinogens, which places large anatomic areas at risk for development of invasive cancer. Therefore, patients who are at high risk for developing invasive carcinoma are so at various levels, such as molecular (i.e., gene loss or amplification), microscopic (i.e., dysplasia, metaplasia), or gross (e.g., polyps, oral premalignant lesions) levels. Recent molecular tests, which identify significant genetic alterations in histologically normal tissues obtained from high-risk patients, have strongly supported this concept of field carcinogenesis.² For example, the mutagen sensitivity assay tests a patient's genetic sensitivity to environmental carcinogens. ²

Chemopreventive Agents
Retinoids, retinamides, carotenoids, cyclooxygenase-2 (Cox-2) inhibitors, and vitamin E have been studied as chemopreventive agents for head and neck cancers. Investigation into the field of biomarkers has also identified two novel agents--epidermal growth factor receptor (EGFR) inhibitors and farnesyltransferase inhibitors (FTIs), which target the EGFR and H-ras genes, respectively. Their use as chemopreventive agents warrants further study.^2,4-6

Retinoids: Retinoids and synthetic analogs and natural derivatives of vitamin A have been among the most widely studied agents in human chemoprevention.³ As early as 1913, the identification of vitamin A as a vital nutrient necessary for the basic processes of cells resulted in significant research of the vitamin in subsequent years. In 1925, Wolbach and colleagues identified cell histopathologic changes associated with higher risk of precancerous lesions due to vitamin A deficiency, leading to the discovery of retinols and the naturally occurring retinoid derivatives.³ Epidemiologic studies evaluating vitamin A ingestion and cancer risk in the 1970s revealed computed indices of total vitamin A intake with a decreased risk of lung cancer.³

Vitamin A is a vague term that includes two large families of dietary factors known as the preformed vitamin A (mainly retinyl esters and retinal/retinol) and provitamin A carotenoids (e.g., beta-carotene, other carotenoids that are precursors of retinol). Preformed vitamin A is found primarily in foods derived from animals, whereas provitamin A carotenoids are commonly found in fruits and vegetables.³

Retinoids are necessary for vital processes such as cell growth, differentiation, and death. Several retinoids,  such as vitamin A, have been shown to suppress or revert epithelial carcinogenesis and prevent the progression of various carcinomas, including those of the skin, lung, bladder, oral cavity, and esophagus, in animal models. Retinoids exert activity in the promotion and progression phases of carcinogenesis that are significant for chemoprevention in humans. Single-chemical activity has been demonstrated with natural retinoids (e.g., 13-cis retinoic acid [13-cRA], 9-cis retinoic acid [9-cRA], and retinyl palmitate) and synthetic retinoids (e.g., fenretinide, N-retinamide). In 1985, Sporn and colleagues redefined retinoids as substances that bind and stimulate one or more receptors, which can lead to the initiation of a biologic response.³

The molecular mechanism of action of retinoids is very similar to that of the steroid hormones in that the retinoid nuclear receptors are part of the steroid receptor superfamily. Two distinct receptors, RAR and RXR, as well as their respective subtypes, distinguish the retinoid receptors from the steroid receptors. These retinoid receptors are DNA-binding transcription components that can stimulate or suppress the gene expression necessary for the cell growth, differentiation, and death. Evaluation of retinoid receptor expression patterns in cancerous, precancerous, and normal tissues reveals the importance of retinoids in cancer progression. However, the exact action through which vitamin A or its derivatives exert their chemopreventive activity is still unclear.^2,3,5 Specific agents and their respective dosing schemas in chemoprevention trials are listed in table 1.

Carotenoids: Dietary beta-carotene has been associated with reduced cancer rates and is one of the most commonly studied carotenoids.² Animal models have demonstrated inhibition of oral malignancy with topical beta-carotene. Epidemiologic study findings have led to further investigation of beta-carotene in phase II and III clinical trials. Furthermore, beta-carotene has proven to possess some activity in oral premalignancy. Early trials have shown that oral leukoplakia responds to beta-carotene at rates as high as 44% to 71%. Adverse effects may include diarrhea, skin discoloration, and in rare cases, ecchymoses and arthralgias.^2,5-7

Cox-2 Inhibitors: Inhibition of cox-2 activity has been the focus of several chemoprevention methods.² One approach to altering carcinogenesis is inhibiting the up-regulation of prostaglandin synthesis in precancerous and cancerous tissue. The theory is that cyclooxygenase catalyzes the production of prostaglandin and mutagenic electrophiles. Prostaglandin levels have been identified in many epithelial cancers, including those of the head and neck, at elevated concentrations. Prostaglandins alter the proliferation of cells and promote angiogenesis, the development of new blood vessels.

The two isoforms of cyclooxygenase are known as cox-1 and cox-2. The overexpression of cox-2 in epithelial cells prevents apoptosis (cell death), resulting in an increase of neoplastic potential of activated cells. Cox-2 is believed to augment the development of vascular growth factors (resulting in neoangiogenesis, the development of new blood vessels located in the tumors) and regulate cytokines involved in chronic inflammation (leading to epithelial carcinogenesis). The overexpression of cox-2 is nearly 100-fold greater in head and neck cancer tissue than in normal tissue. Cox-2 inhibitors have been proven to prevent the development of colonic polyps in patients with familial adenomatous polyposis. Possible prevention of other carcinomas, such as hepatocellular and those of the breast and bladder, has also been suggested. In addition, chronic inflammation is linked to an increased chance of developing epithelial malignancy. Such data warrant the further investigation of cox-2 inhibitors as an effective chemopreventive strategy. However, due to the recent data reported in the APPROVe trial that demonstrate an association between rofecoxib and an increased risk of cardio-vascular events, many of the cox-2 inhibitor chemopreventive trials have been arrested and are being reevaluated.^2,5,8,9

Vitamin E: Vitamin E has a vital role in the enzymatic initiation of hematopoiesis, pollutant detoxification, and drug metabolism. Epidemiologic and laboratory trials have demonstrated the anticarcinogenic activity of vitamin E. Its mechanism of action of antioxidant activity is believed to be related to its antioxidant properties. Topical vitamin E has effectively decreased progression of oral cancer in animal study models.^2,10

A recent meta-analysis evaluating the use of vitamin E in various trials revealed that high doses of the vitamin (>150 IU/day) may increase mortality from any cause and should be avoided.¹¹ These findings have halted numerous current vitamin E chemoprevention trials and warrant further investigation. 

EGFR Inhibitors: The EGFR is a transmembrane protein important in the proliferation and survival of cancer cells. Overall, the overexpression of EGFR on cancer cells leads to the proliferation and sustained growth of these cells, resulting in shorter disease-free intervals and shorter overall survival. Up-regulation of the EGFR and its ligand, tumor growth factor–alpha, occurs early in the multistep development of head and neck carcinogenesis and therefore occurs more frequently with advanced stages of dysplasia. In addition, EGFR overexpression in premalignant lesions tends to be a sensitive indicator of carcinogenic potential.

Tyrosine kinase inhibitors, small-molecule inhibitors of EGFR, are an attractive option for prevention of head and neck cancers due to their relatively mild adverse-effect profile (e.g., skin rash, diarrhea) and availability as an oral formulation. However, rare cases of interstitial pneumonitis have been documented with these agents, which is a potential concern for their use in the chemopreventive setting. ^12,13 Erlotinib and gefitinib are examples of oral EGFR tyrosine kinase inhibitors (TKIs).^2,10

FTIs: Metastasis and tumor invasion and development have been aided by the low-molecule-weight guanine triphosphates (i.e., ras, RhoA, Rac-1, and Cdc42). Members of the ras gene family are the most frequently altered protooncogenes found in various tumor types. Ras mutations are believed to occur in approximately 30% of all human cancers.² Since ras is believed to exert its neoplastic activity via farnesylation, FTIs have been established to prevent this process.^2,5,6

p53 Gene
Tumor-suppressor gene p53 is located on chromosome 17. Overexpression of p53 has been related to increased progression of mild to severe dysplasia to invasive carcinoma. Expression of the tumor suppressor p53 gene on head and neck cancer cells has proven to be indicative of shorter survival and may be useful in identifying individuals who are at higher risk for developing recurrent carcinoma or SPTs.^2,5,6

Clinical Trials
Leukoplakia and erythroplakia are oral lesions directly associated with cancer development and thus are considered excellent research areas for development of chemoprevention. Leukoplakia is defined as a white patch in the oral cavity that cannot be removed by scraping and cannot be classified clinically or histologically as any other definable lesion. Oral leukoplakia occurs in about 0.1% to 0.2% of the general population and transforms into carcinoma in about 2% to 3% of these cases.^2,10 The natural course of leukoplakia is unpredictable, with spontaneous improvement arising in several cases.

Erythroplakia is a red, nonelevated plaque located on the oral or pharyngeal surfaces. The condition is associated with a higher risk for subsequent malignant transformation and is commonly associated with in situ or invasive cancer. Leukoplakia and erythroplakia are frequently correlated with tobacco use (e.g., cigarette smoking, tobacco chew, snuff) and betel quid chewing. Alcohol abuse is an additional risk factor for these conditions. The progression of leukoplakia and erythroplakia to invasive cancer depends mainly on degree of dysplasia, clinical features of the lesions, and minimal improvement in the resolution rate of these lesions after smoking cessation.^2,3,10

Since surgical excision of multiple extensive lesions cannot cure or prevent the development of new lesions, other treatment interventions such as chemopreventive measures should be sought.² Oral leukoplakia lesions can be safely followed histologically and clinically. Most importantly, oral premalignant lesions serve as markers of broad areas of injury and increased risk for cancer progression elsewhere in the aerodigestive system. Consequently, testing of oral premalignancy has been vitally important for cancer chemoprevention. Numerous agents, such as retinoids, have been researched over the years and have shown promising results for the treatment of head and neck cancer.²

Trials in Oral Premalignancy
Retinoid Trials: A placebo-controlled double-blind study examined 44 patients using high-dose 13-cis retinoic acid (13-cRA, 1 to 2 mg/kg/day) for three months.¹⁴ The clinical response rate, measured as a major reduction in the size of the oral leukoplakia, was 67% in the retinoid group compared to 10% in the placebo group (P=.0002). Patients were followed up to six months. The study demonstrated two key points: the toxicities associated with high-dose 13-cRA were frequent and severe, and remission was brief, such that within three months of therapy cessation, more than half of the patients experienced a relapse. Toxicities associated with high-dose 13-cRA include cheilitis, facial erythema, conjunctivitis, skin dryness, and hypertriglyceridemia.¹⁴

A second trial was designed to address the severe toxicities and short-lived remissions with use of high-dose 13-cRA.¹⁵ In this study, 53 patients received induction therapy with high-dose 13-cRA (1.5 mg/kg/day) followed by randomization to maintenance therapy for nine months. Patients whose lesions had responded or remained stable with induction therapy were then randomized to maintenance therapy with either low-dose 13-cRA (0.5 mg/kg/day) or low-dose beta-carotene (30 mg/day). The beta-carotene group was utilized due to low toxicity associated with beta-carotene and results from positive uncontrolled trials. The induction therapy had produced a clinical response rate in 55% of patients, similar to the results of the earlier trial. All patients were assessable for maintenance therapy. The 13-cRA group demonstrated 33% further lesion reduction, as compared to 10% in the beta-carotene group. The rate of disease progression after or during administration of low-dose 13-cRA therapy was only 8% compared to 55% with beta-carotene therapy (P<.001). Although the severity of adverse effects was reduced significantly with low-dose 13-cRA, the reduction was greater in the beta-carotene group, which had minimal adverse effects. ¹⁵

Additional studies were conducted to evaluate the combination of retinoids with beta-carotene. However, due to the negative findings of beta-carotene on lung cancer incidence in the large lung cancer chemoprevention studies (i.e., Alpha-Tocopherol/Beta-Carotene Trial and the Beta-Carotene and Retinol Efficacy Trial), beta-carotene inclusive trials in oral leukoplakia patients who smoked were stopped early.

A study examined 65 patients with oral leukoplakia resulting from chewing betel nut quid or tobacco.¹⁶ Patients were randomized to receive vitamin A 100,000 IU twice weekly or a placebo for six months. Remission was achieved in 57% of the vitamin A group, compared to 3% of the placebo group.¹⁶ There was no evidence of disease progression in patients receiving vitamin A therapy, while progression did occur in 21% of patients receiving placebo.^2,16 Various doses of vitamin A and its derivatives have been studied, but the optimal dosing schema and duration with minimal adverse effects has yet to determined.

Nonretinoid Trials: Several trials have evaluated the use of various agents as chemopreventive measures. For example, one study evaluated the effects of beta-carotene in 130 patients with oral leukoplakia in a three-group trial (i.e., beta-carotene, placebo, and beta-carotene plus retinol).⁶ The results demonstrated that the combination of retinol and beta-carotene was more likely to induce remission than beta-carotene alone.⁶

An attenuated adenovirus that selectively targets the p53 gene was evaluated in a mouthwash (ONYX-015) in 22 patients with oral leukoplakia.¹⁷ Patients were scheduled into three different cohorts: 10¹⁰ plaque-forming units (pfu) daily for five days every four weeks, 10¹⁰ pfu every week for 24 weeks, or 10¹¹ pfu daily for five days followed by weekly administration over the next five weeks. Patients were asked to hold the viral mouthwash in their mouths for at least 30 seconds; many patients found this task quite difficult. Histologic resolution of dysplasia was observed in 37% of patients, but a majority of the responses were temporary. Adverse effects were mild in nature. Further studies need to be conducted to elucidate activity of the p53 gene in the treatment of oral dysplasia.¹⁷ 

A randomized, double-blind, placebo-controlled study assessed the use of a ketorolac tromethamine oral rinse in 57 patients with oropharyngeal leukoplakia to analyze the reduction in lesion size.¹⁸ Patients were instructed to hold 10 mL of a 0.1% ketorolac solution or 10 mL of a placebo solution in their mouths for at least 30 seconds twice daily for 90 days. Both rinses were well tolerated with minimal adverse effects. There were no significant differences between the rinses in regards to reduction of lesion size.¹⁸

Adjuvant Chemoprevention Trials for Prevention of SPTs: A randomized, placebo-controlled, phase III chemoprevention trial evaluated 103 previously treated patients with head and neck cancer, stages I to IV (oral cavity, pharynx, larynx).¹⁹ Patients were randomized to receive high-dose 13-cRA (50 to 100 mg/m² daily) or placebo for one year. There were no major differences in the number of local, regional, or distant recurrences of the initial carcinoma between the two groups. However, the 13-cRA group had a substantially lower number of SPTs. Due to increased toxicity, 33% of patients did not finish the 12-month treatment plan. At median follow-up (32 months), 4% of patients in the 13-cRA group had one or more SPTs, compared to 24% in the placebo group (P=.005). As with previous trials, adverse effects such as cheilitis, skin dryness, conjunctivitis, and hypertriglyceridemia were reported with high-dose 13-cRA. At a 54.5-month follow-up (long-term), the development rate of SPT was 14% in the 13-cRA group, compared to 31% in the placebo group (P=.04).¹⁹

A second study was conducted in an effort to decrease toxicity by utilizing a low dose of retinoids.²⁰ The study, which included 1,191 patients with a history of head and neck cancer, randomized patients to receive either placebo or 13-cRA at 30 mg/day for three years. The long-term results demonstrated that while low-dose 13-cRA did not alter the rate of SPT development, it may be able to delay recurrence rates.¹⁰

The Euroscan trial assessed 2,592 patients who had been definitively treated for their primary tumors (40% lung cancer and 60% head and neck cancer) and randomized them receive either retinyl palmitate, N-acetylcysteine, both agents, or placebo for two years.²¹ The results of this trial did not show any survival benefit or decrease in SPTs with retinyl palmitate, N-acetylcysteine, or a combination of the two.²¹

In a separate study, 316 patients with a previous history of definitively treated head and neck cancer were randomized to receive placebo or etretinate adjuvantly.²² Results of the study did not demonstrate a survival benefit, change in disease-free survival rate, or change in the development rate of SPTs in either group. Adverse effects included cheilitis, conjunctivitis, and dermatologic changes such as cutaneous rash, pruritis, and erythema.²²

Biochemoprevention: Biochemoprevention treatment was developed for patients whose premalignant lesions are resistant to single-agent retinoid treatment and are at high risk of progressing to carcinoma. Biochemoprevention uses a combination of agents, usually retinoids, interferon, and alpha-tocopherol. A nonrandomized study evaluated this triple-drug regimen (isotretinoin 80 mg/m²/day, interferon-alpha 3 million units/m² twice weekly, and alpha-tocopherol 1,200 IU/day) for one year in 36 patients with premalignant lesions, mostly in the laryngeal areas or oral cavity.²³ The study showed that biochemoprevention was effective for laryngeal lesions but not for oral cavity lesions. Based on these results, another trial is currently under way to evaluate induction therapy using biochemopreventive agents for one year followed by maintenance therapy consisting of fenretinide, a retinamide, versus placebo for two years.^23,24

Another biochemoprevention trial was conducted in patients with locally advanced head and neck cancer. ²⁵ Patients received 13-cRA, interferon, and alpha-tocopherol for one year (isotretinoin 50 mg/m²/day; interferon-alpha 3 million units/m ² three times weekly; alpha-tocopherol 1,200 IU/day). At 24 months (median), 14% of patients developed recurrent disease and 86% of the patients completed the yearlong treatment. One patient developed an SPT. Overall survival at one year was 98% and at two years was 91%. Adverse effects included mild to moderate mucocutaneous effects, fatigue, flu-like symptoms, anorexia, hypertriglyceridemia, and peripheral neuropathy. A randomized phase III trial is currently under way to confirm these phase II results.²⁵

Role of the Pharmacist
When patients inquire about the use of vitamin therapy for the prevention of cancer in doses higher than recommended by the FDA, pharmacists should encourage them to consult with their physician prior to initiation. Higher doses of vitamin therapy are associated with increased side effects. If patients are not closely monitored by a health care professional, the adverse effects can be detrimental.

If a patient is currently receiving a chemopreventive agent mentioned in this article, the pharmacist should encourage patient adherence. For example, high doses of retinoid therapy are associated with problematic adverse effects, and nonadherence to therapy is very possible. Since this therapy is recommended for high-risk patients for possible prevention of
invasive carcinoma, adherence is vital.

Conclusion
Chemoprevention is an exciting and promising area for the management of head and neck cancer. High doses of retinoids as single agents have shown activity against oral leukoplakia. However, the adverse effects associated with high-dose retinoids (i.e., , facial erythema, conjunctivitis, skin dryness, and hypertriglyceridemia) may result in increased nonadherence. Concerns regarding the ideal dosing and duration of retinoid therapy as a single agent or in combination with other agents still remain.

Molecular targeted agents such as FTIs, cox-2, and TKIs are an important area of research for future clinical trials since head and cancers represent a progressive genetic disorder. The effectiveness of biochemoprevention using triple therapy consisting of isotretinoin, interferon, and vitamin E needs to be proven through larger trials. In addition, acceptable toxicity with new agents and good patient compliance need to be addressed in future chemoprevention trials. While great strides have been made in understanding the multistep processes of head and neck carcinogenesis, the area of chemoprevention warrants more extensive clinical research.

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