Chemoprevention Strategies in Head and Neck Cancer

Cancer chemoprevention, as first defined in 1976 by Sporn, is the use of natural, synthetic, or biologic chemical agents to reverse, suppress, or prevent carcinogenic progression. ^[1] The success of several clinical trials in cancer prevention in high-risk populations suggests that chemoprevention is a rational and appealing strategy. Cancer chemoprevention has earned serious consideration as a potential means of controlling cancer incidence, having become a top research priority of the National Cancer Institute (NCI). ^{[2, 3, 4, 5]}

Chemoprevention can be categorized as either primary chemoprevention or secondary chemoprevention. Primary chemoprevention is directed at patients with premalignant lesions (mucosal keratosis with atypia and erythroplakia). Secondary chemoprevention is targeted at patients with cancer who, in order to prevent recurrent disease or to prevent metachronous primary diseases, have undergone potentially curative therapy.

The basic cancer-related chemical and biologic sciences, pathology, and epidemiology have contributed to (1) the understanding that antimutagenesis and antiproliferation are the important general mechanisms of chemoprevention and (2) the development of antimutagenic and antiproliferative agents as potential chemopreventive drugs.

Chemoprevention is an appealing strategy with proven success in familial adenomatous polyposis (FAP) and breast cancer. In other malignancies, such as lung and prostate cancers, several agents have been studied, but no strategies have been proven effective. Oral keratosis with atypia is an ideal model for the study of head and neck cancer development and chemoprevention because the lesions are readily accessible to visual examination, diagnostic sampling, and evaluation of response to treatment.

Keratosis is any keratin production located superficially in the epithelium and is normal in skin. Keratin on a mucosal surface is abnormal, but not necessarily dysplastic, regardless of other surface morphologic characteristics. Clinically, keratin appears dull-white, thin or thick, and sometimes rough and papillary and does not rub off. The term leukoplakia describes such white areas, as well as other white lesions that do not rub off. Unfortunately, the term leukoplakia has also been applied to histologic diagnosis of dysplastic lesions, even those that are not white and have no keratosis. This confusion spills over into the literature, complicating evaluation. See the image below.

In discussing chemoprevention in head and neck cancer, only histologic terminology allows significance. Keratosis without atypia and keratosis with atypia are preferable terms for rating the severity of atypia (eg, mild, moderate, severe), which reflects the histology of the lesion.

Erythroplasia is the clinical term for a velvety-red patch that, histologically, is a surface atypia, is usually full-thickness (carcinoma in situ), and is occasionally invasive (microinvasion) but is without keratosis.

Keratosis with atypia and carcinoma in situ are considered premalignant lesions of the oral mucosa. In London in 1851, Sir James Paget was the first to specifically suggest an association between a benign oral mucosal lesion and the subsequent development of oral malignancy. ^[6] He noted the cancer-producing potential of the pipe-smoker's palate (leukokeratosis), and, in 1870, he clearly implied that oral ichthyosis (white keratotic plaque) was a significant precursor to lingual carcinoma.

Histologically, oral keratosis with atypia includes hyperplasia, hyperkeratosis, dysplasia, and carcinoma in situ. Oral keratosis with atypia is considered potentially malignant, with a transformation rate to carcinoma in situ ranging from 3.6-19.8%. ^[7]

The treatment of leukoplakia consists of excisional biopsy, when feasible, with serial section evaluation to determine severity. Multifocal advanced disease represents approximately 10-15% of all oral premalignant lesions and is rarely controlled adequately with local therapy. Surgical excision can be used to remove grossly evident disease but does not address the spread of clonally related cells into normal-appearing mucosa or the existence of other independent premalignant lesions. In addition, ionizing irradiation does not prevent the progress of carcinogenesis. Ionizing irradiation makes a sick mucosa sicker and cannot be used again when the need may be urgent.

Despite recognition of the premalignant nature of oral dysplastic lesions, few, if any, therapies to prevent cancer progression are effective.

Aberrant expression of a variety of molecules characterizes head and neck premalignant conditions. Current clinical parameters cannot predict the potential of malignant transformation in patients with oral premalignant lesions. To date, no reproducible and credible biomarkers of early oral tumorigenesis have been identified.

Incidence

The term head and neck cancer generally refers to cancers that arise in the mucosa of the upper aerodigestive tract. They are a heterogeneous group of tumors, each with its own distinct epidemiologic, anatomic, and pathologic features; natural history; prognosis; and treatment considerations. Head and neck cancers account for approximately 3% of all malignancies. ^[8]  It has been estimated that over 68,000 people in the United States were diagnosed with head and neck cancer in 2021. ^[9]

The American Cancer Society estimates that the incidence of oral cancer is almost as high as that of leukemia, and its mortality rate is about the same as that of melanoma. ^[8] Despite improvements in diagnosis and local management, long-term survival rates in head and neck cancer have not increased significantly over the past 30 years. Of the major cancers, long-term survival rates in head and neck cancer are among the lowest worldwide.

Head and neck cancer continues to be a devastating disease, with high mortality and morbidity rates. Patients may undergo debilitating changes in appearance, speech, and the ability to swallow and breathe. Management of established cancers is difficult, and methods to prevent these cancers from developing are of great interest.

Etiology

Approximately 85-90% of all head and neck cancers can be traced to the use of tobacco products, the excessive consumption of alcohol, or both. ^[10] Both can cause changes in the squamous cells of the head and neck aerodigestive tract. In recent years, the number of nonsmokers and nondrinkers diagnosed with head and neck cancers has increased.

More than 50% of squamous cell carcinomas (SCCs) that arise in the oropharynx, particularly in the palatine tonsils and the base of the tongue, contain oncogenic human papillomavirus (HPV) DNA. ^[11]

The Epstein-Barr virus (EBV) has been strongly linked to the development of nasopharyngeal carcinoma. ^[12]

Risk factors for head and neck cancer

See the list below:

• Tobacco (smoked [ie, cigarettes, cigars, pipes] and smokeless) and marijuana

• Alcohol

• Viruses (EBV [nasopharyngeal], herpes simplex virus, HPV)

• Betel nut, inverted smoking

• Industrial (metals [nickel, chromium], wood dust, textiles, furniture, leather [nasal cavity and peripheral nervous system])

• Chronic irritation (jagged teeth, luetic lesions, gastroesophageal reflux disease)

• Asbestos

• Diet (vitamin A deficiency)

• Prior radiotherapy (to mucosa, salivary gland, thyroid, skin)

• Iron deficiency (Plummer-Vinson syndrome)

• Mutagen-induced chromosome fragility

• Sunlight (cancer of the lower lip and malignant disease of skin)

• Systemic immunosuppression

• Premalignant conditions (oral keratosis with atypia and erythroplakia)

Primary cancer

After successful treatment with surgery, radiation, and chemotherapy, patients with head and neck cancer are at an increased risk of metachronous primary tumor, which is estimated to occur at an annual rate of 3-10%. These tumors are significant threats to long-term survival. ^[13]

The central idea that guides head and neck chemoprevention efforts is the concept of the diffuse injury of epithelium that results from widespread, chronic carcinogen exposure. In the 1950s, Slaughter and colleagues initially described this process as field cancerization. ^[14] Smoking tobacco is a major risk factor for head and neck cancer, and even former smokers are at a higher risk for more than 10 years after quitting.

The exposure to carcinogenic substances and carcinogenic promoters in tobacco smoke leads to genetic changes, called sick mucosa syndrome, over large areas of the oral cavity and the airway epithelium. These changes result in a field cancerization with potential multifocal unsynchronized premalignant and malignant lesions. This may explain the high recurrence rate and the development of further primary tumors after successful treatment of early-stage (I or II) head and neck cancers.

Thus, novel approaches to controlling cancers of the head and neck region should include treatment of the surrounding condemned airway epithelium. Because these cancers develop over a prolonged period of exposure to carcinogens and promoters and because of the multistep nature of carcinogenesis, an opportunity exists to intervene in the process with chemical agents for prevention (ie, chemoprevention). The reversal of this process is the goal of chemoprevention. Other modalities, such as surgery and irradiation, are used to manage the extreme expression of the sick mucosa, but not their underlying cause. Thus, chemoprevention can and should be considered the primary therapy.

Agents used in head and neck cancer chemoprevention include the following:

• Retinoids and vitamin A (beta carotene)

• Vitamin E

• Biochemoprevention

• Selenium

• Cyclooxygenase-2 (COX-2) inhibitors

• Tyrosine kinase inhibitors (TKIs)

• ONYX-015

• Protease inhibitors (PIs)

Retinoids

Retinoids have been shown to induce apoptosis, to suppress carcinogenesis, to decrease growth rate of epithelial cells, and to reduce free radicals. All of these effects have made retinoids the most-studied head and neck cancer chemopreventive agents. ^{[15, 16]} Retinol, retinal palpitate, all-trans -retinoic acid, 13-cis -retinoic acid (13cRA), etretinate, and fenretinide (4-HPR) all have a record of clinical study in the head and neck region, either for the reversal of oral preinvasive lesions or for the prevention of second primary tumors (SPTs). ^{[17, 18, 19]}

A study by Chen et al indicated that regular alcohol use cancels out the benefits of a relatively high serum retinol level in the prevention of head and neck cancer. Such benefits were, however, seen in persons who never drank or did so only occasionally. ^[20]

Oral premalignancy trials

In 1986, Hong et al reported that high-dose (1-2 mg/kg/d) 13-cis -retinoic acid (13cRA) had significant activity in their prospective, randomized, double-blind clinical trial in oral leukoplakia. ^[21] Clinical responses in the 13cRA group versus the placebo group were 67% and 10%, respectively (P = .002). The rate of histopathologic improvement was also significantly higher in the retinoid arm (54% vs 10%; P = .01). The major clinical limitations included a high rate of relapse (>50% within 2-3 mo of discontinuing therapy) and toxicity, which included dry skin, conjunctivitis, cheilitis, and hypertriglyceridemia.

In an effort to address the toxicity and relapse problems of the earlier Hong trial, a follow-up randomized maintenance trial with low-dose 13cRA was designed. ^[22] After a 3-month induction course of high-dose 13cRA, patients received a 9-month maintenance treatment with either low-dose 13cRA (0.5 mg/kg/d) or beta carotene (30 mg/d). As predicted in the study by Hong et al, the induction of high-dose 13cRA produced a high rate of response. In the maintenance phase, only 2 (8%) of 24 patients in the low-dose 13cRA group had progressive leukoplakia, whereas 16 (55%) of the 29 patients who received beta-carotene maintenance progressed (P< .001). Both groups experienced minimal side effects in the maintenance phase, with no differences in grade 3 or 4 cheilitis, dry skin, or hypertriglyceridemia.

In another trial, Koch achieved complete or partial remissions in 45% of patients with premalignant lesions treated with 1 of 3 retinoids—13cRA (isotretinoin), trans-beta-retinoic acid, or aromatic retinoid—after follow-up of up to 6 years. ^[23] In Milan, Italy, in 1988, Chiesa et al began a randomized trial to evaluate the efficacy of systemic synthetic retinoid 4-HPR (200 mg/d for 52 wk) as maintenance therapy versus no intervention after complete laser resection of oral leukoplakia. ^[24] In that study, 3 (8%) of 39 patients in the treated group and 12 (29%) of 41 patients who received no intervention were found to have local relapses or new lesions. 4-HPR was well tolerated, and toxicity was minimal.

Second primary tumor prevention trials

Retinoid therapy has been evaluated in placebo-controlled trials as a chemopreventive agent in the context of localized head and neck cancer after therapy with curative intent.

Hong et al conducted an adjuvant, randomized, double-blind, placebo-controlled, chemopreventive trial of high dose 13cRA for 1 year in 103 patients curatively treated for head and neck squamous cell cancer. ^[25] Trial endpoints included recurrence of the primary disease, development of a second primary tumor (SPT), and survival. With a median follow-up of 32 months, SPTs developed in only 4% of patients treated with 13cRA, compared with 24% in the placebo group. The retinoid treatment did not affect the recurrence of the initial cancer.

The SPTs that developed during the study were located predominantly in the carcinogen-exposed field of the head and neck, lungs, and esophagus. Problems with retinoid treatment are related to drug toxicity and include dry skin, liver toxicity, and spermatogenesis. One third of the isotretinoin-treated patients were unable to complete the year of therapy as planned. The data have been reanalyzed, with the median follow-up extended to 54.5 months. With longer follow-up, the retinoid-treated patients have continued to develop fewer SPTs—7 (14%) in the isotretinoin group, compared with 16 (31%) in the placebo group. ^[26] These results suggest that the beneficial chemopreventive effect of isotretinoin persisted after the year of treatment.

Because the high-dose isotretinoin used in this adjuvant study was poorly tolerated, determining if the chemopreventive effect could be maintained with lower, less toxic doses is of considerable interest. Bolla et al reported the findings of a study that evaluated the efficacy of the synthetic retinoid etretinate to prevent SPTs following squamous cell cancer of the oral cavity or oropharynx. ^[27] Researchers randomly assigned 316 patients to treatment with etretinate (50 mg/d for 1 mo, followed by 25 mg/d for 24 mo) or placebo. The 2 treatment groups were equivalent for both the occurrence of SPTs and relapse of the initial cancer.

Data from an intergroup large-scale phase III trial of low-dose, long-term isotretinoin in stage I or II head and neck squamous cell carcinoma (HNSCC) showed no difference in SPT development or overall survival. Researchers randomized 1,190 patients in this study to receive either 30 mg/d of isotretinoin or placebo; after a 3-year follow-up, the SPT rate in both groups was 4.7%. ^{[28, 29]}

Vitamin A

Vitamin A is essential for the development and maintenance of normal epithelium. Vitamin A deficiency causes a change in the differentiation pathway, resulting in epithelial hyperplasia and squamous metaplasia in laboratory animals. Epidemiologic surveys suggest that the risk of head and neck tumor genesis is increased with vitamin A deficiency. ^[30] The mechanism underlying the chemopreventative effects of vitamin A and its derivatives is the restored expression of retinoic acid receptor-beta (RAR-b) mRNA, which promotes normal tissue growth and differentiation. ^[31]

Subsequent trials have confirmed the activity of vitamin A in oral leukoplakia. In India, Stich et al compared vitamin A (200,000 IU/wk orally for 6 mo) with placebo in users of tobacco or betel nut with well-developed leukoplakia. ^[32] Complete remission rates in the vitamin A and placebo groups were 57.1% (n = 21) and 3% (n = 33), respectively. The development of new keratosis with atypia was suppressed in 100% of the treated group versus 21% of the placebo group.

Studying the ability of retinol to prevent second primary cancers led to the European study on chemoprevention with vitamin A and N -acetylcysteine (EUROSCAN). This was an open-label multicenter trial of over 2,592 patients with head and neck cancer or lung cancer. The endpoint was SPT prevention after treatment with curative intent of early-stage head and neck cancer or lung cancer. In the study, patients were randomized to receive vitamin A (300,000 IU/d followed by 150,000 IU/d in the second year), N -acetylcysteine (600 mg/d for 2 y), both compounds, or placebo. After a median follow-up of 49 months, there were no differences between the placebo group and the 3 active-treatment groups for SPTs, event-free survival, or long-term survival rates. ^[33]

Beta Carotene

Beta carotene is a naturally occurring, nontoxic carotenoid with biologic properties that may be suitable against oral leukoplakia. ^{[34, 35]} Beta carotene was found to inhibit the formation of oral squamous cell carcinoma (SCC) in animal models. ^[36] Results of some trials indicate that beta carotene has substantial activity in oral premalignancy.

Garewal et al described a high response rate in a phase II trial of beta carotene in leukoplakia. ^[37] Twenty-four patients who could be evaluated were treated, 17 of whom had major responses (2 complete, 15 partial), for a response rate of 71%.

In another phase II study of beta carotene in oral leukoplakia, conducted by Suda et al in 1989, the response rate was 44.4%. ^[36] No significant toxicity occurred that required drug discontinuation or dose reduction. Sankaranarayanan et al conducted a double-blind, placebo-controlled trial to evaluate the chemopreventive potential of either vitamin A alone or beta carotene alone in patients with oral leukoplakia in India. ^[38] In their study, 160 patients with oral precancerous lesions received either oral vitamin A or beta carotene for 12 months. The complete regression rates were as follows: 10% in the placebo group, 52% in the vitamin A group, and 33% in the beta-carotene group.

In a study by Kaugars et al, 79 patients with oral leukoplakia received 30 mg/d of beta carotene, 1000 mg/d of ascorbic acid, and 800 IU/d of alpha-tocopherol for 9 months. ^[39] Clinical improvement of the oral lesion was noted in 55.7% of the patients.

Large long-term randomized trials were necessary to evaluate the activity of beta carotene against oral premalignant lesions.

In a randomized, placebo-controlled, double-blind clinical multicenter trial that included 264 patients who had been curatively treated for a recent early-stage SCC of the oral cavity, pharynx, or larynx, patients were randomly assigned to receive either 50 mg/d of beta carotene or placebo; the patients were monitored for up to 90 months. After a median follow-up of 51 months, the 2 groups did not differ in the development of SPTs, local recurrences, and mortality. ^[40]

In a Physician's Health Study (a large randomized, double-blind, placebo-controlled trial that enrolled 22,071 male physicians from the United States), 12 years of supplementation with beta carotene showed virtually no early or late differences in the overall incidence of malignant neoplasms. ^[41]

Another large trial in the United States, the Beta Carotene and Retinol Efficacy Trial (CARET), involved more than 18,000 men and women who were smokers, worked with asbestos, or both. ^[42] After 4 years of 50,000 IU/d of beta carotene, the lung cancer rate in this group increased by 28%, and the cancer mortality rate increased by 17%. The study was discontinued prematurely because of these findings. This study prompted beta carotene to be removed from chemoprevention trials for oral premalignancy in people who smoke.

Vitamin E

The potent antioxidant vitamin E (alpha-tocopherol) has been shown to inhibit the growth of several cancer cell lines in vitro (including pancreas, breast, prostate) and to prevent the development of cancers in oral cavities in animal studies. ^[43]

Oral premalignancy trials

A single-arm phase II study showed that, among 43 patients with oral keratosis with atypia who took 400 IU of vitamin E twice daily for 24 weeks, 20 (46%) had clinical responses, and 9 (21%) had histologic responses. ^[44] Treatment was extremely well tolerated, with excellent patient compliance.

Second primary tumor prevention trials

Investigators at Laval University, in Canada, conducted a randomized, double-blind, placebo-controlled trial to assess whether supplementation with antioxidant vitamins could reduce the incidence of second primary cancers among patients with head and neck cancer.

Compared with patients who received placebo, patients who received alpha-tocopherol supplements had a higher rate of second primary cancers during the supplementation period (HR = 2.88; 95% CI, 1.56-5.31) but a lower rate after supplementation was discontinued. Overall, the 2 groups of patients had similar percentages of participants free of a second primary cancer after 8 years of follow-up. ^[45] Despite the disappointing results of this study, vitamin E has not been completely ruled out as a helpful substance for cancer chemoprevention.

Biochemoprevention

The combination of different biologic agents such as IFN-α, 13-cRA, and α-tocopherol was evaluated in a phase II study as an adjuvant approach to prevent recurrence or second primary tumors in patient with locally advanced squamous cell carcinoma of the head and neck. Retinoids and interferons (IFNs) have single-agent and synergistic combined effects in modulating cell proliferation, differentiation, and apoptosis in vitro and clinical activity in vivo in the head and neck and other sites.

Alpha-tocopherol has chemopreventive activity in the head and neck and may decrease 13-cis-retinoic acid (13-cRA) toxicity. After definitive local treatment with surgery, radiotherapy, or both, patients with locally advanced SCCHN were treated with 13-cRA (50 mg/m2/d, orally, daily), IFN- (3 x 106 IU/m2, subcutaneous injection, 3 times a week), and α-tocopherol (1,200 IU/d, orally, daily) for 12 months. The combination of IFN-α, 13-cRA, and α-tocopherol was generally well tolerated and toxicity was consistent with previous IFN and 13-cRA reports, 86% of patients completing the planned therapy. Median 1- and 2-year rates of overall survival were 98% and 91%, respectively, and of disease-free survival were 91% and 84%, respectively. ^[46]

These preliminary findings prompted conducting a phase III randomized study of this combination to confirm these promising phase II study results.

Selenium

The element selenium (Se) was recognized about 40 years ago as being essential in the nutrition of animals and humans. Epidemiologic data suggest that lower levels of selenium in the blood may contribute to an increased risk of incidence of some cancers. ^[47] A study conducted in India found that patients with low levels of selenium have significantly more head and neck cancers than patients with higher selenium levels. ^[48] The patients who underwent therapy (eg, surgery, radiation, or both) for SCC of the head and neck were given 200 mg of selenium. Supplementation with selenium during therapy resulted in a significantly enhanced cell-mediated immune responsiveness, as reflected in the ability of the patient's lymphocytes to respond to stimulation with mitogen, to generate cytotoxic lymphocytes, and to destroy tumor cells. ^[49]

The findings of this study require confirmation in an appropriately designed independent trial before new public health recommendations regarding selenium supplementation can be made.

Cyclooxygenase-2 Inhibitors

The idea that chronic inflammation and carcinogenesis are intimately linked in the pathogenesis of some neoplasms underlies many of the new approaches to cancer chemoprevention. However, the most established and elucidated connection between chronic inflammation and cancer involves colorectal cancer.

Celecoxib, a highly specific COX-2 inhibitor with minimal toxicity, has already been shown to be effective for the prevention of colon adenomas in patients with familial adenomatous polyposis (FAP). ^[50] COX-2 is considered an inducible isoenzyme that is induced during pain and inflammatory stimuli. Elevated COX-2 levels are known to occur in various neoplasms; for example, it is overexpressed in colon adenomas, which may contribute to adenoma growth, and inhibition of COX-2 may be the mechanism for polyp regression. High COX-2 levels are also found in such neoplasms as non–small-cell lung cancer (NSCLC) and cancers of the breast, liver, esophagus, and bladder. ^{[30, 51, 52]}

Nearly 100-fold greater expression levels of COX-2 were found in HNSCC cells compared with normal oral mucosa. ^[53] The efficacy of COX-2 inhibition that was predicted on the basis of molecular biology results was confirmed in an oral cancer chemoprevention study in which dietary administration of a specific COX-2 inhibitor (celecoxib) and a nonspecific COX-2 inhibitor (piroxicam) reduced oral cancer incidence, the invasiveness of induced cancers, and cancer-associated mortality. The combination of COX-2 and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) leads to the inhibition of cell growth by simultaneously blocking EGFR and COX-2 pathways. This combination holds great potential for HNSCC prevention, treatment, or both. ^[54]

A phase 1 and pharmacokinetic study by Saba et al reported encouraging results from the use of a combination of celecoxib and erlotinib, an EGFR TKI, in the chemoprevention of HNSCC. Histologic analysis in seven patients with premalignant lesions showed complete remission in 43%, partial remission in 14%, stable disease in 29%, and progressive disease in 14%. ^[55]

Aspirin

Aspirin is a nonselective cyclooxygenase (COX) inhibitor that blocks the action of COX-1 and COX-2, in turn inhibiting prostaglandin (PG) synthesis, particularly PGE₂. The expression of COX-2 and PGE₂ in tumors has been proven to be associated with suppressed immune response, enhanced inflammation, increased angiogenesis, augmented cellular proliferation, and inhibited apoptotic pathway, thereby promoting tumor progression and invasion. Thun et al examined the relative risk of death from buccal cavity and pharyngeal cancers in aspirin users and found a 30% nonsignificant risk reduction in some categories of aspirin use. ^[56]

Bosetti et al examined the effect of aspirin use on 965 upper aerodigestive cancers (393 oral and pharyngeal, 225 esophageal, and 347 laryngeal) and noted a 67% risk reduction in users who took aspirin for more than 5 years. ^[57] None of these studies were designed specifically to study the chemopreventive effect of aspirin on HNC.

One hospital-based case-control study showed that aspirin use was associated with a 25% reduction in the risk of head and neck cancer (adjusted odds ratio, 0.75; 95% CI, 0.58-0.96). These effects were more pronounced in individuals with low-to-moderate exposure to cigarette smoke or alcohol consumption. Risk reduction was more significant in women and in patients with cancers of the oral cavity and oropharynx. ^[58] However, larger clinical trials are needed to define the role of aspirin for head and neck cancer chemoprevention.

Targeted Therapy With ONYX-015

Another promising molecular target for head and neck chemoprevention is the TP53 tumor suppressor gene. Approximately 40-50% of HNSCC patients carry an inactivating mutation of TP53. ^[59] Altered TP53 expression is found in up to 45% of dysplastic mucosal lesions of the head and neck. ^[60] ONYX-015 is an attenuated adenovirus designed to selectively replicate in and destroy p53 mutant cells. ^{[61, 62, 63]} The safety and efficacy of topical ONYX-015 application as a chemopreventive agent was studied in patients with oral dysplasia who received a mouthwash formulation held in the mouth for 30 minutes. Histologic resolution of dysplasia was seen in 7 (37%) of the 19 patients. Most responses were transient. ^[64]

The trial also explored the feasibility of topical oral administration of a chemopreventive agent as a mouthwash, the treatment of the entire oral mucosa as a field, and the avoidance of systemic toxicities in a preventive strategy.

Bowman-Birk Inhibitor

Bowman-Birk inhibitor (BBI) is a PI that was identified in soybeans by Bowman in the 1940s and purified by Birk in the early 1960s. Interest in the use of soybean products as cancer-preventive agents emanated from epidemiologic studies that demonstrated low incidence rates of several cancers in populations with a high soy intake. ^{[40, 65, 66]}

Animal studies have shown that BBI can prevent the development of malignancies in several different animal tumor model systems. ^[66] BBI demonstrated clinical activity after oral administration in patients with oral keratosis and atypia. Armstrong et al conducted a 1-month phase IIa clinical trial of BBI concentrate in 32 patients with oral keratosis and atypia; 31% of patients achieved a clinical response, and no detectable side effects were observed. ^[67] The current work on the potential molecular targets for PIs offers encouragement for the clinical application of PIs as chemopreventive agents.

Green Tea Extracts

Green teas contain the following 4 major polyphenols: epicatechin (EC), epigallocatechin (EGC), epicatechin-3-gallate (ECG), and epigallocatechin-3-gallate (EGCG). ^[68] The chemopreventive or antitumor effect of (−)-epigallocatechin-3-gallate (EGCG), the most abundant and most active phenolic constituent of green tea, has been extensively studied in chemically induced rodent carcinogenesis models and in several types of cancer cells in culture. ^[69]

Multiple biologic functions have been attributed primarily to EGCG, and it seems to work as an antioxidant and inhibit cell proliferation, invasiveness, and angiogenesis mediated by signaling transduction pathways involving epidermal growth factor receptor (EGFR), nuclear factor (NF)- B, tumor necrosis factor (TNF)-alpha, AKT, mitogen-activated protein kinase (MAPK), p53, and others. ^{[70, 71, 72]} Prospective cohort data collected over 10 years suggest that consumption of more than 10 cups of green tea a day results in decreased cancer incidence, with a hazard ratio of 0.59. ^[73] Clinical studies evaluating green tea as a single agent or in combination with other natural or synthetic compounds are ongoing at the moment.

Epidermal Growth Factor Receptor and Tyrosine Kinase Inhibitor

Overexpression of epidermal growth factor receptor (EGFR) and its ligands TGF-α or EGF has been observed in 80–90% of SCCHN specimens and correlates with poor disease-free and overall survival and increased risk of disease recurrence and metastasis. One approach to block the EGFR includes targeted agents that inhibit EGFR tyrosine kinase. These TKIs include gefitinib (Iressa) and erlotinib (Tarceva). Erlotinib (Tarceva), an EGFR tyrosine kinase inhibitor (TKI), has shown strong antitumor and chemopreventive efficacies in a variety of cancer types, including SCCHN, through blocking EGFR-related signal transduction pathways. ^[74] Clinical trials evaluating erlotinib as a single agent or in combination with other natural or synthetic compounds are ongoing. ^[75]

Under Investigation

Several promising new compounds are being studied in clinical chemoprevention trials in head and neck cancer:

• EKB-569 - Family of drugs called EGFR inhibitors

• Pioglitazone - Peroxisome proliferator–activated receptor inhibitor

• Ad5CMV - Targets the TP53 gene

• Polyphenols of pomegranate juice

• Curcumin analogs ^[76]

• Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor

A phase IIa trial by Gutkind et al suggested that metformin may be an effective chemopreventive agent against HNSCC. In patients with oral premalignant lesions (OPLs), the investigators found that after 12 weeks of metformin treatment, patients had a 17% partial clinical response rate, with no complete clinical responses. However, there was a 60% histologic response rate, the complete and partial responses being 17% and 43%, respectively. Statistically, the histologic response was significantly greater in current and former smokers than in patients who had never smoked. It was also indicated that metformin encourages modulation of the mTOR (mechanistic target of rapamycin) pathway, with reduced mTOR activity in the basal epithelial layers of the OPLs being correlated with the histologic and clinical responses. Indeed, as the investigators state, the “aberrant activation of the PI3K/mTOR signaling circuitry is one of the most frequently dysregulated signaling events in” HNSCC. ^[77]

See the list below:

• Failure to inform patients about the malignant potential of the disease before and after treatment

• Failure to inform patients of the need for clinical follow-up care

• Failure to counsel to discontinue the use of all forms of tobacco and to limit consumption of alcohol

• Failure to remain alert to signs and symptoms of oral cancer and premalignancy in persons who use tobacco or regularly use alcohol

• Failure to inform patients with early-stage head and neck cancers that a study showed that high doses of vitamin E are associated with a greater risk of renewed carcinogenesis

• Failure to warn patients with cancer that high doses of antioxidants may interfere with their treatment

Landmark trials that have involved 13-cis -retinoic acid (13cRA) demonstrated that chemoprevention of head and neck cancer is possible. However, the largest studies of retinoids as chemopreventive agents were negative and, thus, disappointing. Molecular targeted agents such as cyclooxygenase-2 (COX-2) inhibitors, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), farnesyltransferase inhibitors (FTIs), and protease inhibitors (PIs) are important potential treatments. Future clinical trials should test these new agents and combinations of these agents.

The field of chemoprevention remains an exciting and challenging area of research. Although progress toward chemoprevention of head and neck cancer has been made, this field is still in its earliest stages of development and remains investigational. We are nowhere near the ultimate desired goal of possessing safe and effective preventive agents that can be easily given to the population at high risk for head and neck cancer, as fluoride can be added to drinking water to prevent dental caries. The next generation of chemoprevention trials will involve novel, molecularly targeted agents in patients stratified based on risk factors and clearly defined biomarkers. ^[78] Future directions in the field of chemoprevention will be proposed that are based on recently acquired mechanistic insight into carcinogenesis.

Table. Selected Head and Neck Chemoprevention Trials (Open Table in a new window)