US Pharm. 2006;8:79-84.

Oral cancer is a major public health issue in the United States and other parts of the world. Cancers of the oral cavity accounted for 274,000 cancers worldwide in 2002, with almost two thirds occurring in men.1 Worldwide, oral cancer is the sixth most common cancer in men, and it accounts for 3% of all cancers in the U.S.2 Unfortunately, 60% of oral cancers are in an advanced stage by the time the patient or clinician detects them. Approximately 30,000 new cases are diagnosed yearly in the U.S., with approximately a 50% five-year survival rate. The pharmacist can have a pivotal role in screening for oral cancers and campaigning for awareness of the risk factors and early signs and symptoms. This article contains information to help the pharmacist effectively recognize and control the disease.

Incidence
Forty percent of head and neck cancers occur in the oral cavity. The term oral cancer encompasses a diverse group of tumors arising from the oral cavity (i.e., lip, tongue, floor of the mouth, gums, and soft palate). The most common sites for oral cancer are the tongue and floor of the mouth.

An estimated 30,990 new cases of oral cancer are expected to be diagnosed in the U.S. in 2006, and approximately 7,430 people will die of the disease.3 Between 1975 and 2002, incidence and mortality rates were higher among males than among females and highest for black males.4

Risk Factors
Cigarette Smoking: The primary risk factor for oral cancer is the use of tobacco in all forms. Approximately 75% of oral cavity and pharyngeal cancers are attributed to the use of smoked and smokeless tobacco, and the rate increases with the amount smoked or chewed and the duration of use. There are roughly 44.5 million (21%) adult smokers and 3.75 million (22%) high school student smokers in the U.S. Smokers are six times more likely than nonsmokers to develop oral cancer. Cigarettes are the predominant form of tobacco used; however, other forms of tobacco, including smokeless tobacco, cigars, and pipes, are also used. Those who smoke filtered cigarettes and those who quit smoking are at a substantially lower risk of oral cancer than are users of other forms of tobacco and current smokers.5,6

Cigarette smoke contains about 4,000 chemical agents, including more than 60 carcinogens (e.g., carbon monoxide, tar, arsenic, lead).7 Nicotine is primarily responsible for addiction to smoking.

Pipe smokers have an especially high risk for lip cancer because of the static contact of the pipe stem with the lower lip. Cigar smokers who inhale deeply are six times more likely to develop and die from oral cancer. The same carcinogens found in cigarette smoke are also found in pipe and cigar smoke.

Smokeless Tobacco (Chewing Tobacco): Smokeless tobacco products include chewing tobacco and sucked (moist oral) tobacco. Oral cancer risks are much lower from smokeless tobacco use than from cigarette smoking, and no synergistic effect between smokeless tobacco use and cigarette smoking among males has been found.8,9 The buccal (cheek) mucosa, gums, and inner soft tissue surface of the lips are common sites of cancer in those who use smokeless tobacco. Most types of smokeless tobacco contain tobacco-specific nitrosamines, which are the culprits for oral cancer.

In addition to tobacco use, the use of chewing products such as betel nuts, paan, chaalia, gutka (a mixture of betel nuts and chewing tobacco), naswar, and areca increases the risk for oral cancer. These products are socially acceptable in Southeast Asia, the South Pacific Islands, and India. Although chewers of betel nuts generally spit out the juices, they swallow some juice, which enters the bloodstream. Arecoline, an alkaloid found in betel nuts, remains in the organs.10  Chewers of betel nuts who also smoke and drink are 195 times more likely to develop cancer of the esophagus than are those who do not.

Marijuana: Marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer.11 The carcinogenic properties of marijuana smoke are similar to those of tobacco.

Alcohol Abuse: All forms of alcohol have been linked to oropharyngeal cancer. Compared to heavy tobacco use, heavy alcohol consumption is less of an independent risk factor but is an increased synergistic risk factor when combined with heavy tobacco use. There are many different criteria for heavy drinking, but the consensus definition is more than four drinks per day.12,13 Alcohol use may be a stronger risk factor for cancer of the oral cavity than for cancer of the larynx and pharynx. Alcohol is a weaker risk factor for laryngeal cancer than is cigarette smoking; however, cancer of the oral cavity has an increased incidence among those who smoke and abuse alcohol.14 The incidence of oral cancer may remain high several years after alcohol cessation.15

The exact mechanism of action of alcohol's carcinogenicity has not been determined; however, it may be related to the carcinogenic effect of acetaldehyde, the first metabolite of ethanol.16,17 Another study suggested that p15-gene methylation can be induced by chronic smoking and drinking and may have a role in the early stages of head and neck cancer.18

Age: The majority of oral cancers are seen in patients older than 40, with an average age of diagnosis of about 63 years. More than 90% of oral cancers occur in patients older than 45, and the incidence steadily increases until age 65, when the rates stabilize.

Gender: Men have twice the risk of oral cancer as women, and men older than 50 are at the greatest risk. The yearly incidence of oral cancer is much greater for males (15.7 per 100,000) than for females (6.0 per 100,000).19 In females, the incidence is relatively high in southern Asia (8.3 per 100,000).1

Mouth Rinses: Ethyl alcohol is added to mouth rinses as a solvent for other ingredients and as a preservative. In 1985, Mashberg et al. found that cancer was not statistically associated with mouthwash use in alcohol or tobacco users.20 Currently, there is insufficient clinical evidence to suggest a relationship between ethyl alcohol found in mouth rinses and oral cancer.21

Ultraviolet Light: Excessive exposure to solar radiation (sunlight) is associated with an increased incidence of lip cancer. Specifically, ultraviolet B radiation causes sunburns and is the form of UV radiation responsible for lip and skin cancer. 

Irritation: Although it has been suggested that chronic irritation to the lining of the mouth from poorly fitting or defective complete dentures may be a risk factor for oral cancer, the majority of studies have shown no correlation.22

Human Papillomavirus Infection: Infection with human papillomavirus (HPV) has been associated with increased incidence of oral squamous cell carcinoma. Viruses cause proto-oncogenes to become oncogenic, which can cause altered expression of their products and lead to cancer.10

The genotypes of HPV most commonly found in oral carcinoma are HPV 16 and 18; however, HPV can be detected in normal oral tissue. Thus, linking viruses to oral cancer is still in question, and more research is needed before a definitive association can be established.

Poor Nutrition: There may be an association between the consumption of fruit and vegetables and a reduced risk of oral cancer, but it is still controversial.23

Screening for Oral Cancer
Screening for oral cancer involves examining people for early stages of cancer, even though no symptoms are present. Routine screening for oral cancer is controversial. In 2004, the U.S. Preventive Services Task Force (USPSTF) concluded that screening for oral cancer does not lead to improved health outcomes for either high-risk adults (e.g., those older than 50 years who use tobacco) or for average-risk adults in the general population.24 They also found that there is no evidence that screening is harmful. As a result, the USPSTF could not determine whether the benefits outweigh the harms of oral cancer screening.

However, the American Cancer Society and the National Cancer Institute strongly emphasize that the routine examination of asymptomatic and symptomatic patients can lead to detection of earlier-stage cancers and premalignant lesions.25,26 They also state that there is no definitive evidence that screening reduces mortality.

Direct inspection using a dental mirror, tongue depressor, and gauze is the most commonly recommended method of screening for oral cancer; however, the sensitivity and specificity of this method is empirically based. An individual can also perform a self-examination. See TABLE 1 for directions for performing a self-examination.

Clinical Considerations: Signs and Symptoms
Early signs of oral cancer are typically painless and difficult to detect without a thorough head and neck examination by a dentist or physician. See TABLE 2 for common signs and symptoms of oral cancer.

Clinically, oral cancer appears as white (leukoplakia) or red (erythroplakia) lesions. Leukoplakia is the most common precancerous lesion of the oral cavity. Eryth­ roplakia is less common than leukoplakia; however, it is more frequently associated with a high risk for oral cancer. If either type of lesion is detected, its cause should be determined and the patient should be treated or monitored.

The Pharmacist's Role in Oral Cancer
Unlike dentists and physicians, pharmacists have not been routinely included in the oral cancer screening process. Although the pharmacist cannot actually participate in oral cancer screening, he or she is in an ideal position to increase awareness and knowledge of the risk factors for and early warning signs of oral cancer as well as strategies to reduce the risk, including tobacco cessation (TABLE 3). The pharmacist should encourage his or her patients not to use tobacco and to limit alcohol use in order to decrease their risk for oral cancer. Pharmacists should ask patients who smoke if they are interested in smoking cessation. Pharmacists can develop smoking cessation programs, using numerous organizations and their Web sites for assistance (TABLE 4).

Many people discuss mouth problems with their pharmacist. They may request a product for the treatment of ulcers, sores, and/or pain in the mouth. While the majority of these complaints resolve in a few weeks, problems that persist could be early warning signs of cancer, and patients who have them should be referred to a dentist.

The pharmacist can create posters, newsletters, pamphlets, and fact sheets for patients. When the pharmacist provides medication counseling to patients who use tobacco or drink alcohol, he or she can also discuss the incidence, risk factors, and signs and symptoms of oral cancer. Patients who use tobacco products should conduct a self-examination at least once a month, as well as visit their dentist. The frequency of visits is based on individual needs; however, every six months to a year typically is adequate. More frequent visits are necessary for people who smoke and use alcohol.27

Summary
Tobacco use and consumption of alcohol are both independent risk factors for oral cancer, in addition to synergistically increasing oral cancer risk. Pharmacists should be alert to the possibility of oral cancer in people who use tobacco or alcohol or both.

Pharmacists can increase the awareness of oral cancer and knowledge of its major risk factors and clinical signs. They can also be involved in smoking cessation programs and encourage patients to limit alcohol intake. It has been documented that avoidance of tobacco smoking and alcohol consumption (or the reduction of alcohol consumption) is the most desirable way to prevent primary oral cancer as well as secondary cancers of the aerodigestive system.28

The pharmacist should be an integral part of the oral cancer patient education team. He or she should also participate in screening and educational programs to increase the awareness and knowledge of oral cancer.

REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
2. Day TA, Davis BK, Gillespie MB, et al. Oral cancer treatment. Curr Treat Options Oncol. 2003;4:27-41.
3. American Cancer Society. Cancer Facts and Figures 2006. Atlanta, Ga.: American Cancer Society; 2006.
4. Morse DE, Kerr AR. Disparities in oral and pharyngeal cancer incidence, mortality and survival among black and white Americans. J Am Dent Assoc. 2006;137:203-212.
5. Kabat GC, Chang CJ, Wynder EL. The role of tobacco, alcohol use, and body mass index in oral and pharyngeal cancer. Int J Epidemiol. 1994;23:1137-1144.
6. Znaor A, Brennan P, Gajalakshmi V, et al. Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer. 2003;105:681-686.
7. CDC. Tobacco Use in the United States. Available at: www.cdc.gov/tobacco/overview/tobus_us.htm.
8. Accortt NA, Waterbor JW, Beall C, Howard C. Cancer incidence among a cohort of smokeless tobacco users (United States). Cancer Causes Control. 2005;16:1107-1115.
9. Accortt NA, Waterbor JW, Beall C, et al. Need to educate primary caregivers about the risk factor profile of smokeless tobacco users. J Cancer Educ. 2005;20:222-228.
10. Chen PC, Pan CC, Kuo C, Lin CP. Risk of oral nonmalignant lesions associated with human papillomavirus infection, betal quid chewing, and cigarette smoking in Taiwan: an integrated molecular and epidemiologic study. Arch Pathol Lab Med. 2006;130:57-61.
11. Zhang ZF, Morgenstern H, Spitz MR, et al. Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev. 1999;8:1071-1078.
12. Brouha X, Tromp D, Hordijk GJ, et al. Role of alcohol and smoking in diagnostic delay of head and neck cancer patients. Acta Otolaryngol. 2005;125:552-556.
13. Talamini R, Bosetti C, La Vecchia C, et al. Combined effect of tobacco and alcohol on laryngeal cancer risk: a case-control study. Cancer Causes Control. 2002;13:957-964.
14. Choi SY, Kahyo H. Effect of cigarette smoking and alcohol consumption in the aetiology of cancer of the oral cavity, pharynx and larynx. Int J Epidemiol. 1991;20:878-885.
15. Franceschi S, Levi F, Dal Maso L, et al. Cessation of alcohol drinking and risk of cancer of the oral cavity and pharynx. Int J Cancer. 2000;85:787-790.
16. Harris EL. Association of oral cancers with alcohol consumption: exploring mechanisms [editorial]. J Natl Cancer Inst. 1997;89:1656-1657.
17. Harty LC, Caporaso NE, Hayes RB, et al. Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. J Natl Cancer Inst. 1997;89:1698-1705.
18. Chang HW, Ling GS, Wei WI, Yuen AP. Smoking and drinking can induce p15 methylation in the upper aerodigestive tract of healthy individuals and patients with head and neck squamous cell carcinoma. Cancer. 2004;101:125-132.
19. Gloeckler Ries LA, Miller BA, Hankey BF, et al., eds. SEER cancer statistics review, 1973-1991. Bethesda, Md: US Department of Health and Human Services, Public Health Service, National Cancer Institute; 1994. Report No. NIH-94-2789.
20. Mashberg A, Barsa P, Grossman ML. A study of the relationship between mouthwash use and oral and pharyngeal cancer. J Am Dent Assoc. 1985;7:200-208.
21. Carretero Pelaez MA, Esparza Gomez GC, Figuero Ruiz E, Cerero Lapiedra R. Alcohol-containing mouthwashes and oral cancer: critical analysis of literature. Med Oral. 2004;9:116-123.
22. Rosenquist K, Wennerberg J, Schildt EB, et al. Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol. 2005;125:1327-1336.
23. Pavia M, Pileggi C, Nobile G, Angelillo IF. Association between fruit and vegetable consumption and oral cancer: a meta-analysis of observations studies. Am J Clinical Nutrition. 2006;83:1126-1134.
24. Screening for oral cancer: a brief evidence update for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality. 2004. Available at: www.preventiveservices.ahrq.gov.
25. National Cancer Institute. Oral Cancer (PDQ) Screening. Available at: www.cancer.gov/cancertopics/pdq/screening/oral/patient.
26. National Cancer Institute. Oral cancers: research report. U.S. Department of Health and Human Service. Public Health Service, National Institutes of Health 1991; NIH publication 92-2876.
27. Kaugars GE, Abbey LM, Page DG, et al. Prevention and detection of lip cancer--the dentist's role. J Calif Dent Assoc. 1999;27:318-323.
28. Day GL, Blot WJ, Shore RE, et al. Second cancers following oral and pharyngeal cancers: role of tobacco and alcohol. J Natl Cancer Inst. 1994;86:131-137.

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