Medical Clinics of North America
Volume 83 • Number 1 • January 1999
Copyright (c) 1999 W. B. Saunders Company 



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OTOLARYGOLOGY FOR THE INTERNIST

CURRENT OPTIONS IN MANAGEMENT OF HEAD AND NECK CANCER PATIENTS
Alex J. Correa MD 
Brian B. Burkey MD 

Department of Otolaryngology, Vanderbilt-Bill Wilkerson Center for Otolaryngology and Communication Sciences, Vanderbilt University Medical Center, Nashville, Tennessee

Address reprint requests to
Brian B. Burkey, MD
Vanderbilt University Medical Center
Department of Otolaryngology
S-2100 Medical Center North
Nashville, TN 37232-2559

Head and neck cancer represents a great number of clinical entities because tumors can arise from essentially any tissue type in this region. Skin, muscle, bone, lymphoid, adipose, and specialized tissue, such as olfactory mucosa, are all represented. To focus discussion, this article concentrates on cancers of the upper aerodigestive tract, particularly oral cavity and laryngeal tumors.



INCIDENCE AND DEMOGRAPHICS
The incidence of newly diagnosed head and neck cancers in the United States, excluding skin cancers, was estimated to reach 70,000 cases annually in 1997. As a group, this represents 5% of all cancers diagnosed yearly in North America. Squamous cell carcinoma (SCC) is the predominant type, accounting for more than 90% of cases. [6] Greater than 30,000 of these involve the oral cavity and oropharynx, representing 30% of head and neck cancers, and more than 10,000 new cases of laryngeal cancer are estimated to be found. These disease entities are predicted to kill 8440 and 4230 individuals. [1] Incidence rates are greater than 2:1 male-to-female for oral cavity cancers and are greatest in men over 40 years of age. The discrepancy in male-to-female ratio is even more pronounced in laryngeal tumors, in which carcinoma is between four and five times more common in men. For laryngeal cancer, this ratio has declined in the last 20 years and is thought to reflect the increased number of women using tobacco products during this period. Laryngeal cancer is generally a disease of the elderly, with a peak incidence in the 50s and 60s. [3] 



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RISK FACTORS
There is a strong association between cancers of the upper aerodigestive tract and tobacco use of any kind. Epidemiologic studies have shown that the risk of malignancy is six times greater for smokers than nonsmokers. [32] A linear relationship between the number of cigarettes smoked and the risk of developing laryngeal cancer has been shown. [38] There has been an increased incidence of oral cancers among young men. This increase is presumed to result from the rise in popularity of smokeless tobacco (snuff). In the southern United States, there is an increased incidence of oral cancers among older women because of the higher prevalence of this habit. A study done in North Carolina confirmed this association by showing an increase of oral cancers in a group of women snuff users who did not smoke. [29] Of interest, 75% of these tumors involve only 10% of the mucosal surface area of the mouth. This involvement is primarily in the region of the gingivobuccal sulcus or groove and extends posteriorly toward the retromolar trigone area and involves the lateral tongue. It is believed that pooling of carcinogen-containing secretions contributes to this.
In certain parts of India as well as other countries, the practice of mixing cured tobacco with betel nuts has proven to be a highly irritating mixture to oral mucosa and associated with cancers. More than 200 million persons are thought to engage in this practice worldwide. A resultant 2.8 times higher relative risk of cancer exists for these individuals, and this increases to more than 10 times when smoking is also practiced. [24] 
Alcohol use is also a major risk factor for cancers of the upper aerodigestive tract. In studies controlled for smoking, a direct relationship has been found between high alcohol intake and an increased risk of oral cancers. In American men, the synergistic effect of alcohol and smoking increases the risk of disease 2.5 times over the simple additive risk of the two alone. [5] The synergistic role of alcohol abuse in laryngeal cancer has been clearly established, [16] [20] but it is unclear if it has the same carcinogenic effect when acting alone. [42] [48] 
Certain environmental exposures have been implicated as risk factors. Controlling for smoking and alcohol use, paint fumes, plastic byproducts, wood dust, asbestos, and gasoline fumes have all been noted to increase the cases of laryngeal cancer when there is chronic exposure. [8] [10] [34] [41] [47] Gastroesophageal reflux disease is now thought to be a significant risk factor for cancer of the larynx and especially the anterior two thirds of the vocal cords. [27] [33] [35] [45] 
Human papillomavirus infection is another factor implicated in the carcinogenesis of upper aerodigestive tract tumors. Human papillomavirus has been detected in oral mucosa having varying degrees of premalignant characteristics, such as dysplasia or leukoplakia. In one study, human papillomavirus-16, in particular, was isolated from 36% of oral cavity cancers. [25] 


HISTOPATHOLOGY
Excluding cancers of the skin, SCC statistically dominates in the head and neck region. Ninety-five percent of malignancies in the oral cavity are of this type, and these exhibit varying degrees of differentiation. The oral cavity is defined as the area extending from the vermilion border of the lips to a plane between the junction of the hard and soft palate superiorly and the circumvallate papillae of the tongue inferiorly. Within this region is the buccal mucosa, upper and lower alveolar ridges, floor of mouth, retromolar trigone, hard palate, and 

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anterior two thirds of the tongue. The lips are the most common site of malignancy in the oral cavity and account for 12% of all head and neck cancers, excluding nonmelanoma skin cancers. [49] SCC is the most common histologic type, and 88% to 98% of these involve the lower lip. This predilection to the lower lip has been attributed to sun exposure. [49] 
Verrucous carcinoma is a variant of SCC that can sometimes be found in the oral cavity. It has features that distinguish it from SCC both in appearance and in its behavior. It is usually a broad-based, whitish, cauliflower-like tumor that histologically shows marked keratinization. These tumors are relatively rare, representing less than 5% of all oral cavity cancers. [15] It has been associated with HPV infections, smokeless tobacco, and irritation from poorly fitting dentures. [13] 
Minor salivary gland tumors can also arise from the region of the oral cavity and comprise a small percentage of malignancies. These include adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and acinic cell carcinoma. Melanomas, lymphomas, and malignancies arising from bone are even less common.
In laryngeal carcinomas, the overwhelming predominance is also for SCC. These comprise more than 95% of primary laryngeal lesions and often are found in areas of mucosa with varying degrees of dysplasia or carcinoma in situ. They characteristically have clusters of atypical cells sending out tongues of malignancy that invade the surrounding stroma. Verrucous SCC can also be found in the larynx and comprises 1% to 4% of tumors. [17] Rarer lesions, such as spindle cell SCC, basaloid variant SCC, adenocarcinoma, adenoid cystic carcinoma, chondrosarcomas, and neuroendocrine tumors, contribute only about 1% of total cases. [7] 


SIGNS AND SYMPTOMS
Patients who present with oral cavity tumors often verbalize complaints of nonhealing ulcers in their mouth, loosening of teeth, dentures that no longer fit correctly, trismus, or weight loss. Additionally, dysphagia, odynophagia, bleeding, and referred otalgia may be present. It is important for the clinician to maintain a high index of suspicion, especially if cofactors such as tobacco use or alcohol abuse are present. Up to 30% of oral cavity cancer presentations have evidence of a cervical metastasis, either palpable or occult, at initial evaluation. [40] This percentage excludes patients with hard palate and lip cancers. These subsites have lower incidences of nodal metastases ranging from 10% to 25%. [11] In contrast, the oral tongue has a rich blood supply and lymphatic drainage, which accounts for the fact that up to 66% of patients with primary tongue lesions have neck disease at presentation. [21] Rarely the first signs of oral cavity tumors are distant metastases. When present, these metastases are often to lung, bone, or liver.
Presenting symptoms for laryngeal cancer depend on the sites involved. Glottic cancers often present with hoarseness as an early complaint because the true vocal cords are involved. Later symptoms include dysphagia, odynophagia, globus sensation, referred otalgia, chronic cough, hemoptysis, or stridor. Lesions of the supraglottis tend to be discovered in the later stages and present more frequently with palpable neck masses than do glottic tumors. Earliest symptoms include dysphagia, odynophagia, hemoptysis, and referred otalgia. Hoarseness and stridor are usually later findings. Primary subglottic tumors are rare and present with dyspnea on exertion or stridor.



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DIAGNOSTIC PROCEDURES

Examination
First and foremost in the diagnosis of head and neck cancers is the need for a thorough physical examination, including visualization of the nasopharynx and larynx. Bimanual examination of the floor of the mouth is important to evaluate the extent of oral cavity tumors and their involvement of adjacent structures. The cranial nerve examination also provides information regarding depth of invasion. Flexible fiberoptic endoscopes have become extremely valuable in assessing patients for upper aerodigestive tract tumors. They allow full visualization of the nasal vault, nasopharynx, base of tongue, hypopharynx, and larynx along with limited access to the pyriform sinuses. They also can more accurately identify and characterize vocal cord mobility.

Imaging
Imaging studies are mainly useful in assessment of primary lesions. Generally, contrast-enhanced computed tomography (CT) scans are helpful in determining the extent of tumor infiltration into the deep tongue musculature and the involvement of the mandible by tumor. Detection of grossly positive nodal disease, particularly when central necrosis is present, is enhanced with contrast-enhanced CT scans. The accuracy in detecting nodal metastases is reportedly improved from 70% to 93% when physical examination is combined with CT, but occult disease can still be missed. [43] For this reason, selective nodal neck dissection or primary irradiation to the involved neck is often still performed for cancers with high incidences of occult cervical lymph node metastases, even in the face of negative CT scans. CT in the evaluation of laryngeal cancer functions primarily as an adjunct to the physical examination in the staging of tumors. It is particularly useful in upstaging cancers that have deeper invasion or invasion of adjacent structures that is difficult to evaluate on physical examination. In particular, information regarding preepiglottic space invasion, laryngeal cartilage invasion, paraglottic space spread, tongue base invasion, postcricoid extension, and subglottic extension can be gathered. CT for evaluation of neck disease in this setting can add information about the status of the carotid artery in relation to a nodal mass and possibly in gross extracapsular spread of tumor. The former can assist in preoperative planning if carotid sacrifice may be necessary.
Magnetic resonance imaging is becoming more popular in the assessment of head and neck tumors because of its improved definition of soft tissue in the region. The authors primarily employ it in assessing and differentiating tumors of the parapharyngeal space and in tumors arising from the parotid gland. It also is superior in definition of skull base tumors as well as in evaluating perineural invasion.

Fine Needle Aspiration
Fine-needle aspiration for cytologic evaluation of discrete neck masses has revolutionized the management of patients with this presentation. It has reduced the frequency and the potential morbidity that is associated with open neck biopsies of lymph node metastases from unknown primaries. Fine-needle aspiration 

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is now the standard of care for initial tissue diagnosis in this setting and has an accuracy of greater than 95% for SCC of the upper aerodigestive tract. The diagnosis of SCC on fine-needle aspiration with an unknown primary site dictates that the evaluation continues in search of a head and neck or lung lesion. If the diagnosis is of lymphoma, the route of open biopsy for definitive tissue diagnosis may be indicated. 

Operative Endoscopy
Direct laryngoscopy and rigid cervical esophagoscopy are essential in the evaluation of head and neck cancers. Even clinically evident tumors, such as those that appear limited to the oral cavity, require complete evaluation of the mucosal surfaces in the upper aerodigestive tract. Direct visualization allows accurate assessment of size, location, and full extent of mucosal involvement. Digital palpation of the vallecula and tongue base can aid in diagnosing submucosal spread of tumors. Biopsies can confirm the diagnosis, and comparative histology can be performed of previous fine-needle aspiration results if available. The subglottis, esophagus, and tracheobronchial tree are routinely evaluated to rule out synchronous primaries, which can approach a 20% incidence.


CLINICAL STAGING
The TNM staging system used for oral cavity cancers is a clinical staging system that allows physicians to compare results across patients, discuss prognosis, and design appropriate treatment regimens. [2] T refers to tumor size at the primary site, N refers to the status of the cervical chain of lymph nodes, and M refers to presence or absence of distant metastases (Table 1) (Table Not Available) . The same system is employed for laryngeal tumors (Table 2) (Table Not Available) . The basic premise of these systems is that smaller cancers with no nodal disease have a better prognosis than a larger lesion with positive neck nodes. It suggests a stepwise progression of disease from the primary site to regional nodes then on to distant sites. This system has inherent problems in that the true extent of head and neck tumors is often difficult to determine clinically before the time of operation. An example is in the floor of mouth, where a seemingly early T2 may actually invade deep tongue musculature and ultimately be a T4.


MANAGEMENT

Surgery
Surgery remains the gold standard and the basis for much of the current therapy in SCC of the head and neck. Treatment is designed to encompass both the primary lesion and the involved neck. This is particularly the case in advanced cancers such as stage III and IV.
In the oral cavity, a wide range of treatment options exists between limited resection of lip lesions to composite resections involving tongue, floor of mouth, and mandible. Reconstruction options include primary closure, skin grafts, and local and regional flaps as well as free tissue transfer. [9] Microvascular free tissue transfer has gained increasing popularity over the last 10 years for reconstruction secondary to the improved swallowing and rehabilitation results seen with 

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TABLE 1 -- TNM STAGING OF ORAL CAVITY CANCER 
Modified from American Joint Committee for Cancer Staging and End-Results Reporting. Chicago, American Joint Committee on Cancer, 1988; with permission. The original source for this material is the AJCC Manual for Staging of Cancer, ed 3, 1988, published by Lippincott-Raven Publishers, Philadelphia.
 (Not Available)

innervated or sensate flaps. [44] They provide sensory feedback for improvement in the oral phase of swallowing. These flaps are also generally thinner than many of the regional flaps previously employed and allow improved oral mechanics when compared to bulkier flaps. The variety of flaps now employed give the reconstructive surgeon a number of options for recreating the functional characteristics of dynamic tissue such as the tongue and pharynx. 
Surgery in laryngeal cancer is dictated by the stage and subsites of tumor involvement. Early glottic lesions may be curatively treated through endoscopic resection, whereas more advanced cancers may still require a total laryngectomy. [14] A variety of conservation or partial laryngeal resections are now being employed whenever possible, including vertical hemilaryngectomy, supraglottic laryngectomy, supracricoid laryngectomy, and near-total laryngectomy. Evaluation by the involved head and neck surgeon helps determine the eligibility of patients for conservation laryngeal surgery.

Radiation Therapy
Radiation therapy can be used as adjuvant treatment preoperatively or postoperatively and as primary therapy in some cases. Currently the majority 

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TABLE 2 -- TNM STAGING OF LARYNGEAL CANCER 
Modified from American Joint Committee on Cancer: Manual for Staging of Cancer. Philadelphia, JB Lippincott, ed 4, 1992; with permission of the AJCC, Chicago.
 (Not Available)

of adjuvant therapy is administered in the postoperative period after resection of advanced tumors. It is particularly indicated in cases of clinically positive cervical nodal disease with extracapsular spread of tumor. It is also used with high-risk primary tumors, such as those that involve the base of tongue, those with surgically close tumor margins, those with evidence of perineural spread on pathologic examination, and those with high incidences of occult nodal metastases in unoperated necks. Primary radiation therapy is indicated in early laryngeal cancers such as stage I or II disease, early tonsil or base of tongue lesions, early pharyngeal cancers (T1 or T2) and essentially all nasopharyngeal cancers. 


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Chemotherapy
The use of chemotherapy in SCC of the head and neck is being extensively studied to determine its ultimate role. Chemotherapy as neoadjuvant treatment is currently the subject of a number of clinical trials. Much interest has been generated by reports such as that of the Department of Veterans Affairs Laryngeal Study Group, in which laryngeal organ preservation was evaluated. [46] Three cycles of induction chemotherapy with cisplatin and 5-fluorouracil were followed by radiation therapy. Salvage surgery was then reserved for those patients with residual disease. The control arm received standard surgery followed by radiation therapy. Indications included stage III and IV disease without evidence of pharyngeal mucosa or laryngeal cartilage involvement. The contraindications included obstructing airway lesions, patients unreliable for follow-up, previous irradiation to the head and neck region, and patients with kidney disease and resulting decreased creatinine clearance. Thirty-six percent of patients in the experimental arm had an incomplete response to the three cycles of chemotherapy and had to proceed to surgical salvage. Overall, two thirds of the patients were able to preserve their larynges and showed a decrease in the rate of distant metastases. There was no survival advantage noted at 5 years posttreatment. Three other similar trials have also failed to show improvement in survival with neoadjuvant therapy. [19] [28] [39] The third arm of these trials, radiation only, is being evaluated to make comparisons to the previous two.
Adjuvant or concomitant chemotherapy and radiation therapy is another area of investigation gaining popularity. [18] The goals of chemotherapy in this setting are to enhance the effect of radiation, to improve locoregional control, and to eradicate early micrometastatic disease. The key component involves the enhancement or sensitization of tumor cells by chemotherapy for subsequent radiation. Some studies have shown promising improvements in locoregional recurrence rates. [4] To date, chemoradiation has not been recommended outside of the clinical trial setting for the intent of prolonging survival, although its use for organ preservation (laryngeal) has been popular in the community.
Intra-arterial adjuvant chemotherapy is a modality that has gained support in some centers and has shown some increases in tumor response rates in early studies. [37] Postoperative adjuvant chemotherapy is another area that is debated. There is interest in studying its efficacy in patients at high risk for distant metastases. Although not proven to date, some studies suggest a possible benefit in increased survival (J Johnson, personal communication). Chemotherapy is also used as palliative treatment in end-stage disease when the goal is improving quality of life in these final stages. Methotrexate and paclitaxel (Taxol) have been used for this indication.


NEW ADVANCES

Gene Therapy
Gene therapy is an area that shows much promise and is the subject of many ongoing trials in advanced head and neck cancer patients. This therapy involves the introduction of novel genes into patient somatic cells to produce proteins that have a therapeutic effect. Liu et al [31] demonstrated that growth suppression of head and neck tumor cell lines could be accomplished by a gene insertion technique. An attenuated adenovirus vector was used to introduce wild-type p53 gene into cancer cells and cause apoptosis (programmed cell 

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death). The emergence of the polymerase chain reaction as a tool in genetic sequencing has accelerated the identification of other tumor oncogenes and suppressor genes. Retroviruses and herpes simplex virus vectors are also being evaluated. Currently, there is an ongoing trial in humans that uses a replication-deficient adenovirus for transmission of wild-type p53 gene for subsequent overexpression of this gene product. [12] Patients must have evidence of advanced local or regional cancer that is unresectable or for which no resection with adequate margins is possible. 

Interferon Therapy
Interferon is now used postoperatively in advanced cutaneous melanoma cases as an adjunct to standard surgical therapy. Results of the multicenter randomized Eastern Cooperative Oncology Group (ECOG) trial released in 1996 documented that interferon alfa-2b prolongs the relapse-free interval and the overall survival in patients with high-risk melanomas that have been resected. [26] High risk was defined by tumor thickness 4 mm or greater or clinically positive nodal disease. An increase in median disease-free survival from 1.0 to 1.7 years was noted along with increases in overall survival from 2.8 to 3.8 years. This is the first interferon agent currently in use to show significant changes in these outcome measures.

Chemoprevention
The idea of chemoprevention with agents such as 13- cis retinoic acid has gained attention as an adjunctive approach potentially to reverse carcinogenesis or prevent the development of invasive cancers. In head and neck cancer trials, retinoids have been shown to cause regression of premalignant lesions such as oral leukoplakia. [22] [30] High doses were required, and the responses proved to be temporary. Hong et al [23] observed that there was a significant protective effect against development of a second upper aerodigestive tract primary cancer in patients who took cis-retinoic acid. Low doses of the drug were needed, and it was generally well tolerated. This protective effect was lost when the treatment was discontinued. The results to date are promising, but the ultimate role of retinoids has yet to be established. Further studies are in progress with retinoids alone and in combination with other chemotherapeutic agents.

Photodynamic Therapy
Photodynamic therapy is the selective destruction of tumor cells by administering a photosensitizing agent systemically then using an argon dye-pumped laser to lyse those cells with selective uptake. Despite early encouraging results, predictable tumor ablation has yet to be achieved. [36] Problems with uptake of photosensitizer by tumor cells and the ability to deliver laser energy to the entire tumor have plagued efforts thus far. Currently, this technology remains experimental, but it is possible that this modality may play an increasing role in palliation of advanced cancers, in the treatment of early superficial cancers, and in diffuse disease of the upper aerodigestive tract.



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CONCLUSION
This article outlines the current management for patients with SCC of the upper aerodigestive tract. These patients require proper diagnosis, based on a high level of suspicion and examination, with subsequent staging and development of a treatment paradigm. This treatment program of surgery, radiation, or chemotherapy is best developed by a devoted head and neck oncologic team involving surgeons, radiation and medical oncologists, and rehabilitative specialists with significant experience in the care of head and neck oncologic patients. In this way, new protocols and surgical options can be appropriately offered to patients with advanced cancers.
Despite these new advancements in the treatment of patients with advanced stage SCC of the head and neck, little progress has been made in overall survival. Chemotherapy combined with radiation therapy as neoadjuvant therapy may allow patients to keep their larynges, but they often succumb to disease nonetheless. Also, several new avenues of investigation that are currently being explored have been outlined, one of which may ultimately provide the answer for this devastating disease.

References

1. American Cancer Society: Cancer Facts and Figures--1997. Washington, DC, American Cancer Society, 1997 

2. American Joint Committee for Cancer Staging and End-Results Reporting. Chicago, American Joint Committee on Cancer, 1988 

3. Austen DF: Larynx. In Schottenfeld D, Fraumani JF (eds): Cancer Epidemiology and Prevention. Philadelphia, WB Saunders, 1982 

4. Bachaud JM, David JM, Boussin G, et al: Combined postoperative radiotherapy and weekly cisplatin infusion for locally advanced squamous cell carcinoma of the head and neck: Preliminary report of randomized trial. Int J Radiat Oncol Biol Phys 20:243-246, 1991 

5. Baden E: Prevention of cancer in the oral cavity and pharynx. CA Cancer J Clin 37:49, 1987 

6. Batsakis JG: Tumors of the Head and Neck: Clinical and Pathological Considerations, ed 2. Baltimore, Williams & Wilkins, 1979, pp 200-225 

7. Batsakis JG, Luna MA, El-Naggar AK: Nonsquamous carcinomas of the larynx. Ann Otol Rhinol Laryngol 101:1024, 1992 

8. Brown LM, Mason TJ, Pickle LW, et al: Occupational risk factors for laryngeal cancer on the Texas Gulf Coast. Cancer Res 48:1960, 1988 

9. Burkey BB, Coleman JR: Current concepts in oromandibular reconstruction. Otolaryngol Clin North Am 30:621-629, 1997 

10. Chan CK, Gee JB: Asbestos exposure and laryngeal cancer: An analysis of the epidemiologic evidence. J Occup Med 30:23, 1988 

11. Chung CK, Johns ME, Cantrell RW, et al: Radiotherapy in the management of primary malignancies of the hard palate. Laryngoscope 90:576-584, 1980 

12. Clayman GL, El-Naggar AK, Roth JA, et al: In vivo molecular therapy with p53 adenovirus for microscopic residual head and neck squamous carcinoma. Cancer Res 55:1-6, 1995 

13. Colman MF, Krugman ME, Wescott WB, et al: White, exophytic lesions of the left lateral surface of the tongue. J Am Dent Assoc 111:78-80, 1985 

14. Davis RK: Endoscopic surgical management of early glottic laryngeal cancer. Otolaryngol Clin North Am 30:79-84, 1997 

15. Elliott GV, MacDougal JA, Elliott JD: Problems of verrucous squamous carcinoma. Ann Surg 177:21-29, 1973 

245


16. Falk RT, Pickle LW, Brown LM, et al: Effect of smoking and alcohol consumption on laryngeal cancer risk in coastal Texas. Cancer Res 49:4024, 1989 

17. Ferlito A: Diagnosis and treatment of verrucous squamous cell carcinoma of the larynx: A critical review. Ann Otol Rhinol Laryngol 94:575, 1985 

18. Gupta NK, Pointon RC, Wilkinson PM: A randomized clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer. Clin Radiol 38:575-581, 1987 

19. Head and Neck Contracts Program: Adjuvant chemotherapy for advanced squamous cell carcinoma: Final report. Cancer 60:301-311, 1987 

20. Hedberg K, Vaughn TL, White E, et al: Alcoholism and cancer of the larynx: A case-control study in western Washington. Cancer Causes Control 5:3, 1994 

21. Ho CM, Lam KH, Wei WI, et al: Occult lymph node metastasis in small oral tongue cancers. Head Neck 14:359-363, 1992 

22. Hong WK, Endicott J, Itri LM, et al: 13-cis Retinoic acid treatment of oral leukoplakia. N Engl J Med 315:1501-1505, 1986 

23. Hong WK, Lippman SM, Itri LM, et al: Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck. N Engl J Med 323:795-801, 1990 

24. Jusawalla DJ, Despandi VA: Evaluation of cancer risk in tobacco chewers and smokers: An epidemiologic assessment. Cancer 28:244-252, 1971 

25. Kirchner JA: Vocal Fold Histopathology. San Diego, College Hill Press, 1986 

26. Kirkwood JM, Strawderman MH, Ernstaff MS, et al: Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: The Eastern Cooperative Oncology Group trial est 1684. J Clin Oncol 14:7-12, 1996 

27. Koufman JA: The otolaryngologic manifestation of gastroesophageal reflux disease (GERD): A clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Laryngoscope 101(suppl 53):1-78, 1991 

28. Laramore GE, Scott CB, Al-Sarraf M, et al: Adjuvant chemotherapy for resectable squamous cell carcinomas of the head and neck: Report on Intergroup Study. Int J Radiat Oncol Biol Phys 23:705-713, 1992 

29. Lindberg R: Distribution of cervical lymph node metastasis from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 29:1446-1449, 1972 

30. Lippman SM, Benner SE, Hong WK: Cancer chemoprevention. J Clin Oncol 412:851-873, 1994 

31. Liu TJ, Hang WW, Taylor DL, et al: Growth suppression of human head and neck cancer cells by the introduction of wild-type p53 gene via a recombinant adenovirus. Cancer Res 54:3662-3667, 1994 

32. Mashberg A, Bofetta P, Winkelman R, et al: Tobacco smoking, alcohol drinking, and cancer of the oral cavity and oropharynx among U.S. veterans. Cancer 72:1369-1375, 1993 

33. Morrison MD: Is chronic gastroesophageal reflux a causative factor in glottic carcinoma? Otolaryngol Head Neck Surg 99:370, 1988 

34. Muscat JE, Wynder EL: Tobacco, alcohol, asbestos, and occupational risk factors for laryngeal cancer. Cancer 69:2244, 1992 

35. Olson NR: Laryngopharyngeal manifestations of gastroesophageal reflux disease. Otolaryngol Clin North Am 24:1201, 1991 

36. Ossoff RH, Pelzer HJ, Atiyah RA, et al: Potential applications of photoradiation therapy in head and neck surgery. Arch Otolaryngol Head Neck Surg 110:728-730, 1984 

37. Robbins KT, Storniolo AM, Kerber C, et al: Rapid superselective high-dose cisplatin infusion for advanced head and neck maligancies. Head Neck 14:364-368, 1992 

38. Rothman KJ, Cann CI, Flanders W, et al: Epidemiology of laryngeal cancer. Epidemiol Rev 2:195-209, 1980 

39. Schuller DE, Metch B, Mattox D, et al: Prospective chemotherapy in advanced resectable head and neck cancer: Final report of the Southwest Oncology Group. Laryngoscope 98:1205-1211, 1988 

40. Shah JP, Candela FC, Poddar AK: The patterns of cervical lymph node metastasis from squamous carcinoma of the oral cavity. Cancer 66:109-113, 1990 

246


41. Smith AH, Handley MA, Wood R: Epidemiological evidence indicates asbestos causes laryngeal cancer. J Occup Med 32:499, 1990 

42. Spitz MR, Fueger JJ, Goepfert H, et al: Squamous call carcinoma of the upper aerodigestive tract: A case comparison analysis. Cancer 61:203, 1988 

43. Stevens MH, Harnsberger HR, Mancuso AA, et al: Computed tomography of cervical lymph nodes. Arch Otolaryngol 111:735, 1985 

44. Urken ML: The restoration or preservation of sensation in the oral cavity following ablative surgery. Arch Otolaryngol Head Neck Surg 121:607-612, 1995 

45. Ward PH, Hanson DG: Reflux as an epidemiologic factor in carcinoma of the laryngopharynx. Laryngoscope 99:666, 1989 

46. Wolf G, Hong W, Fisher S: Larynx preservation with induction chemotherapy and radiation in advanced laryngeal cancer: Final results of the VA laryngeal cancer study group cooperative trial. Proc Am Soc Clin Oncol 12:277, 1993 

47. Wortley P, Vaughn TL, Davis S, et al: A case-control study of occupational risk factors for laryngeal cancer. Br J Ind Med 49:837, 1992 

48. Zheng W, Blot WJ, Shu XO, et al: Diet and other risk factors for cancer in Shanghai, China. Am J Epidemiol 136:178, 1992 

49. Zitch RP: Carcinoma of the lip. Otolaryngol Clin North Am 26:265-277, 1993 


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