Учебники / Otolaryngology - Basic Science and Clinical Review

issues should be evaluated expeditiously and treated by appropriate specialists so that the patient’s functional status is optimal prior to treatment.

PROGNOSIS

Prognosis varies with site and stage of lesion. In general, patients with laryngeal cancer have the best prognosis. Patients with hypopharyngeal cancer have the worst prognosis. Head and neck cancer is classified as stages I to IV based on theAJCC TNM (tumor, node, metastasis) staging system (Tables 10A-1 to 10A-6). Classification is anatomical site specific: oral cavity, oropharynx, nasopharynx, hypopharynx, supraglottis, and glottis. Tumor stage depends on site, but generally T1 to T3 indicates increasing tumor size, and T4 indicates extension to adjacent sites. Node staging is based on size, number, and side of neck involved and is uniform for all sites except the nasopharynx. Metastasis (M) is either MO (no metastasis), MI (metastatic), or MX (unknown). The risk of distant metastases (stage IV) increases with increasing neck disease. Patient cure is achieved in over 80% of stage I patients and over 60% of stage II patients. For patients with more advanced disease (stages III and IV), cure is attained in fewer than 30% of cases, although some stage III patients have a better prognosis.

TABLE 10A-1 THE TNM SYSTEM OF A PRIMARY TUMOR*

*Other tumor classes vary by anatomical site. TNM, tumor, node, metastasis.

TABLE 10A-2 ORAL CAVITY AND OROPHARYNX TUMOR

TREATMENT

Treatment regimens vary with HNSCC tumor site, stage, and institutional preference. Generally, early (stage I or II) lesions can be treated with surgery or radiation alone. Late-stage lesions are treated with combinations of surgery, radiation, and chemotherapy.

SURGICAL CONSIDERATIONS

The patient’s functional status and preferences, prior treatment, and the tumor size and site all affect surgical decision making. These factors should be weighed carefully to determine the best treatment approach.

Oral Cavity

The oral cavity is bounded anteriorly by the junction of skin and vermilion border of lip, posteriorly by the hard and soft palate junction, circumvallate papillae, and anterior tonsillar pillars, and laterally by the buccal mucosa. Subsites within the oral cavity include the alveolus, retromolar trigone, floor of the mouth, oral tongue, lip, and hard palate. HNSCC of the oral cavity is particularly amenable to surgery. Smaller tumors are easily excised

TABLE 10A-3 SUPRAGLOTTIS TUMOR STAGES

TABLE 10A-4 GLOTTIS TUMOR STAGES

with little morbidity. Larger lesions tend to invade bone and are better cleared with surgery followed by radiation. If depth of invasion is significant, treatment of the neck is recommended. Depending on size and site, defects can be left to granulate, closed primarily, or covered with a skin graft, a local flap, a locoregional flap, or a free flap. For lesions that involve the periosteum of the mandible with minimal cortical invasion, a marginal mandibulectomy usually will suffice, given that there is adequate mandibular height. For more significant invasion, a segmental madibulectomy is recommended. Lateral mandibular defects can be reconstructed with a pectoralis major mycutaneous flap, whereas anterior defects are better closed with a fibular or iliac crest free flap. (For tumor classification, see Table 10A-2.)

Oropharynx

The oropharynx lies posterior to the oral cavity and extends from the level of the hard palate to the hyoid bone. It is bounded anteriorly by the junction of the hard and

TABLE 10A-5 HYPOPHARYNX TUMOR STAGES

TABLE 10A-6 NASOPHARYNX TUMOR STAGES

involvement of cranial nerves, infratemporal fossa, hypopharynx, or orbit

soft palates, anterior tonsillar pillars, and circumvallate papillae.The oropharynx includes the base of the tongue, tonsils, soft palate, and posterior pharyngeal wall.

Cancers of the oropharynx can be treated surgically. Common approaches to the oropharynx include suprahyoid, mandibulotomy, and lateral pharyngotomy. Very small lesions can be resected transorally. Large lesions involving the mandible require composite resection. A pectoralis major myocutaneous flap provides adequate coverage of soft tissue defects in this region, although a radial forearm free flap tends to be thinner, can be reinnervated, and may allow better swallowing function. For large defects or if the patient has had previous radiation, soft tissue coverage with a vascularized flap is recommended to avoid fistula and vessel exposure. (For tumor classification, see Table 10A-2.)

Larynx

The larynx is divided into supraglottic, glottic, and subglottic regions. The supraglottic larynx includes the epiglottis, aryepiglottic folds, false vocal cords, and roof of the ventricle. The glottic larynx includes the floor of the ventricles, true vocal cords, and anterior and posterior commissures. The subglottis begins 0.5 mm below the free edge of the vocal cords and extends to the inferior border of the cricoid cartilage.

Surgical treatment of laryngeal cancer is diverse. Surgical options include conventional conservation surgery, transoral endoscopic laser surgery, supracricoid partial laryngectomy, and total laryngectomy. The theory behind conventional conservation surgery is based on work by Kirchner that shows the spread of cancer is influenced by fibroelastic ligaments and membranes, which confine the tumor to anatomical compartments.

Conventional conservation surgery can be divided into vertical and horizontal approaches. Vertical approaches involve anterior and posterior vertical

incisions that include a segment of supraglottis, glottis, and subglottis. Operations under this classification include the hemilaryngectomy and frontolateral laryngectomy. Horizontal approaches involve superior and inferior horizontal incisions that remove lesions above the true vocal cords. Operations under this classification include supraglottic laryngectomy and extended supraglottic laryngectomy. The supracricoid laryngectomy expands indications for conservation surgery. It involves removal of a cylindrical segment of larynx above the cricoid, maintaining the arytenoids on at least one side. Limitations include arytenoid fixation, posterior commissure involvement, cricoid cartilage involvement, and extralaryngeal spread.

For laryngeal tumors that invade through cartilage, strap muscles, or significantly into the subglottis, conservation surgery is not appropriate, and organ-sparing chemoradiation protocols are not as effective. For these very advanced laryngeal tumors, total laryngectomy is the treatment of choice. (For tumor classification, see

Tables 10A-3 and 10A-4.)

Hypopharynx

The hypopharynx partially surrounds the larynx. It begins at the level of the hyoid bone and ends at the esophageal introitus.The hypopharynx includes the piriform sinuses, pharyngeal walls, and postcricoid region.

HNSCC in the hypopharynx tends to behave aggressively. Squamous cell cancers in the hypopharynx that are not cured following organ-sparing chemotherapy and radiation are often difficult to resect or are unresectable. If the tumor is resectable at the time of presentation, many oncologists recommend primary surgery followed by radiation. Surgery involves laryngectomy and partial pharyngectomy and often requires closure with vascularized tissue such as a pectoralis major myocutaneous flap. Obviously, the patient’s preferences in such a decision are critical. If risks are understood, organ-sparing protocols are reasonable options as well.

Nasopharynx

The nasopharynx is bounded superiorly by the basiocciput and basisphenoid, posteriorly by the C1 and C2 cervical bodies, anteriorly by the choanae, and inferiorly by the soft palate.The lateral walls are occupied primarily by the eustachian tube orifice. Immediately posterior to the eustachian tube orifice is the fossa of Rosenmüller, where most nasopharyngeal carcinomas originate. Due to the close proximity of cranial nerves, nasopharyngeal carcinoma often presents with cranial nerve dysfunction. The most common cranial nerves

involved are VI and V; however, cranial nerves II, IV, IX, X, XI, and XII can be involved. Most nasopharyngeal carcinomas respond well to radiation and chemotherapy. (For tumor classification, see Table 10A-6.)

Neck

Lymph node groups are divided into levels. Level 1 includes the submandibular and submental nodes, levels 2 to 4 are located between the posterior border of the sternocleidomastoid (SCM) and the strap muscles. These are separated into upper jugular (level 2), midjugular (level 3), and lower jugular (level 4) nodes. Level 5 is located behind the SCM and extends to the trapezius. It is bordered inferiorly by the clavicle.

Neck dissections performed for HNSCC include the radical neck dissection, modified radical neck dissection, and selective neck dissections. The radical neck dissection includes removal of all five nodal groups, the SCM, the internal jugular vein (IJV), and the spinal accessory nerve (CN11). The modified neck dissection involves removal of all five nodal groups; however, one or more of the other three structures (SCM, IJV, or CN11) are preserved. Selective neck dissections remove only those nodal groups at highest risk for tumor involvement. The risk depends on primary tumor location and size.

Generally, a modified radical neck dissection is performed on all clinically positive neck disease if the primary site is also being managed surgically. Neck dissections are also performed on all persistent neck disease following definitive organ-sparing protocols. At some institutions, elective neck dissections are performed on patients with nodal disease greater than 3 cm prior to chemoradiotherapy. Others recommend neck dissection for all N2 disease. Still others recommend observation if the neck is clinically negative following treatment. Neck dissections generally are recommended in patients with primaries greater than 4 mm in depth in the oral cavity, for patients with supraglottic cancer, and for patients with any advanced HNSCC. For supraglottic tumors, bilateral neck dissections are performed because lymphatics cross in the midline. Increasingly, selective neck dissections are performed in the N0 neck. Levels 1 to 3 (or 4) are dissected for oral cavity cancers and levels 2 to 4 for laryngeal, oropharyngeal, and hypopharyngeal primary sites.

RADIOTHERAPY

Radiotherapy may be used to treat head and neck cancers as the definitive (curative) therapy or as the postoperative (adjuvant) therapy. When radiotherapy is used for the

definitive purposes, it may be given as a single modality or in a combined modality with chemotherapy. Recent advances include the use of intensity modulated radiotherapy (IMRT), which arranges the radiation beam so there is a sharper dose gradient between the target tumor volumes and the normal tissue/organs. IMRT provides dose escalation to the tumors and additional normal tissue sparing.The ability to deliver high doses to a selected volume enables the radiation oncologist to reirradiate recurrent diseases/second primaries in a previously irradiated field. In the following sections, brief discussions of the role of radiotherapy in the management of head and neck cancers will be presented.

Single Modality

Surgery is indicated for early-stage diseases of the head and neck region if there is no sacrifice of a critical normal organ function or if the patient has no contraindication to surgery. Prognosis for early-stage diseases (AJCC stage groupings I and II) depends on the anatomical site, the size of the tumors, the nodal status, the histology/grade of the diseases, and the patient’s physical condition, such as weight loss and the ability to tolerate the treatment. In general, the radiation dose ranges from 66 to 72 Gy with a 1.8 to 2.0 Gy daily dose. Other factors that affect the success of radiotherapy are the total dose delivered, the daily dose, and the frequency of treatment interruptions (i.e., the number of elapsed days to complete a course of radiotherapy). Typical control rate for a T1 tonsillar lesion is approximately 80 to 85%; for T2 tonsillar lesions, 75 to 85%. Early-stage lesions in the larynx have higher control rates than other head and neck sites if treated with radiotherapy alone.The control rate for T1a glottic cancers is approximately 90%; for T1b tumors, approximately 80%.The laryngeal function is preserved in 74% of T2 glottic cancers.

Hyperfractionated radiotherapy, which delivers a dose twice daily, is used to prevent late-occurring side effects such as fibrosis and nerve damage. Generally, doses are 1.2 Gy twice daily.This technique was studied by the University of Florida with excellent results for treatment of T3/T4 laryngeal lesions (65% local control for T3 and 60% for T4).

Other altered fractionations, such as accelerated concomitant boost (accelerated hyperfractionation), which uses two different doses in the last 10 to 12 days of radiotherapy, and continuous, hyperfractionated, accelerated radiotherapy (CHART, three doses per day) are adopted for overcoming the repopulation effect after initiation of radiotherapy with or without chemotherapy.

The commonly used doses for the accelerated hyperfractionation are 1.8 Gy and 1.5 Gy.The CHART regimen uses 1.5 Gy 3 times daily.

A randomized study, RTOG 9003 (RadiationTherapy Oncology Group, Fu et al, 2000), showed that the accelerated hyperfractionation regimens improve local tumor control significantly, by approximately 10 to 15%.There is a trend toward better disease-free survival as compared with standard daily radiotherapy. The CHART regimen demonstrated the importance of controlling tumor repopulation to prevent tumor recurrence. It was also observed that the acute radiation side effects were more severe among patients who received the accelerated hyerfractionation regimen than patients who were treated with standard fraction.

Chemoradiotherapy

For locally advanced diseases; that is, stages III and IV, the treatment results for radiotherapy alone are not as successful as surgery with or without postoperative radiotherapy.TheVeteransAffairs Laryngeal Cancer Study Group trial in 1991 was a landmark investigation, that introduced chemotherapy as a standard treatment option for advanced laryngeal cancer.The study showed that induction chemotherapy using cis-platinum and 5-Fluorouracil (5-Fu) followed by radiation therapy, with surgical salvage of tumors that were unresponsive, resulted in preservation of the larynx in over 60% of patients while maintaining survival rates equal to total laryngectomy followed by radiation. This approach quickly became the standard of care for appropriate patients who wanted to preserve their larynx.

Recent randomized phase III trials of cisplatin-based induction chemotherapy followed by radiotherapy with or without concurrent chemotherapy for laryngeal and hypopharyngeal cancers showed that organ preservation can be achieved with similar overall survival as surgery followed with radiotherapy. Concurrent chemoradiotherapy is superior to induction chemotherapy followed by radiotherapy.

Chemotherapy that was given alternately with radiotherapy was also shown in a randomized phase III study to improve significantly overall survival for stage III and IV head and neck cancers. An RTOG study (H 00129) is ongoing to compare concurrent chemotherapy with daily radiotherapy (2 Gy daily) and accelerated hyperfraction radiotherapy (1.8 Gy 1.5 Gy in the accelerated phase) for the diseases in the oropharynx and oral cavity. Most practices are using combined modality chemoradiotherapy with cisplatin and 5-fu for locally advanced stage head and neck cancers, even with limited data.

Adjuvant Radiotherapy

Radiotherapy is often indicated postoperatively (adjuvant therapy). It is commonly recommended for positive margins, large tumors, extracapsular extension of lymph node metastasis, more than three involved lymph nodes, multiple recurrences for high-grade lesions, perineural invasion, or situations in which the operating surgeon is concerned for residual diseases. Postoperative radiotherapy has been shown to improve survival.A treatmentrelated factor that affects local tumor control is the elapsed time between surgery and the beginning of postoperative radiotherapy. Although recently debated, most studies agree that the local recurrence rate is significantly higher if radiotherapy begins more than 6 weeks after surgery.

Reirradiation

When previously irradiated patients develop in-field recurrence or a second malignancy, surgical salvage may not always be feasible. In present practice, chemotherapy may be offered to patients for palliative treatment. Reports from the University of Texas M. D. Anderson Cancer Center as well as Massachussetts General Hospital showed that for selected patients treated again with chemotherapy and reirradiation, the reported local control rate may be as high as 50%, and the 5-year survival may be up to 20%.The treatment-related side effects are well tolerated. RTOG recently closed a phase II study (RTOG 99-11) to evaluate the efficacy of this approach. The treatment regimen is 1.5 Gy twice daily every other week to a total dose of 60 Gy. Cisplatin and Paclitaxel are given daily with radiotherapy. Radiation myelitis is expected to be less than 6%. A review of the toxicity of the enrolled cases showed no excessive number of carotid artery hemorrhages.

Management of Xerostomia and Mucositis

The acute radiation reactions that have the most impact on a patient’s sense of well-being are xerostomia and oral mucositis. For xerostomia, artificial saliva may be used. Pilocarpine, a cholinomimetic drug used to increase salivation, has been given frequently to patients by radiation oncologists with mixed results. The benefit from the use of oral pilocarpine is still controversial. Amifostine, a prodrug analogue of cysteamine thought to protect normal cells by acting as a free radical scavenger, may be used alone or together with pilocarpine. The combined use of these two drugs is being investigated as well. For selected sites of head and neck cancers, transposition of submandibular gland to the

submental region has shown effectiveness in singleinstitution experience. RTOG is conducting a study (RTOG 0244) to investigate the benefit of this procedure. Carefully planned IMRT for treating head and neck cancers has been shown to decrease the severity of xerostomia significantly without sacrificing tumor control.

The management of oral mucositis includes pain control and prevention of infection. Local anesthetics such as viscous xylocaine may be used. For severe pain, fentanyl patches, Roxicet elixir, and Roxanol may be added. Morphine mouthwash has been shown to be effective. Nystatin oral suspension for topical use with fluconazole for more serious infection is commonly practiced. A mixed solution that may contain a combination of Benadryl, Mylanta, Decadron, nystatin, antibiotic, morphine, or viscous xylocaine is also widely used for head and neck patients. Rinsing the mouth with saline or sodium bicarbonate solution frequently is a preventive measure. It is also important for patients to have frequent evaluations by a dentist with experience in treating patients with HNSCC. Special emphasis on hydration and nutrition is important to help patients tolerate chemoradiotherapy for head and neck cancers.

CHEMOTHERAPY

Chemotherapeutic agents are used in combination with surgery and radiation to treat advanced head and neck cancer. Such regimens include induction chemotherapy, concomitant chemoradiotherapy, adjuvant chemotherapy, and palliative chemotherapy.

Induction and Concomitant Chemotherapy

The Veterans Affairs study showed that induction chemotherapy and radiotherapy are equivalent to laryngectomy followed by radiotherapy. However, it did not include a radiation alone arm; hence the contribution of induction chemotherapy was unclear. More recently, the RTOG 91-11 compared induction chemotherapy followed by radiation, concurrent chemoradiation, and radiation alone. In this trial, 88% of patients in the concomitant chemoradiation arm preserved their larynx at 2 years compared with 75% of those treated with induction chemotherapy and 70% of those treated in the radiation-alone arm. Overall survival did not vary significantly between groups. Concomitant chemoradiation therapy is now the preferred approach to laryngeal preservation, although radiation can be advised for patients who cannot withstand the toxicity of combined chemoradiation.

Concomitant chemoradiotherapy has been postulated to improve locoregional control and eradicate systemic micrometastasis by the following mechanisms:

1.Spatial cooperation: radiation is used to control locoregional disease and chemotherapy is used to control micrometastatic disease

2.Nonoverlapping toxicity: chemotherapy and radiotherapy have different mechanisms of toxicity that are additive to the tumor but less potentiating to normal tissues.

3.Chemotherapy decreases the ability of radiotherapydamaged tumor cells to repair.

4.Chemotherapy has cytotoxic activity against radioresistant (e.g., hypoxic) tumor cells.

5.Chemotherapy potentially has selective cytoprotective properties for normal tissues, allowing higher radiation doses (rationale for mucosal protectants).

6.Specific chemotherapeutic drugs such as fluorouracil, cisplatin, and taxanes induce cell cycle

arrest at the G2 checkpoint, where the cell is most radiosensitive.

Several different approaches have been used in concomitant chemoradiotherapy.The most frequently used has been standard radiotherapy or hyperfractionated radiotherapy with platinum-based chemotherapy. Phase III randomized trials and meta-analyses have shown statistically significant improved survival using concomitant chemotherapy and radiation for locally advanced squamous cell carcinomas for all sites in the head and neck. These trials have resulted in increased toxicity, including mucositis and systemic toxicity. These complications, however, have been manageable. Based on these trials, most major cancer centers now consider concomitant chemoradiotherapy a reasonable option for locally advanced carcinomas of the head and neck.

Nasopharyngeal carcinomas are distinct carcinomas of the head and neck. They occur in a younger age group, have a geographic distribution, metastasize early, and are more responsive to radiation and chemotherapy. There is a strong association between these tumors and Epstein-Barr virus, particularly in patients from southeastern China. The incidence of nasopharyngeal carcinoma in southeastern China has been reported as 10 to 20 per 100,000 men.Worldwide incidence of these tumors is less than 1 per 100,000, and it is a rare tumor in the United States.

Stage I and II lesions are treated with aggressive radiotherapy. Stage III and IV lesions are treated with chemoradiotherapy. Chemotherapy regimens usually

have included cisplatin and fluorouracil with or without epirubicin. Five-year survival rates for stage I and II disease have been reported in a range of 50 to 90%, and for stage III and IV disease 17 to 60%. Unlike other carcinomas of the head and neck, surgery has a very limited role in the management of nasopharyngeal carcinomas.

Adjuvant Chemotherapy

Following definitive locoregional therapy, adjuvant chemotherapy has been given to control microscopic residual disease and micrometastatic disease. Adjuvant therapy has been proven to be of significant value in the management of breast and colorectal cancer.There have been a number of phase III trials of adjuvant therapy for head and neck cancers. Although there appears to be some reduction in the incidence of distant metastases, adjuvant therapy has not been demonstrated to improve survival.The vast majority of deaths related to head and neck cancer are due to local and regional failures and not to disseminated metastatic disease. At this time, adjuvant chemotherapy has not been shown to have a role in the management of carcinomas of the head and neck.

Palliative Chemotherapy

Chemotherapy has been used in the management of head and neck cancers that are recurrent, metastatic, unresectable, and considered incurable. It is in these settings that new systemic therapeutic modalities are initially evaluated in clinical trials. Phase I are doseescalation trials evaluating toxicity and establishing maximum tolerated doses. They may involve single or multiple agents. Phase II trials are designed to determine the efficacy of new therapeutic regimens after their dose tolerance has been determined in phase I trials. Response rates are usually compared with previous trials (historic controls). Phase III trials usually are randomized and are always comparative. New therapeutic regimens are compared with standard therapy.

The primary goal of palliative therapy is to improve the patient’s quality of life.This can be accomplished by relieving pain, preserving or improving organ function, and preventing obstruction of the airway or esophagus. Although in some instances survival may be prolonged, survival is not the primary goal of palliative therapy. Some clinical trials, however, have established prolonged survival with palliative therapy.

Single-agent methotrexate therapy has been the standard palliative therapy for head and neck cancer. It is well tolerated, convenient, and inexpensive. Response rates range from 15 to 30% with a median duration that

generally has been less than 6 months. Multiagent chemotherapy with cisplatin and fluorouracil has demonstrated higher response rates (30–50%) and may prolong survival slightly.This regimen is more toxic, less convenient, and more expensive. It may be the regimen of choice for some patients with good performance status. Several new therapeutic regimens are being evaluated for recurrent and metastatic squamous cell cancer. These include taxanes, vinorelbine, and gemcitabine in singleand multiagent trials.

QUALITY OF LIFE

HNSCC is a devastating illness. Following treatment, patients often experience problems with speech, swallowing, and disfigurement.Although multiple treatment approaches are often available for a given HNSCC patient, not all treatments will have the same impact on the patient’s quality of life. Choice of treatment will often result in a trade-off between chance of cure and the patient’s quality of life. There are good data regarding cure rates associated with various treatment regimens. We are starting to see good data comparing these regimens (e.g., radiation alone vs combined chemoradiotherapy). Unfortunately, data on quality of life are lacking. Quality of life outcomes research relies on patients’ reports. Data should be collected prospectively and include validated measures of social, emotional, physical, and psychological function.This field of HNSCC research is in the early phases of development, but it will ultimately provide important information to patients and oncologists who together face difficult treatment decisions.

MOLECULAR BIOLOGY OF HEAD AND NECK CANCER

Advances in our understanding of HNSCC molecular biology give promise to the future development of more sophisticated methods to prevent, diagnose, and treat this cancer. Through these efforts significant reductions in morbidity and mortality are envisioned.

There is ample evidence that UADT mucosa undergoes a stepwise progression to squamous cell carcinoma. This is seen at the clinical, histological, and molecular levels. At the clinical level, affected mucosa progresses from leukoplakia or erythroplasia to raised or ulcerated lesions harboring squamous cell carcinoma. At the histological level, this progression can be seen as worsening dysplasia that develops into carcinoma in situ and finally invasive carcinoma on serial biopsies. On the molecular level, tumor tissues show escalating numbers

of genetic alterations. In most cases the accumulation of genetic alterations is a result of exposure to tobacco and alcohol. Other risk factors, such as viral exposure and heredity, also play a role, as outlined previously. Although the exact order and number of genetic events required for cancer development are still under investigation, six important steps are believed to be necessary. These are loss of growth inhibition signals and programmed cell death; immortalization; and acquisition of autonomous proliferation, angiogenesis, and the ability to invade tissue.

Oncogenes are genes whose protein products are involved in cell growth regulation so that overexpression or mutation results in disregulated cell growth. Epidermal growth factor receptor (EGFR), a member of the erbB family of receptor tyrosine kinases, is one such oncogene that has been studied in HNSCC. EGFR and its ligand, transforming growth factor (TGF- ), are overexpressed in 90% of HNSCC. Binding of TGF- , EGFR, and other growth factors to the extracellular domain results in phosphorylation and receptor activation that stimulates tumor growth through autocrine and paracrine pathways. Oncogenes overexpressed in HNSCC include other growth factors or growth factor receptors (hst1/fibroblast growth factor 4, int2/fibroblast growth factor 3, Her2/erbB2), intracellular signal transducers (ras, stat3), transcription factors (c-myc/N-myc), regulators of cell cycle (cyclin D1), and inhibitors of apoptosis or programmed cell death (Bcl2).

Tumor suppressor genes inhibit tumor cell growth. Such genes are involved in cell cycle arrest and apoptosis. The p53 is the most studied tumor suppressor gene in tissue specimens of head and neck cancer. It is located on chromosome 17p13 and encodes a nuclear protein that regulates the G1/S transition of the cell cycle (see Chapter 19). It can induce cell-cycle arrest and DNA repair or apoptosis in response to genetic damage. Inactivation of p53 most often occurs by point mutation, although rearrangements, deletions, and inactivation by viral proteins are also possible. Studies have reported mutations in 25 to 69% and overexpression in 15 to 60% of oral cancers. Other important tumor suppressor genes that are frequently inactivated in HNSCC include inhibitors of cell cycle progression (p16, p21, and p27kip).

Telomerase is an enzyme thought to be involved in cell immortalization; telomeres are highly conserved, repeated DNA sequences located at the ends of chromosomes. Normally, cells fail to replicate the 5 end of linear DNA, resulting in progressive loss of telemetric DNA with each cell division. It is believed that this loss of DNA signals the cell to enter senescence.

The telomerase enzyme adds DNA sequences before each cell division, resulting in immortalization of the cell. Telomerase is usually only active in germ cells and hematopoetic cells, but is present in most cancers, including HNSCC.

Matrix metalloproteinases (MMPs) are important regulators of the extracellular environment. MMPs and related proteins (A Disintegrin And Metalloproteinase [ADAMs]) represent a family of proteinases that can process almost any component of the extracellular matrix. These proteinases are down-regulated by inhibitors such as tissue inhibitors of metalloproteinases (TIMPs). MMPs process molecules involved in cell–cell and cell–matrix interactions such as CD44 and integrin molecules. Disregulation of MMPs and related proteins can result in cell dissociation and invasion. MMPs also cleave growth factor–binding proteins, releasing mitogens that lead to cell division and inhibition of apoptosis. Some MMPs, including MMP1 and MMP3, have been shown to be overexpressed in HNSCC and associated with lymph node metastases.

Cyclooxygenase is an important regulatory enzyme in the production of prostaglandins from arachidonic acid. Cyclooxygenase-1 is produced under normal conditions. Cyclooxygenase-2 (COX-2) is induced by pathophysiological factors such as inflammatory stimuli and oncogenes and is overexpressed in premalignant and malignant UADT lesions. Prostaglandins produced by COX-2 exert their effect by binding to both cell surface and nuclear hormone receptors and are involved in cell proliferation, angiogenesis, antiapoptosis, invasion, and metastases.

Retinoids are derivatives of the natural compound retinal (vitaminA). Retinoids mediate gene trascription by binding to retinoic acid receptors. Retinoic acid receptors comprise a family of homoand heterodimers. When activated, they bind to the promoter region of genes, resulting in antiproliferative and proapoptotic effects.

CHEMOPREVENTION

Chemoprevention includes strategies to prevent or reverse carcinogenesis before an invasive cancer develops or to prevent a second primary cancer in patients who have had a previous cancer cured.

Clinical trials with various retinoids have studied histopathologically confirmed oral premalignant epithelial dysplastic lesions. Hong et al used high-dose isotretinoin (13-cis-retinoic acid,Accutane) in 44 patients with dysplastic oral epithelial lesions; 67% of the patients had major responses, compared with a 10% response in the placebo group. Within 3 months after

discontinuing therapy, 50% of the lesions recurred. High-dose isotretinoin was associated with significant side effects, including cheilitis, conjunctivitis, and hypertriglyceridemia.

In a randomized study using high-dose isotretinoin induction followed by maintenance with either lowdose isotretinoin or beta-carotene, 8% of the patients on isotretinoin had progression of their oral lesions; 55% of the beta-carotene group had progression of oral lesions. Maintenance therapy was not associated with significant side effects. Other studies have evaluated vitamin A, retinamide, and fenretinide, and have not proven them to reverse oral premalignant lesions.

Several phase three studies have been conducted using retinoids for the prevention of second primary cancers in patients who had received definitive therapy for a primary head and neck cancer. Initial reports showed reduction of second primary tumors with a high-dose regimen. However, follow-up studies failed to show adequate benefit.

Retinoids have significant toxicity in the high doses used in these studies Molecular biology has provided new information on how retinoids regulate gene expression and has led to the development of synthetic retinoids that may be less toxic and more effective in the prevention of cancer.

A study comparing beta-carotene with placebo over 12 years in 22,000 physicians showed essentially no difference in the incidence of cancer, stroke, myocardial infarction, and death. A study comparing beta-carotene plus vitamin A with placebo was stopped after 4 years because of a significantly increased incidence of lung cancer and overall mortality in the study group. COX-2 inhibitors currently are under investigation in phase II clinical trials as chemopreventive agents in patients with leukoplakia and dysplasia. At this time, chemopreventive therapy for head and neck cancer must be considered investigational. The use of chemopreventives should be limited to controlled clinical trials.

EARLY DETECTION

No symptom or symptom complex is strongly correlated with HNSCC for any subsite except the larynx; consequently, most HNSCC patients present at late stage. Because oral cavity cancer is the most common site for HNSCC and it is fairly easy to examine, it seems that screening examinations would be beneficial. However, a systematic review concluded there is insufficient evidence to assess the effectiveness of

community-based screening programs. Despite the American Cancer Society’s and National Cancer Institute’s emphasis that oral examinations could prevent many deaths, only 16% of respondents to the Centers for Disease Control and Prevention’s 1998 National Health Interview Survey had ever undergone an oral cavity exam. Selected high-risk populations are most likely to benefit from screening exams. Detection rates have reached 2.4% in highly targeted populations compared with no cases to 0.1% for general screening.

Adjunctive tools to the physical exam include toluidine blue vital dye used as a rinse or applied directly to suspicious lesions.Toluidine blue has yielded specificities between 45 and 93% and sensitivities between 72 and 100%. The oral cytobrush that generates a cytology specimen has yielded impressive results in the hands of academicians. There is insufficient evidence to evaluate the effectiveness of toluidine blue and oral cytobrush in high-risk community settings.

Current research focuses on molecular approaches for accurate prognosis and early detection. Although epithelial dysplasia remains the most important predictive factor, DNA content, aberrant oncogenes, integrin expression, p53 expression, and loss of heterozygosity at chromosome 3p or 9p show some promise in predicting which lesions will progress to cancer. Loss of heterozygosity refers to loss of one allele of a gene. Loss of one allele of a tumor suppressor gene through chromosomal deletion and the other allele through a different mechanism will lead to a functional deficit of the tumor suppressor. Microsatellites are repetitive DNA sequences that are scattered throughout the genome. Microsatellite instability refers to the expansions and deletions within these regions that are frequently seen in various cancers. These differences in macrosatellites between normal and tumor samples can be identified by polymerase chain reaction (PCR) and used to detect regions of allelic loss. DNA promoter hypermethylation also leads to inactivation of tumor suppressor genes and can be detected by PCR methods. Hu and colleagues (2002) reviewed molecular detection approaches for smoking associated tumors. Several markers have been studied in HNSCC saliva and serum. Spafford and colleagues showed loss of heterozygosity or microsatellite instability in 1 of 23 markers in 79% of saliva samples from 44 HNSCC patients and in none of 43 healthy control subjects. Boyle et al identified tumor-specific p53 mutations in five of seven saliva samples from patients with HNSCC. Abnormal promoter hypermethylation has been detected in the saliva of 11 of 17

HNSCC patients. Mitochondrial DNA mutations have been detected in six of nine saliva samples from HNSCC by direct sequencing. Franzman’s group showed that hyaluronic acid was elevated in eight and hyaluronidase elevated in saliva of 11 of 11 HNSCC patients. Microsatellite markers have been identified in the serum of 6 of 21 patients with HNSCC. In 50 patients with paired serum and tissue, the same promoter hypermethylation pattern in one of three genes (p16, MGMT, and DAP-K) was found in 42% of patients.

High throughput techniques have revolutionized the search for head and neck tumor markers. Ribonucleic acid (RNA) or DNA samples are hybridized to complementary (c)DNA arrays that permit analysis of thousands of genes simultaneously. Similarly, surface-enhanced laser desorption/ionization–time of flight (SELDI-TOF) mass spectrometry and antibody microarrays have been used to analyze samples from HNSCC patients and normals to develop a protein-level signature for HNSCC. Although these methods may not be feasible for mass screenings, they facilitate identification of the most important markers. Once reliable markers are identified, less expensive screening modalities such as enzyme-linked immunosorbent assay (ELISA) can be developed for early-detection programs.

PREDICTING RESPONSE AND PROGNOSIS IN

HEAD AND NECK CARCINOMA

Tumors exhibit wide variations in their response to radiation and chemotherapy. Recent research has focused on the identification of markers that may predict the response of an individual tumor to cytotoxic radiation and/or chemotherapy.A number of biological markers have been shown to be predicative of poor response to radiation and/or chemotherapy. Identified markers include p53 mutations, p53 overexpression, epithelial growth factor receptor (erbB1) overexpression, erbB2 mutations, cyclin Dl (BCL1) overexpression, tumor hypoxia, angiogenic factors, tumor microvascular density, and thymidylate synthetase.

Head and neck carcinomas that express high levels of thymidylate synthetase have been shown to be more resistant to fluorouracil therapy than tumors with low levels of thymidylate synthetase. In view of this, chemotherapy for tumors with high levels of thymidylate synthetase should include agents other then fluorouracil.

Previously, tissue electrodes have measured tissue oxygenation. Recently, positron emission tomography,

which can more accurately identify and map tissue oxygen levels, has become available.This may allow for prospective prediction of appropriate therapeutic agents for individual tumors. Squamous cell carcinomas of the head and neck have a disorderly microvascular supply that results in areas containing large numbers of hypoxic cells. These hypoxic cells are resistant to radiation and to certain chemotherapeutic drugs. Conversely, bioreductive drugs such as mitomycin C have increased cytotoxicity in areas of hypoxia.The cytotoxicity of drugs such as fluorouracil and cisplatin are not affected by levels of tissue oxygenation.

Hypoxic areas in tumors induce the formation of angiogenic factors such as vascular endothelial growth factor (VEGF).These angiogenic factors result in areas of increased tumor vascularity, which have increased resistance to some chemotherapeutic agents. Tumor microvascular density, which can be induced by angiogenic factors, is a known predictor of poor tumor response. Tumors with high microvascular density may respond to antiangiogenic factors. The predictive value of these biological markers needs to be validated in prospective therapeutic trials. If validated biological markers may become of great value in customizing therapy for specific carcinomas.

CLINICAL TRIALS

Several strategies have been used to inhibit VEGFmediated signals. These include anti-VEGF antibodies and agents that inhibit the VEGF receptor tyrosine kinase. Phase III trials using anti-VEGF agents in various cancer types, in combination with chemotherapeutic agents, are ongoing.

Gene therapy is currently being evaluated in several phase II clinical trials. One trial involves transfection of the normal p53 gene into carcinomas with mutant p53 using an adenovirus vector. Another phase II trial used a mutant adenovirus that replicates selectively in p53deficient human tumor cells, resulting in tumor cell lysis, and objective tumor responses were demonstrated. The adenovirus does not replicate in normal cells with functional p53 genes.

Therapeutic approaches targeting EGFR are also under investigation. Strategies include blockade of the extracellular receptor domain and inhibition of the tyrosine kinase activity, among others. Most of these studies are in phase I–II testing. EGFR antagonists are being studied alone (with modest effects reported) as well as in combination with chemotherapy or radiation. Results of these studies are pending.

SUMMARY

In recent years, we have seen several advances in the management of head and neck cancer. Chemotherapy has been shown to be of value in organ preservation, thus decreasing morbidity. Present data support the use of concomitant chemotherapy and radiation therapy as treatment for locally advanced squamous cell carcinoma of the head and neck where surgery is not a good option.Advances in microvascular surgery have resulted in improved reconstruction and function following surgical extirpation of these cancers. Future advances in immunology and molecular biology promise to provide us with greater knowledge about the etiology, diagnosis, prognosis, and prevention of cancer. With this new knowledge, utilizing immunotherapy and gene therapy, along with improved traditional head and neck cancer treatment, cancer will be more effectively managed with less morbidity and better survival. New knowledge about individual cancers should also allow for more customized therapeutics based on biological markers that predict more accurately an individual tumor’s behavior and response to specific therapeutic modalities.

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