Barbara A. Conley*
Arlene A. Forastiere†
*Department of Medicine, Michigan State University, East Lansing, Michigan
†Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
‡Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Tumors of the head and neck are the sixth most common malignancy in the United States, with a yearly incidence of 40,000 to 50,000 cases. Ninety percent of these cancers involve squamous cell histology. The most common sites are the oral cavity, pharynx, larynx, and hypopharynx. Nasal cavity and paranasal sinus cancers, salivary gland malignancies, and various sarcomas, lymphomas, and melanoma are less common.
The worldwide incidence of head and neck squamous cancer is more than 500,000 cases per year, and in the United States, it comprises approximately 4% to 5% of all new cancers and 2% of all cancer deaths (11,000 per year) (1). Most patients are older than 50 years, and incidence increases with age; the male-to-female ratio is 2.5:1. The age-adjusted incidence is higher among black men, and, stage-for-stage, survival among African Americans is lower overall than in whites. Approximately 34% of oral and pharyngeal cancers present as localized disease, 46% present as locoregional (i.e., locally advanced or involving regional lymph nodes) disease, and 10% present as metastatic disease.
Tobacco and alcohol use are major risk factors for developing cancer. Heavy alcohol consumption increases the risk twofold to sixfold, whereas smoking increases the risk fivefold to 25-fold, depending on gender, race, and the amount of smoking. Both factors together increase the risk 15-fold to 40-fold. Smokeless tobacco and snuff are associated with oral cavity cancers. Case–control studies show that the relative risk for developing erythroplasia cancer in tissues in contact with snuff powder (cheek and gum) is nearly 50-fold (2). In many parts of Asia and some parts of Africa, chewing betel with or without tobacco and slaked lime is associated with premalignant lesions and oral squamous cancers (3,4).
Alcohol and tobacco affect the entire respiratory mucosa, leading to multifocal mucosal abnormalities known as “field cancerization” (5). There is a 2% to 6% per year risk for a second head and neck, lung, or esophageal cancer in patients with a history of cancer in this area. Those who
continue to smoke have the highest risk. Second primary cancers represent a major risk factor for death among survivors of an initial squamous carcinoma of the head and neck (6,7,8).
Epstein-Barr virus (EBV) has been detected in virtually all nonkeratinizing and undifferentiated nasopharyngeal cancers but less consistently in squamous nasopharyngeal cancers (reviewed in 9). Correlation has been observed between the presence of papillomavirus and oral and oropharynx cancers (10,11,12).
Other risk factors include sun exposure (lip cancer); occupational exposure to nickel (nose and ethmoids), radium (antrum), mustard gas (sphenoid), chromium (sinuses and nose), leather (ethmoids and nasal cavity), and wood dust (ethmoids and nasal cavity); radiation exposure (thyroid and salivary gland cancer); EBV exposure (nasopharyngeal cancer); and, possibly, vitamin A deficiency and marijuana. Disorders of DNA repair (e.g., Fanconi anemia) as well as organ transplantation with immunosuppression are associated with increased risk of squamous head and neck cancer.
PREVENTION AND CHEMOPREVENTION
The most important recommendation for prevention of head and neck cancer is to avoid smoking and to limit alcohol intake. Premalignant lesions occurring in the oral cavity, pharynx, and larynx manifest as leukoplakia (a white patch that does not scrape off and that has no other obvious cause) or erythroplakia (friable reddish or specked lesions) (see Table 1.1.). The risk of leukoplakias without dysplasia progressing to cancer is about 4%. However, up to 40% of severe dysplasias or erythroplasias progress to cancer. Retinoids can reversibly improve premalignant histology. In a small randomized placebo-controlled trial in patients treated for a head and neck cancer, isotretinoin decreased the incidence of second primary tumors (13). A larger definitive randomized, placebo-controlled trial in patients with curatively treated stages I and II head and neck squamous cell carcinoma failed to find any benefit of 13-cis-retinoic acid in preventing
second primary cancers or in survival (14). Euroscan, a large European chemoprevention trial that randomized patients with stage I to stage III non–small cell lung cancer or head and neck squamous cancer to either vitamin A (as retinyl palmitate) or N-acetylcysteine (a free radical scavenger), neither drug or both drugs, also failed to find preventive benefit (15).
TABLE 1.1. Premalignant Lesions
Presently, there is no effective chemoprevention for patients at risk for head and neck squamous cancer. Chemoprevention outside a clinical trial is not recommended and is potentially harmful. Two large randomized chemoprevention trials for lung cancer demonstrated a worse outcome for those patients randomized to Vitamin A and β-Carotene (CARET study) or to β-Carotene alone (ATBC study) (16,17,18,19).
A simplified depiction of extracranial head and neck anatomy is presented in FIG. 1.1.
FIG. 1.1. Sagittal section of the upper aerodigestive tract. (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag, New York, http://www.springer-ny.com.)
The patterns of lymphatic drainage divide the neck into several levels (see FIG. 1.2). Level I comprises the submental or submandibular nodes; level II (upper jugular lymph nodes) extends from the skull base to the hyoid bone; level III (middle jugular lymph nodes) is the area between the hyoid bone and the lower border of the cricoid cartilage; level IV (lower jugular lymph nodes) is the area between the cricoid cartilage and the clavicle; level V is the posterior triangle; level VI is the anterior compartment from the hyoid bone to the suprasternal notch, bounded on each side by the medial carotid sheath; and level VII is the area of the superior mediastinum. Masses more than 3 cm in greatest dimension are generally groups of nodes or a single node, with the tumor extending into the soft tissues (20). Knowledge of the lymphatic
drainage of the neck assists the surgeon in planning the extent of neck resection and in locating a primary tumor when a palpable lymph node is the initial presentation.
FIG. 1.2. Diagram of the neck showing levels of lymph nodes. Level I, submandibular; level II, high jugular; level III, midjugular; levelIV, low jugular; level V, posterior jugular; level VI, tracheoesophageal; level VIII (superior mediastinal) is not shown. (Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer-Verlag, New York, http://www.springer-ny.com.)
Staging is based on physical examination and imaging tests. The staging system put forth by the American Joint Committee for Cancer (AJCC) (see Table 1.2) and the Union Internationale Contre le Cancer (UICC) [tumor, node, metastasis (TNM)] is used. The AJCC classification (20) emphasizes resectability status by dividing advanced disease stages into stage IVA (resectable), stage IVB (unresectable), and stage IVC (distant metastatic disease).
TABLE 1.2. TNM Staging of Head and Neck Tumors
The T classification indicates the extent of the primary tumor. It differs for each site. For primary tumors of the oral cavity, hypopharynx, and oropharynx, lesions greater than 4 cm are classified as T3. Vocal cord paralysis with a larynx or hypopharynx primary indicates at least T3. Lesions with local invasion of adjacent structures indicate T4.
The N classification is uniform for all primary sites, except nasopharynx. For all primary sites except nasopharynx, any clinical lymph node involvement indicates at least stage III, and nodes larger than a single 3-cm ipsilateral node are classified as stage IV regardless of T stage.
The presence of distant metastasis (M1) indicates stage IVC disease. Mediastinal lymph node involvement is considered distant metastasis.
Tumor grade has not shown significant association with outcome and is not considered when staging head and neck cancers.
Signs and symptoms are usually secondary to mass effect and/or pain from primary tumor or involved lymph nodes and invasion of adjacent structures or nerves (see Table 1.3) Adult patients with any of these symptoms for more than 4 weeks should be referred to an otolaryngologist. Delay in diagnosis is common: either patient delay or repeated courses of antibiotics for otitis media or sore throat, for example. A lateralized firm cervical mass in an elderly smoker is highly suggestive of squamous cell carcinoma. For nasopharyngeal cancers, the most common presenting symptom is a neck mass, sometimes in the posterior triangle. In advanced lesions, cranial nerve abnormalities may be present.
TABLE 1.3. Common Presenting Signs and Symptoms of Head and Neck Cancer
With the exception of hypopharyngeal and nasopharyngeal cancers, distant metastases are uncommon at presentation. The most common sites of distant metastases are lung and bone; liver involvement is less common.
The history should include:
The physical examination should include:
Abnormalities are suggested by asymmetry in the physical examination. Referral for direct and indirect laryngoscopy should be strongly considered for symptoms of hoarseness or sore throat not cured by a single course of antibiotics.
Friability (easy bleeding), an indicator of an early malignant process and erythroplakia (Table 1.1), is frequently associated with severe dysplasia or carcinoma in situ and the site should be biopsied. When neck mass is the first presentation, the primary site can be located and biopsied in approximately 80% of cases. If no primary site is obvious, tissue diagnosis
can be obtained by fine needle aspiration (FNA) biopsy of the node, with sensitivity and specificity approaching 99%. A nondiagnostic FNA does not rule out the presence of tumor.
Computerized tomography scan (CT scan) remains the primary imaging study for evaluation of metastatic adenopathy. Magnetic resonance imaging (MRI) may complement the CT scan. Positron emission tomography (PET) scans are being used more frequently to detect tumors that are not obvious on other scans, but this technique is still under evaluation (21,22).
Laryngoscopy and nasopharyngoscopy should be performed. With occult primary tumors, directed biopsies of the nasopharynx, tonsil, base of tongue, and pyriform sinus should be performed (see FIG. 1.3). Bilateral tonsillectomy will sometimes reveal the source of an occult cancer.
FIG. 1.3. Evaluation of cervical adenopathy when a primary cancer of the head and neck is suspected.
Surgical biopsy of a neck mass is contraindicated if a squamous cell carcinoma is suspected. Studies show that open biopsy may worsen local control, increase the rate of distant metastases, and decrease overall survival rate, possibly by spreading the disease at the time of the biopsy. Finally, an open biopsy does not provide any information additional to that obtained from FNA, and laryngoscopy is still necessary for treatment planning.
WORK-UP AND STAGING EVALUATION
After the diagnosis of cancer is established, the patient should be clinically staged by physical examination and radiologic studies, usually by CT scan and/or MRI of the primary tumor, neck, and chest. CT scan better defines the cortical bone and is better than MRI for evaluating metastatic adenopathy. MRI has superior soft tissue contrast, does not involve radiation, and may be better than CT scan for primary tumor staging. PET scanning is still undergoing evaluation for sensitivity and specificity (21,22). A chest radiograph or chest CT scan is indicated for all patients because of the risk of a second malignancy. Additional studies vary according to the clinical stage, symptoms, and primary site.
The most important determinant of prognosis is stage at diagnosis. The 5-year survival for stage I patients exceeds 80% but is less than 40% in stage III and IV disease. Most patients have locally advanced disease involving one or several lymph nodes on one or both sides of the neck. The presence of a palpable lymph node in the neck generally decreases the survival rate by 50% compared to the same T stage without node involvement.
Most relapses occur locoregionally. Distant metastases are more commonly seen later in the course of the disease, or as part of relapse after successful initial treatment, and predominantly involve lung, bone, and liver. The lifetime risk of developing a new cancer for a patient with head and neck cancer is 20% to 40% (6,8). After 3 years, development of a new cancer represents the greatest survival risk (seeTables 1.4, 1.5 and 1.6).
TABLE 1.4. Head and Neck Cancer: Oral Cavity
TABLE 1.5. Head and Neck Cancer: Oropharynx and Larynx
TABLE 1.6. Head and Neck Cancer: Hypopharynx, Nasal Cavity, Paranasal Sinuses, and Nasopharynx
Careful examination of the head and neck is warranted in individuals with risk factors or suggestive symptoms. Mucosal abnormalities and palpable neck masses should be biopsied (see the section, Diagnosis).
The United States Preventive Task Force (http://www.ahcpr.gov/clinic/uspstfix.htm) does not recommend regular screening for oral cancer in the general population but recommends counseling for cessation of tobacco use and limitation of alcohol intake. The American Cancer Society (http://www.cancer.org) recommends oral examination or dental appointments. The oral examination should include inspection of all mucosal areas, assessment of range of motion of tongue, bimanual palpation of floor of mouth, palpation of the tongue, and assessment of dental health. Any of the complaints described earlier require evaluation, especially if symptoms persist for more than 4 weeks or after treatment for presumed infection.
The management of patients with head and neck cancer is complex. The choice of treatment modality depends on the stage and site of disease. Patients with locally advanced disease should be evaluated (prosthodontics, nutrition, speech, and swallowing) by a multidisciplinary team including otolaryngologist or head and neck surgical oncologist, radiation oncologist, medical oncologist, dentist, and personnel involved in rehabilitation before treatment is initiated.
In general, either surgery or radiation is effective as single-modality therapy for patients with early-stage disease (stage I or II) for most sites. The choice of modality depends on local expertise, patient preference, and functional result. For the 60% of patients with locally advanced disease (stage III, IV, and M0), combined-modality therapy is indicated.
The nature of the surgical procedure is determined primarily by the size of the tumor and the structures involved. Extensive surgeries and those involving function of the tongue
frequently require myocutaneous flaps or microvascular free flaps to achieve a more functional reconstruction.
Resectability depends on the experience of the surgeon and the rehabilitation team. In general, a tumor is unresectable if the surgeon believes that all of the gross tumor cannot be removed or that local and distant control will not be achieved after surgery even with adjuvant radiation therapy. Generally, involvement of the skull base, pterygoid, and deep neck musculature, and of the major vessels portends a poor outcome with surgery as a primary modality.
Cervical lymph node dissections may be elective or therapeutic. Elective neck dissections are done at the time of surgery in patients with necks that are clinically negative when the risk of a positive lymph node is at least 30%. Therapeutic neck dissections are done for clinically obvious masses. Cervical lymph node dissections are classified as radical, modified radical, or selective. The radical dissection includes removal of all lymph nodes in the neck from levels I to V (Fig. 1.2), including removal of the internal jugular vein, spinal accessory nerve, and sternocleidomastoid muscle. This surgery is now rarely performed because of excessive morbidity, especially loss of shoulder function. The modified radical dissection preserves one or more of the nonlymphatic structures. In selective neck dissections, only certain levels of lymph nodes are removed on the basis of the specific lymphatic drainage from the primary site. With no palpable or CT scan evidence of clinical nodal involvement, nodal metastases will be present beyond the confines of an appropriate selective neck dissection less than 10% of the time. Sentinel lymph node dissection and PET scanning are currently being evaluated for use in diagnosing positive lymph nodes in patients with necks that are clinically negative.
The use of radiation as a single therapy in early-stage tumors (i.e., T1 and T2) is as efficacious as surgery. The choice of therapy depends on expected quality of life, functional outcome, sequelae of therapy, and options for treatment in case of recurrence.
In locally advanced tumors (i.e., T3 and T4), radiation therapy is combined with surgery. In general, postoperative radiation is preferred over preoperative radiation according to the results of two randomized prospective studies that show superior local control and minimally increased survival in the postoperative radiation arm in hypopharyngeal cancer patients (23).
Postoperative radiotherapy is recommended for patients at high risk for local recurrence [i.e., T4 tumor, close or positive margins (<5 mm), perineural or perilymphatic or vascular invasion by the tumor, multiple or large positive nodes, and/or extracapsular invasion (23)].
The radiation type (i.e., dose, fractionation regimen, and indication for brachytherapy) varies for specific sites and for definitive versus adjuvant therapy. The standard fractionation regimen in the United States is 1.8 to 2.0 Gy once daily, 5 days per week. The total dose of irradiation for definitive treatment is in the range of 70 to 80 Gy depending on the treatment schedule given and on the ability to shield normal tissue. Recent large randomized trials of hyperfractionated accelerated radiation as the primary treatment modality in locally advanced disease have shown improved local control but no or minimally increased survival with b.i.d. or t.i.d. fractionation as well as with the “concomitant boost” technique, in which radiation is given daily early in the course, then twice daily at the end of the course, with the second treatment representing a “boost” volume (24,25). Most of these regimens result in increased acute toxicities but similar long-term toxicities compared to daily fractionation. Conformal and Intensity Modulated Radiation Therapy techniques are being used to conform and confine the radiation dose to the tumor while maximally sparing the normal tissue, particularly salivary glands (26,27).
Common severe acute radiation toxicity includes epidermitis, mucositis, loss of taste, xerostomia, dysphagia, and hair loss. Dental evaluation and necessary extractions should be performed before radiation because dental extractions in a radiated mandible can lead to osteonecrosis (28). Dentulous patients should be given prophylactic fluoride. Patients receiving radiation are at high risk for tooth decay due to the xerostomia caused by injury to the salivary glands as well as mucosal damage. The drug amifostine has been shown in a randomized trial to decrease the
incidence of chronic severe radiation-induced xerostomia from 57% to 34% in patients receiving postoperative radiation (single agent) to a maximal dose of 60 cGy (29).
Brachytherapy can be used as a definitive treatment for early-stage tumors or combined with external beam radiation in more advanced lesions in selected tumors (e.g., tongue, floor of mouth, tonsil, and nasopharynx) with excellent results. Brachytherapy is an option for recurrent cancers of the head and neck, particularly in previously irradiated patients.
Until relatively recently, chemotherapy was used mainly for palliation of patients with locally recurrent or disseminated disease without proven survival advantage. Combination chemotherapy yields higher response rates but has increased toxicity and no proven survival advantage when compared with single agents. The choice of single-agent or combination chemotherapy depends on the patient's preference and performance status.
Single agents with more than 10% response activity are listed in Table 1.7(30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50). Several Combination regimens have been developed to improve response rates. (see Table 1.8) (51,52,53,54,55,56,57). The combination of cisplatin and infusional 5-fluorouracil (5-FU) produces a 70% response rate and a 27% complete remission (CR) rate in chemotherapy-naive patients (58), but the response rate is 30% to 35% in patients who have relapsed after radiation therapy.
TABLE 1.7. Active Chemotherapeutic Agents for Squamous Cell Cancer of the Head and Neck
TABLE 1.8. Active Combination Chemotherapeutic Regimens for Squamous Cell Cancer of the Head and Neck
Platinum-based chemotherapeutic regimens and the single agent methotrexate are the most commonly used regimens for metastatic disease. Carboplatin may be slightly less active than cisplatin for head and neck squamous cancer, but carboplatin combinations with other chemotherapy agents are generally better tolerated than those with cisplatin. Carboplatin is preferred in patients at high risk for cisplatin toxicity, that is, those with renal dysfunction, neuropathy, or hearing loss (59).
Both docetaxel and paclitaxel have shown antitumor activity (39,40,41,42,43,44). Several dosing schedules for paclitaxel have been investigated. Three-hour infusions are probably the best balance between theoretically optimum exposure and tolerable toxicity (60). Docetaxel is usually administered at doses of 60 to 100 mg per m2 every 3 to 4 weeks. Weekly schedules are being evaluated for both drugs. Taxane combinations, including paclitaxel with ifosfamide and cisplatin or carboplatin, and docetaxel with cisplatin and 5-FU (61) show promising response rates.
Prior to the use of taxane combinations, meta-analyses and randomized trials demonstrated improved response for cisplatin compared with methotrexate, improved response for cisplatin and 5-FU combination compared with single drugs, and improved response for cisplatin and 5-FU combination when compared with other regimens for treatment of recurrent or metastatic head and neck squamous cancer (62,63). In the metastatic or recurrent setting, the response rate of cisplatin and infusional 5-FU combination (Table 1.8) is approximately 30%, with less than 10% complete responses. A randomized trial of cisplatin and 5-FU versus carboplatin (300 mg per m2) and 5-FU versus weekly methotrexate in patients with recurrent or metastatic head and neck squamous cancers demonstrated response rates of 32%, 21%, and 10%, respectively. Median survival was not improved by combination chemotherapy (6.6, 5.0, and 5.6 months, respectively) (51).
The role of chemotherapy has expanded significantly over the last decade because of the results of clinical trials incorporating chemotherapy in multimodality regimens for previously untreated disease.
Studies have evaluated the use of chemotherapy administered before (i.e., neoadjuvant or induction chemotherapy), during (i.e., concomitant chemotherapy), or after (i.e., adjuvant chemotherapy) radiation therapy or surgery.
Combined modality (chemoradiation) is indicated for patients with locally advanced disease that would require total laryngectomy if treated by surgery and who wish to preserve the larynx, for patients who are technically resectable but who are not medically fit enough for surgery, and for patients with technically unresectable locally advanced cancer. In the patient who presents with locally advanced tumor concomitant with distant metastasis, local control of the disease may prevent infectious and necrotic complications.
Induction chemotherapy followed by definitive radiation therapy in patients responding to chemotherapy has been studied for organ preservation in patients with locally advanced cancers of the larynx and of the hypopharynx. No significant survival difference has been demonstrated for chemotherapy followed by radiotherapy compared to surgery followed by radiotherapy in these patients (64,65). Close follow-up is indicated in the event that salvage surgery is needed. For laryngeal cancer, concomitant cisplatin and radiation therapy leads to better local control and organ preservation than neoadjuvant chemotherapy and radiation or radiation alone (66). Induction chemotherapy followed by radiation did not show any benefit when compared to radiation alone.
Presently, induction chemotherapy followed by radiation therapy can be considered standard only for patients with previously untreated locally advanced squamous cancers in the hypopharynx. Cisplatin, 100 mg per m2 IV, on day 1 and 5-FU, 1,000 mg per m2 daily as continuous IV infusion, for 5 consecutive days (days 1 to 5), repeated every 3 weeks, followed by radiation therapy in patients who were complete responders exhibited equivalent survival rates in a phase III trial compared to surgery followed by radiation therapy (65). Induction chemotherapy does not increase surgical or radiation therapy complications. Prognostic factors for survival include performance status, tumor site, and stage.
The rationale for concomitant chemoradiation is based on experimental evidence of synergism between chemotherapy and radiation that is theoretically mediated by interference of chemotherapy with multiple intracellular radiation-induced stress-response pathways involved in apoptosis, proliferation, and DNA repair (67). The finding that certain chemotherapeutic agents (e.g., cisplatin, 5-FU, taxanes, and hydroxyurea) can induce radiosensitivity and increase log cell kill for radiation supports this treatment strategy. Cisplatin, the most extensively evaluated drug in recent large randomized trials, has the advantage of not having mucositis as toxicity, although as a radiation enhancer, it does increase radiation-induced mucositis.
Recent meta-analyses and randomized clinical trials published before 1994 show that for locally advanced head and neck squamous cell carcinoma, concomitant chemoradiation produces a small but significant survival advantage of about 8% compared to radiation therapy alone (68,69,70). The U.S. intergroup compared concomitant cisplatin and radiation to split-course radiation with cisplatin and 5-FU to standard radiation alone in patients with unresectable head and neck squamous cancer and showed that concurrent cisplatin at 100 mg per m2 every 21 days with daily radiation significantly improved survival rates (71). A randomized trial of cisplatin and 5-FU followed by radiation versus concurrent cisplatin and 5-FU with radiation in patients with unresectable head and neck cancer showed similar survival rates but improved locoregional control for the concomitant arm. This early study highlighted the importance of aggressive supportive care for concomitant regimens, including adequate fluid and electrolyte support (72). Concomitant platinum-based chemoradiation has become standard therapy for patients with unresectable advanced head and neck cancer with good performance status.
Although no randomized phase III trial has been done, results using taxanes with 5-FU and/or cisplatin show promising results as do regimens containing 5-FU and hydroxyurea with concomitant twice-daily radiation, with both chemotherapy and radiation administered together every other week (73). A phase randomized II study compared three regimens of concurrent chemoradiation for stage III or IV head and neck squamous carcinoma in 241 patients: a continuous infusion of cisplatin (10 mg/m2/day) and 5-FU (400 mg per m2) daily for the final 10 days of once-daily radiation (chemotherapy boost), hydroxyurea (1 g every 12 hours) and 5-FU (800 mg/m2/day) continuous infusion for 5 days with radiation (entire regimen given every other week), or paclitaxel (30 mg per m2) and cisplatin (20 mg per m2) given weekly with daily radiation. Grade 4 or greater toxicity occurred in 22%, 29%, and 23% of patients in each arm, respectively, although three deaths occurred in the chemotherapy boost arm. The estimated
2-year disease-free and overall survival rates were 38.2% and 57.4%, 48.6% and 69.4%, and 51.3% and 66.6%, respectively (74).
Current studies are evaluating the possibility that induction chemotherapy followed by chemoradiation and/or surgery can increase locoregional disease-free and overall survival rates for patients with locally advanced head and neck squamous cancer.
Agents that inhibit epidermal growth factor receptor (EGFR) signaling are being evaluated as radiation enhancers in head and neck squamous cancers. More than 90% of head and neck squamous cancers express EGFR (75), and increased expression has been correlated with poorer survival rates after radiation therapy (76,77). Upregulation of EGFR after radiation has been noted in cell lines (78). Blocking EGFR signals enhances radiosensitivity and chemotherapy effects in preclinical models (79). Clinical studies are ongoing with combinations of EGFR inhibitors with radiation and with standard chemotherapy agents. A recent phase III trial of cisplatin with either placebo or the EGFR antibody C225 in patients with metastatic or recurrent head and neck squamous cancer found no significant advantage in adding the EGFR inhibitor (80). Additional molecular alterations, in addition to expressing EGFR, are likely to be important for response to EGFR inhibitors.
Elective lymph node dissection is often carried out after chemoradiation in patients with N2, N3, or multiple nodes at diagnosis, regardless of nodal response to chemoradiation, when complete response is obtained at the primary site. N2 or greater nodes often (about 20%) harbor tumor even if a clinically complete response is obtained in the neck with chemoradiation (81). Surgical salvage may be attempted if complete control is not achieved at the primary or locoregional site. Major complications with surgical salvage are found in about 52% of patients previously treated with organ-preserving regimens (82).
As expected, concomitant regimens are associated with increased toxicity compared with sequential chemoradiation. Patients should be followed closely for dehydration, electrolyte abnormalities, and adequacy of nutritional intake. Most centers place enteral feeding tubes prophylactically prior to the start of treatment for patients undergoing concomitant chemoradiation because the incidence of grade 3 or greater mucositis is 70% to 80%.
A large randomized study in resected patients with stage III or IV disease compared adjuvant radiation therapy with adjuvant chemotherapy followed by radiation. This trial showed improved local control and overall survival rates approaching statistical significance for a subset of patients treated with chemotherapy who were at high risk for local recurrence. Patients with low-risk disease (negative resection margins, one or no positive nodes, and no extracapsular spread of tumor) did not benefit from adjuvant chemotherapy (83).
Adjuvant concomitant cisplatin and radiation in patients at high risk for recurrence after surgery has been studied both in Europe and in the United States. Both studies found a possible benefit in disease-free or overall survival for patients receiving concomitant cisplatin and radiation (84,85).
SITE-SPECIFIC HEAD AND NECK TUMORS
The oral cavity includes the lip, anterior two thirds of the tongue, floor of the mouth, buccal mucosa, gingiva, hard palate, and retromolar trigone. Approximately 20,000 new cases are diagnosed annually in the United States. Squamous cell carcinoma is the histologic type observed in most cases.
The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites are shown inTable 1.4. Early lesions (stages I and II) are treated with surgery or radiation therapy as single-modality therapy. For resectable locally advanced disease (stages III and IV, and M0), surgery followed by radiation therapy is
indicated (see FIG. 1.4). Definitive radiation therapy with or without chemotherapy is an option for patients with resectable disease at any stage who have high medical or surgical risks, or according to patient preference (based on discussions about quality of life, functional outcome, and toxicity profile of each treatment). Treatment for locally advanced and metastatic disease is discussed in subsequent text.
FIG. 1.4. Treatment for head and neck squamous cell carcinomas (M0).
The oropharynx includes the base of the tongue, tonsils, posterior pharyngeal wall, and the soft palate.
The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the oropharynx are shown in Table 1.5. Treatment may include primary surgery and postoperative radiotherapy or primary radiation therapy, with chemotherapy if stage III or IV, thereby reserving surgery for management of regional node metastases or for salvage of persistent disease. Chemoradiation is an acceptable standard of care for treating locally advanced oropharyngeal cancer when organ preservation is desired. Randomized trials show that concurrent chemotherapy and radiotherapy significantly improve locoregional control and survival compared with radiotherapy (86). Increased complexity and toxicity of this combined-modality approach mandates that the patient has adequate performance status and psychosocial resources.
More than 9,500 cases of laryngeal cancer were diagnosed in the United States in 2003. Risk factors are a history of tobacco and/or alcohol intake. In addition, certain dietary factors and exposure to wood dust, nitrogen mustard, asbestos, and nickel have been implicated as etiologic factors. The male-to-female ratio for laryngeal cancer is 4.5:1, with a peak incidence in the sixth decade of life. This disease is 50% more common in African Americans than in whites and 100% more common in whites than in Hispanics and Asians. More than 95% of laryngeal cancers are squamous cell carcinomas.
Laryngeal cancers can be supraglottic, glottic, and/or subglottic. The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the larynx are shown in Table 1.5.
Early cancers not requiring laryngectomy (T1–T2 N0) are usually treated with radiation. If lymph nodes are involved, neck dissection and/or neck radiation is indicated. Locally advanced resectable tumors (T3–T4 or T2 N+) may be treated with surgery and adjuvant radiation if locoregional risk factors are present (i.e., close or positive margins, T4 tumor, lymphatic or vascular or perineural involvement, vascular invasion, multiple positive nodes, extracapsular invasion, subglottic extension, or prior tracheostomy). An alternative is the use of combined radiation and chemotherapy. In 1991, the Veterans Administration Laryngeal Study Group trial established (64) that sequential chemotherapy with cisplatin and infusional 5-FU followed by radiation therapy in highly responsive patients resulted in equivalent survival and a larynx preservation rate of about 66% compared to treatment with surgery followed by radiation. However, high volume T4 disease (with destruction of larynx or massive extension of supraglottic laryngeal cancer to the base of tongue) should be treated with surgery followed by radiation therapy rather than by organ preservation therapy, if possible.
A subsequent randomized phase III trial conducted in the United States comparing radiation therapy alone, sequential chemotherapy and radiation therapy, and concomitant cisplatin and radiation therapy for organ preservation in patients with locally advanced laryngeal cancer demonstrated that concurrent cisplatin (100 mg per m2 on days 1, 22, and 43) and radiation therapy resulted in better laryngectomy-free survival, larynx preservation rate, and local–regional control rate than either sequential (induction) cisplatin and 5-FU followed by radiation therapy or radiation therapy alone. Induction chemotherapy followed by radiotherapy was shown to have no advantage over radiotherapy alone. Survival rate was not significantly different for the three treatments, in part reflecting the ability to surgically salvage laryngeal cancer patients treated for organ preservation. It is of interest to note that patients who received any chemotherapy regardless of receiving radiotherapy or not had a lower metastatic rate at 2 years than did patients who received radiation alone (66).
Speech rehabilitation is critically important for patients with advanced laryngeal cancer who are undergoing total laryngectomy. Phonation options include a mechanical electrolarynx, esophageal speech, and tracheoesophageal puncture. Most patients can obtain satisfactory communication through one of these techniques.
Patients whose lesions are unresectable or patients who are considered to have high surgical risks are candidates for definitive radiation therapy with chemotherapy if performance status is good. The treatment for a patient with metastatic disease is discussed later.
The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for specific subsites of the hypopharynx are shown in Table 1.6.
Early cancers not requiring laryngectomy (most T1 N0–N1; small T2 N0) can be treated with surgery or radiation. Locally advanced resectable tumors (T3–T4 any N) may be treated with surgery followed by radiation or sequential or concomitant chemoradiation. In these cases, surgery involves total laryngectomy and partial or total pharyngectomy and neck dissection.
Even with this radical surgery and the consequent functional impairment of the tumor, the survival prognosis is poor.
Combined-modality treatment with chemotherapy and radiation allows organ function preservation with chances of survival being equivalent to that after surgery. Patients who achieve a CR at the primary site after two to three cycles of induction chemotherapy (Table 1.6) receive definitive radiation, whereas those achieving less than CR at the primary site undergo surgery. A large randomized trial is in progress comparing induction chemotherapy followed by radiation therapy to concomitant chemoradiation in patients with hypopharyngeal cancer. The outcome of this trial will provide more definitive information on the most efficacious therapy.
Patients who are prone to high surgical or medical risks can be treated with radiation. The management of metastatic disease is discussed later.
Nasal Cavity and Paranasal Sinuses
The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for carcinomas of the nasal cavity and paranasal sinuses are shown in Table 1.6.
Most tumors are squamous cell carcinomas and are usually slow growing with low incidence of metastasis.
Carcinomas of the nasal cavity and paranasal sinuses are usually detected in patients in advanced stages because of the relatively silent tumor location. Treatment follows the same general guidelines as those for oral cancer. If feasible, surgery is the preferred primary management.
The epidemiology, natural history, common presenting symptoms, risk of nodal involvement, and prognosis for nasopharyngeal cancer are shown in Table 1.6. It is extremely rare in most parts of the world, with an incidence of less than 1 case per 100,000 population. However, it is endemic in certain areas, including North Africa, Southeast Asia, China, and the far northern hemisphere. EBV is strongly associated with nasopharyngeal carcinoma. This association has been demonstrated by serologic studies and by the detection of the viral genome in tumor samples. Diet (salt-cured fish and meat) and genetic susceptibility are other probable risk factors; tobacco and alcohol are not risk factors, except in a minority of cases.
The World Health Organization (WHO) classification divides nasopharyngeal carcinoma into three types: type I, keratinizing squamous cell carcinoma; type II, nonkeratinizing squamous cell carcinoma; and type III, undifferentiated carcinoma (20). Type II, the most common, is also sometimes referred to as lymphoepithelioma because of the characteristic exuberant lymphoid infiltrate accompanying malignant epithelial cells.
The most common initial presentation is a neck mass. Other presenting signs and symptoms are related to tumor growth, with resulting compression or infiltration of neighboring organs. These include serous otitis media, nasal obstruction, tinnitus, pain, and involvement of one or multiple cranial nerves.
Nasopharyngeal carcinoma has a high metastatic potential to regional nodes and distant sites. WHO type I has the greatest propensity for uncontrolled local tumor growth and the lowest propensity for metastatic spread (60% clinically positive nodes) compared with WHO type II and type III cancers (80% to 90% clinically positive nodes). Even though type I WHO cancer is associated with a lower incidence of lymphatic and distant metastases than are types II and III, its prognosis is worse because of a higher incidence of deaths from uncontrolled primary tumors and nodal metastases.
The prognoses for different stages of nasopharyngeal carcinoma are shown in Table 1.6.
General treatment guidelines are shown in FIG. 1.5. Surgery is usually not recommended because of anatomic considerations and the pattern of spread of the cancer via the retropharyngeal lymphatics. Radiation has been the standard treatment, with good results (local control
rates: T1–T2, 70% to 90%; T3–T4, 30% to 65%), and remains the standard of care for early (stages I and II) cancer.
FIG. 1.5. Treatment of nasopharyngeal carcinoma (M0).
In a randomized trial in the United States, concurrent cisplatin (cisplatin 100 mg per m2 every 21 to 28 days) and daily radiation followed by three courses of adjuvant cisplatin and 5-FU was shown to improve overall survival (76% for concurrent chemoradiation versus 46% for radiation therapy alone) (87). On the basis of this study, concurrent chemoradiation followed by adjuvant chemotherapy is considered standard treatment for locally advanced nonmetastatic (stages III and IV) nasopharyngeal cancer in the United States. Other drugs, such as taxanes, appear to have activity but have not been evaluated extensively.
ADVANCED HEAD AND NECK TUMORS: UNRESECTABLE, RECURRENT, AND METASTATIC DISEASE
In patients with good performance status (ECOG 0-1), concurrent radiation and chemotherapy is considered standard treatment for patients with newly diagnosed locally advanced unresectable disease. In several recent trials, chemoradiation therapy was shown to improve the overall survival, disease-free survival, and/or local control when compared with radiation therapy alone. Several cisplatin- or carboplatin-containing regimens and several standard and altered fractionation-radiation regimens have been evaluated. In patients with poor performance status, radiation alone is a reasonable option.
Local or regional recurrences can sometimes be salvaged by radiation therapy or surgery. In patients unable to undergo resection, re-irradiation with a dose of 60 cGy with or without concomitant chemotherapy can achieve prolonged survivals in about 15% to 20% of highly selected patients (88). In nasopharyngeal carcinoma, a second course of radiation may be delivered. If salvage is not possible, palliative treatment will be guided by the performance status of the patient.
Single-agent or combination chemotherapy is indicated for palliation of patients with good performance status with local or distant recurrence and of those patients presenting with distant metastasis. Combination chemotherapy achieves higher response rates at the cost of increased toxicity when compared with single-agent chemotherapy. The most active agents are listed in Table 1.7. Cisplatin plus infusional 5-FU (Table 1.8) or cisplatin with a taxane are the most commonly used combination-chemotherapy regimens. Weekly methotrexate or taxanes have also shown some activity in patients with advanced head and neck tumors. Oral agents, such as gefitinib (Iressa) may have some palliative effect (30,31,32,50). The choice of single-agent or combination chemotherapy (61) depends on preference and performance status of patients. Patients with good performance status, no prior chemotherapy for treatment of recurrent disease, and minimal tumor burden may benefit most from combination chemotherapy. A small subset of these patients may achieve durable CR and prolonged survival. However, the median response duration to combination or single-agent chemotherapy is about 3 months.
The median survival for patients with locally recurrent or disseminated disease is 6 to 9 months, and only 20% to 30% are alive at 1 year. No therapy has been shown to affect survival rate. Therefore, whenever possible, patients should be encouraged to enroll in clinical trials that evaluate new agents or new combination regimens.
Cancer of Unknown Primary Site (of the Head and Neck)
The work-up of a patient with a neck mass is shown in Fig. 1.3. In 10% of cases, a primary tumor is not found, and the term “cancer of unknown primary site” is used.
Cervical lymph node involvement (except supraclavicular) by carcinoma indicates a head and neck primary tumor. Unknown primary tumors of the head and neck are usually treated with neck dissection and radiation. The prognosis is roughly equivalent to cancers with the same N (nodal) status. Five-year survival ranges from 30% to 50% in patients treated definitively.
A supraclavicular mass often represents spread from an infraclavicular (thoracic or abdominal) cancer, and the work-up and treatment of these cancers is beyond the scope of this chapter.
Salivary Gland Cancer
Salivary gland cancers make up about 3% of all head and neck cancers diagnosed in the United States yearly. Tobacco and alcohol consumption are not risk factors, except possibly in women. Ionizing radiation and certain occupational exposures (e.g., in workers in rubber and automotive industries, wood workers, and farm workers) have been associated with the development of salivary gland cancer.
The salivary glands are classified as major (parotid, submandibular, and sublingual) and minor (distributed along upper aerodigestive tract, predominantly in the oral and nasal cavities and the paranasal sinuses). Most of the salivary gland cancers arise from the parotid glands; sublingual and minor salivary gland cancers are rare.
Most salivary gland tumors are benign, and the most common histology is pleomorphic adenoma, which is characterized by slow growth and few symptoms, and is most frequently seen in the parotid gland. The most common presentation of benign salivary gland tumors is asymptomatic swelling of the lip, the parotid, or the submandibular or the sublingual glands. Persistent pain or neurologic involvement (mucosal or tongue numbness and facial nerve weakness) suggests malignant disease. The benign salivary gland tumors are listed in Table 1.9.
TABLE 1.9. Salivary Gland Benign Tumors
The clinical characteristics and prognosis of specific malignant salivary gland tumors are shown in Table 1.10.
TABLE 1.10. Salivary Gland Malignant Tumors: Clinical Characteristics and Prognosis
Surgery is the mainstay of treatment for all localized stages of salivary gland tumors. Postoperative radiation is indicated for localized tumors of high-grade histology, that are large, with close or positive margins, and/or positive regional lymph nodes. Radiation is the primary treatment for unresectable tumors. The role of chemotherapy is limited to the management of locally recurrent, unresectable disease or distant metastatic disease. There is no established standard chemotherapy for salivary gland cancer. Regimens employing cisplatin, carboplatin, anthracyclines, taxanes, cyclophosphamide, and 5-FU result in transient responses in 14% to
30% of patients with adenocarcinoma or mucoepidermoid carcinoma (89), but the effect on survival is unknown. Patients with good performance status should be encouraged to enter clinical trials.
Curative treatment of patients with head and neck cancer should be followed by a comprehensive head and neck physical examination every 1 to 3 months during the first year after
treatment, every 2 to 4 months during the second year, every 3 to 6 months from years 3 to 5, and every 6 to 12 months after year 5. The thyroid-stimulating hormone (TSH) level should be checked every 3 to 6 months if the thyroid is irradiated. Generally, thyroid hormone replacement therapy should begin when, and if, TSH remains stably elevated, before symptoms of hypothyroidism appear. Up to 50% of patients will develop hypothyroidism by 5 years after radiation therapy to the head and neck. Patients with nasopharyngeal tumors who were treated with radiation are at risk for pituitary failure (90,91).
The highest risk of relapse is during the first 3 years after treatment. After 3 years, a second primary tumor in the lung or head and neck is the most important cause of morbidity or mortality. Because of this risk, a semiannual chest radiograph is recommended. Some recurrences, as well as second primaries, can be treated with curative intent.
OTHER HEAD AND NECK TUMORS
Soft tissue sarcomas of the head and neck are relatively rare. Of head and neck sarcomas, 80% are seen in adults and 20% are in children. These tumors are heterogeneous and can present in any head and neck site, commonly as a submucosal or subcutaneous painless mass. In the hypopharynx and nasopharynx, the presenting symptoms may be cranial nerve abnormalities or airway or swallowing difficulties. As in sarcomas at other sites, grade is an important prognostic indicator. High-grade, aggressive tumors such as malignant fibrous histiocytoma, angiosarcoma, osteogenic sarcoma, neurofibrosarcoma, and soft part sarcomas tend to be locally aggressive and spread along neurovascular structures, fascia, and bone. In addition to aggressive local behavior, there is a high risk for metastatic disease, particularly in lung, bone, central nervous system, and liver. Metastatic disease may occur without local lymph node involvement. Sarcomas may arise after radiation therapy, but this is very uncommon in the head and neck region. The prognosis for these secondary sarcomas may be worse than for primary sarcomas.
Treatment depends on stage, age of the patient, tumor type, location, and size. Wide margin en bloc resection is the goal, but may not be possible because of the proximity of vital structures. Adjuvant postoperative radiation and/or brachytherapy can improve local control in aggressive sarcomas. The major indications for adjuvant radiation are high-grade sarcomas or positive margins, lesions greater than 5 cm, and recurrent sarcoma. Elective neck radiation is not necessary because the incidence of occult positive lymph nodes is low. Soft tissue and possibly osteogenic sarcomas may benefit from adjuvant or neoadjuvant chemoradiation. Such patients should be referred to clinical trials when possible. Overall survival rate approaches 60% for patients with sarcomas of the head and neck (92,93).
Mucosal melanomas represent less than 1.5% of all melanomas. About 50% of mucosal melanomas occur in the head and neck, and more than 20% of melanomas that occur in the head and neck region are mucosal. The age of diagnosis is 60 to 80 years. The hard palate is the most common site. Nearly one-third of these tumors are amelanotic. The proportion of mucosal melanomas is higher in African American and Hispanic populations than in white populations. Although rare in the United States, mucosal melanomas are more frequent in Japan and in some parts of Africa. Mucosal melanomas may be multiple, may have satellite lesions, may invade angiolymphatics, and can metastasize. They behave more aggressively than skin melanomas. Lymph node metastasis is observed at presentation in up to 48% of patients. Surgery is the mainstay of treatment for local or locoregional disease. Prophylactic lymph node dissection is not recommended. Radiation, when used, is usually employed adjuvantly for positive margins or used palliatively for local recurrence or unresectability. Adjuvant use of radiation has not been shown to improve survival. Prophylactic nodal radiation is not recommended. Chemotherapy and
immunotherapy have been studied, but the effect of these interventions on survival when used as palliation or as adjuvant therapy has not been defined. Patients should be encouraged to enter clinical trials where available. Mean overall 5-year survival is 17% (range 0% to 48%) (94).