The Washington Manual of Oncology, 3 Ed.

Head and Neck Cancer

Douglas Adkins • Loren Michel • Tanya Wildes • Jessica Ley • Wade Thorstad • Brian Nussenbaum

 I. APPROACH TO THE HEAD AND NECK CANCER PATIENT. Although there are many similarities between head and neck cancers arising from different sites, there are important site-specific differences in anatomy, etiology, molecular biology, and natural history. Collectively, these differences produce functional consequence that must be considered when deciding the optimal treatment approach. In addition, patients with head and neck cancer often have comorbid illnesses related to the effects of tobacco and alcohol use that may further complicate therapy.

1. BACKGROUND
2. Squamous cell cancer of the head and neck (SCCHN) is an example of the multistep process of carcinogenesis consisting of accumulated genetic mutations that result in histologic changes ranging from hyperplasia to dysplasia to carcinoma in situ to invasive cancer. A number of genetic aberrations have been identified. Loss of tumor suppressor gene function, including p16, p53, and RB, are frequent, and amplification of the proto-oncogene cyclin D1, overexpression of the epidermal growth factor receptor (EGFR), and mutations in NOTCH1, FBXW7, and FAT1 also occur.
3. Risk factors. For most patients, tobacco, often augmented by alcohol, is the source of carcinogens that results in these genetic aberrations. The incidence of new cancers of the head and neck is estimated at 45,000 per year in the United States, most of which are smoking-related. These figures underscore the importance of educating patients about smoking cessation. The male-to-female ratio is approximately 3:1. Among nonsmokers (estimated 15% of patients with SCCHN), viruses, including human papilloma virus (HPV) and Epstein–Barr virus (EBV), are causal factors. While smoking may induce SCC across all oral mucosal sites, HPV and EBV are most strongly implicated in the development of SCC of the oropharynx and nasopharynx, respectively.

 III. OVERVIEW OF THERAPY FOR CANCERS OF THE HEAD AND NECK

1. General considerations. Care of patients with cancers of the head and neck requires a multidisciplinary team that includes specialists in surgery, radiation oncology, medical oncology, nursing, speech pathology, dentistry, and supportive care. Nutritional support often plays an essential role in the care of these patients because swallowing may be impaired by the disease or as a consequence of therapy. Placement of a gastrostomy tube is often needed to provide an avenue to administer nutrition, fluids, and medications. Narcotics (transdermal and oral) are necessary to control pain due to tumor or treatment-related effects. The functional status of the patient and location of the tumor play a key role in determining the management of the patient. The following overview addresses the approach to the patient with SCCHN. Variation in therapy does occur, depending on site, and these variations will be discussed in their appropriate sections.

The staging system for all sites of head and neck cancer, except for nasopharyngeal cancer, follows the same principles. T stage is subdivided into T0 (no evidence of primary tumor), T1 (≤2 cm), T2 (>2 but ≤4 cm), T3 (>4 cm), T4a (moderately advanced), and T4b (very advanced). N stage is subdivided into N0 (no regional lymph node involvement), N1 (single ipsilateral lymph node ≤3 cm), N2a (single ipsilateral lymph node >3 cm but ≤6 cm), N2b (multiple ipsilateral lymph nodes, none >6 cm), N2c (bilateral or contralateral lymph nodes, none >6 cm), and N3 (lymph node >6 cm). M stage is divided into M0 (no distant metastases) and M1 (distant metastases present). Stages I and II are defined by the presence of T1N0M0 and T2N0M0, respectively. Stage III is defined by T3N0M0 or T1-3N1. Stage IV may be subdivided into IVA (T4aN0-1M0 or T1-3N2), IVB (T4bN0-3M0 or T0-4N3), and IVC (any T and N plus M1).

1. Management of early-stage cancers (stage I to II). Early-stage SCCHN is managed with either surgery or definitive radiation therapy. Both approaches have similar cure rates. Advantages of surgery include shorter treatment and recovery time and avoidance of radiation toxicity including mucositis, xerostomia, and dental caries. However, surgery can result in organ dysfunction including speech and/or swallowing problems, particularly with open techniques, and has limited applicability in patients with poor performance status and comorbidities. Radiation therapy is an alternative to a surgical procedure that would result in unacceptable cosmesis and/or organ function. However, radiation therapy is given over an extended interval, and resolution of acute toxicities often requires several months. Also, chronic radiation toxicity (particularly xerostomia) is common, but can be somewhat mitigated with advanced techniques. Regional differences in the general approach to early-stage cancers exist, often hinging on advanced surgical or radiation expertise among members of the treatment team. The ultimate goal is a high cure rate with minimum morbidity.
2. Management of locally advanced, nonmetastatic disease (III to IVB)
3. Primary surgery. Surgery to remove all visible tumors may be used as the initial therapy for locally advanced cancers of the head and neck. Current approaches to surgery increasingly involve procedures such as transoral endoscopic CO₂ laser or robotic resection and selective neck dissections. In contrast to open procedures and radical neck dissections, these more recent approaches to surgery lower the morbidity of the procedure and improve the likelihood of acceptable postoperative function. Following complete resection, adjuvant radiation-based therapy is usually recommended to most patients with locally advanced disease. In some patients, a biopsy of the primary tumor by the surgeon and fine needle aspiration biopsy of suspicious regional nodes is performed for diagnosis, after which the patient is referred for definitive radiation-based therapy. Critical information regarding the delineation of tumor can be obtained with operative-based and sometimes with office endoscopy prior to proceeding with definitive nonsurgical therapies.
4. Adjuvant therapy. Following complete tumor resection, adjuvant therapy with postoperative radiation (POART) or radiation and concurrent chemotherapy (POACRT) is usually given to patients with locally advanced disease. Adjuvant therapy is recommended when there is involvement of one or more cervical lymph nodes, perineural involvement, lymphovascular invasion, and/or a positive surgical margin at the site of primary tumor resection. The total radiation dose in the adjuvant setting is 60 to 66 Gy administered to the primary and involved lymph nodes, and 50 Gy to lower risk nodal stations in the neck. The duration of radiation therapy is 6 to 7 weeks, with treatment optimally starting 4 to 6 weeks postoperatively. The exact fractionation schema, portals, and use of boost-dose radiation are determined by site. POACRT is recommended for tumors with high-risk pathologic features: involved cervical lymph nodes with extra-nodal extension and/or positive surgical margins (N Engl J Med 2004;350:1937; N Engl J Med 2004;350:1945). Some also include the following as high-risk features: tumors with perineural and lymphovascular invasion, multiple positive cervical nodes, and/or large (T3 or T4) primary tumors.
5. Definitive chemoradiation. Concurrent chemotherapy and radiation (CRT) is the standard of care for the nonsurgical management of locally advanced cancers of the head and neck in patients who are able to tolerate such therapy (those with good performance status and few or no comorbidities). The MACH-NC meta-analysis of 93 randomized trials of 17,346 patients demonstrated a significant overall survival (OS) benefit with CRT compared with radiation therapy alone (Radioth Oncol 2009;92:4). The OS benefit is 6.5% at 5 years with CRT. However, the acute toxicity (particularly mucositis and renal dysfunction) of CRT is greater than that of radiation alone, which may partly explain why the OS benefit of CRT is greatest for patients under age 60 years and who have good performance status and few comorbidities.

 Several chemotherapy agents have been combined concurrently with radiation therapy; however, the most commonly used agent is cisplatin. Recently, the EGFR inhibitor cetuximab was also shown to improve OS when given concurrently with definitive radiation therapy. Other chemotherapy agents that may be given with radiation therapy include carboplatin or taxanes (paclitaxel or docetaxel).

 Cisplatin is widely recognized as the gold standard that other agents are compared to when given concurrently with radiation therapy in SCCHN. Two common regimens include cisplatin 100 mg/m²administered on days 1, 22, and 43 of radiation or cisplatin 30 to 40 mg/m² administered weekly during radiation.

 A randomized trial of cetuximab given concurrently with radiation therapy versus radiation alone for definitive treatment of locally advanced squamous cell carcinoma of the oropharynx, larynx, and hypopharynx demonstrated an OS benefit with cetuximab. In the cetuximab arm of the trial, cetuximab (400 mg/m²) was given 1 week before initiation of radiation, followed by 250 mg/m² weekly for the duration of the radiation (total of eight doses). Median OS increased from 29.3 months in the radiation alone arm to 49 months in the cetuximab plus radiation arm (p = 0.006). Survival at 3 years favored the cetuximab and radiation arm over the radiation alone arm (55% vs. 45%, p = 0.05, respectively). The toxicities were similar between the two arms with the exception of a greater risk of skin toxicities (acneiform rash and radiation dermatitis) and infusion reactions in the cetuximab arm. Surprisingly, the risk of mucositis with cetuximab and radiation was similar to that with radiation alone. An update of this trial confirmed that the OS benefit of cetuximab added to radiation persisted through 5 years of follow-up (Lancet Oncol 2010;11:21). Also, a retrospective analysis of this study found an association of grade 2 or greater acneiform rash with better OS and disease control in the cetuximab and radiation arm. Interestingly, the patients who benefited the most from the addition of cetuximab to radiation had the phenotypic features of HPV-related SCCHN: oropharyngeal site, younger age, limited smoking history, small T classification, and better performance status.

 Thus, level I evidence supports the use of single agent cisplatin or cetuximab in combination with radiation therapy. However, a recent randomized trial (RTOG 0522) demonstrated that the addition of cetuximab to cisplatin and radiation resulted in more toxicity and no benefit. Retrospective analysis of RTOG trials found poorer disease control rates and OS when delivered doses of cisplatin were lower than the target doses, supporting the importance of dose intensity. The benefit of adding 5-FU or taxanes to cisplatin with radiation is uncertain.

4. Salvage surgery following definitive chemoradiation. If a complete tumor response is not achieved following definitive CRT or if the cancer recurs locally or regionally after CRT, salvage surgical resection of the primary tumor site and/or the neck nodes may result in long-term survival in a fraction of patients. However, salvage surgery may be technically challenging following CRT, and the morbidity of the procedure may be significant.
5. Induction chemotherapy before definitive chemoradiation. Randomized trials of induction chemotherapy have shown mixed results. The MACH-NC meta-analysis of these trials found that a survival benefit was not consistently observed with induction chemotherapy except in the subset of patients given cisplatin and 5-FU (PF). The TAX 324 trial compared two different induction regimens consisting of PF or PF plus docetaxel (TPF) given before definitive CRT with weekly carboplatin (N Engl J Med 2007;357:1705). TPF (docetaxel 75 mg/m² on day 1, cisplatin 100 mg/m² on day 1, and 5-FU 1,000 mg/m² CIVI daily on days 1 to 4 every 3 weeks) was compared with PF (cisplatin 100 mg/m² on day 1 and 5-FU 1,000 mg/m² CIVI daily on days 1 to 5 every 3 weeks) given for three cycles before definitive CRT. The median OS was significantly longer in the TPF arm compared with that in the PF arm (70.6 months vs. 30.1 months; p = 0.0058). The OS benefit of TPF over PF persisted at 6 years in an updated analysis (Lancet Oncol2011;12:153). The TAX 323 trial was a randomized trial of similar design that compared TPF versus PF except that all patients had unresectable disease and all were treated with definitive radiation therapy alone (N Engl J Med 2077;357:1695). This trial also showed an OS benefit in the TPF arm compared with the PF arm.

 The PARADIGM trial compared induction chemotherapy followed by definitive CRT with CRT alone using TPF as the induction chemotherapy (Lancet Oncol 2013;14:257). There was no improvement in OS for induction chemotherapy, possibly related to the failure to accrue the target number of patients and unexpectedly high OS in both arms perhaps due in part to the rising incidence of HPV-related oropharynx squamous cell carcinoma (OPSCC), which carry a better prognosis. In a recently reported randomized trial by the Spanish Head and Neck Cancer Cooperative Group (TTCC), induction chemotherapy failed to improve PFS or OS (Ann Oncol 2014;25:216). However, most patients in the induction chemotherapy arms did not receive the full dose of radiation therapy owing to excessive toxicity, which arguably may have been mitigated by more aggressive supportive care. The results of another randomized trial (GCTCC Italy) of induction chemotherapy followed by CRT compared with CRT alone are pending.

 Induction chemotherapy may also be used as a method to predict tumor response to CRT. Early trials showed that a favorable response (partial or complete) at the primary tumor site to induction chemotherapy as assessed by clinical examination predicted for better long-term disease control after definitive CRT, whereas if the primary tumor site response to induction chemotherapy was unfavorable, it was less likely that the cancer would be cured by CRT alone. Such patients are usually treated by surgery followed by postoperative adjuvant therapy.

 Current studies are investigating the use of induction chemotherapy as a method to select patients with favorable prognosis to be candidates for de-intensification CRT.ECOG 1308 is a phase II trial of patients with HPV-related OPSCC that uses the tumor response to induction chemotherapy to direct patients to standard dose (69.3 Gy) RT (if less than complete response [CR]) or to lower dose (54 Gy) RT (if CR). All patients receive cetuximab with RT. With early follow-up, the 1-year progression-free survivals were similar in both arms.

1. Management of locally and/or regionally recurrent disease. Patients with local or regional recurrence only should be evaluated for potential salvage surgery or radiation therapy. If salvage surgery is not possible, and radiation therapy has previously been administered, concurrent chemotherapy with repeat irradiation may be effective in some patients. However, tissue tolerance, the extent of earlier radiation, and significant toxicity limit routine recommendation for this approach. Patients who are not candidates for local therapies may be treated with palliative chemotherapy.
2. Management of metastatic disease. Median OS of patients with metastatic SCCHN is 6 to 8 months. Lung, bone, and liver are the most common sites of distant disease. HPV-related OPSCC may display unusual patterns of metastases delayed and multiorgan recurrences. Several standard chemotherapeutic agents have activity against SSCHN and can provide palliation of symptoms. These include cisplatin, carboplatin, 5-FU, paclitaxel, docetaxel, methotrexate, pemetrexed, ifosfamide, and gemcitabine. The most common first-line therapy is a platin combined with a second agent, usually a taxane or 5-FU. Combination chemotherapy results in a greater tumor response rate than single agent therapy, but median OS is similar with both treatment options (J Clin Oncol 1992;10.2:257). First-line chemotherapy has a tumor response rate of 20% to 40%. The ECOG 1395 study showed similar response rates, OS, and toxicity for the combinations of cisplatin and 5-FU or paclitaxel. (J Clin Oncol 2005;23:3562) (E1395). Furthermore, the ECOG 1393 showed no differences between high-dose (175 mg/m²) and low-dose (135 mg/m²) paclitaxel when combined with cisplatin (J Clin Oncol 2001;19:1088). In patients with platinum-refractory SCCHN, the tumor response rate of alternative standard chemotherapy is low.

Cetuximab has activity as first-line therapy and in platinum-refractory SCCHN. A randomized trial showed that the addition of cetuximab to platinum and 5-FU significantly improved median OS (10.1 vs. 7.4 months, respectively) and PFS (5.6 vs. 3.3 months, respectively) (N Engl J Med 2008;359:1116). This trial was the first to demonstrate an OS benefit with a targeted agent in incurable SCCHN. In platinum-refractory SCCHN, single agent cetuximab resulted in a tumor response rate of 13% and a disease control rate of 46% (J Clin Oncol 2007;25:2171). However, median time to progression (TTP) and OS were only 70 and 178 days, respectively. Erlotinib and gefitinib are EGFR tyrosine kinase inhibitors that have also been used to treat SCCHN. In a phase II trial, erlotinib resulted in a tumor response rate of 4%, a disease control rate of 38%, and a median OS of 6 months (J Clin Oncol 2004;22:77). Similar outcome data were seen with gefitinib. Both drugs are generally well tolerated, with the most common side effects being fatigue, rash, and diarrhea. The addition of gefitinib to docetaxel did not improve outcomes in poor prognosis patients with SCCHN (J Clin Oncol 2013;31:1405).

1. Complications of disease
2. Aspiration with risk of pneumonia should be considered in the patient with fever or cough. Weight loss or risk of aspiration may require placement of feeding gastrostomy tubes. Some patients will minimize aspiration with certain postures (chin tuck maneuver) or dietary modification, and consultation with a speech pathologist is often helpful in rehabilitation. Shortness of breath should prompt evaluation of the airway and the potential need for tracheostomy.
3. Fungating tumors may ulcerate, bleed, and cause airway obstruction. Invasion of the carotid artery by tumor may be a terminal event and may be heralded by an episode of sentinel bleeding.
4. Pain control. Inability to swallow may limit narcotic analgesic choices. Transdermal fentanyl patches allow longer pain relief, with concentrated opiate elixirs for breakthrough pain. Opiate doses should be titrated to achieve pain control. Tumors invading nerves at the skull base may produce neuropathic pain syndromes that are helped by coanalgesics such as amitriptyline or gabapentin.
5. Paraneoplastic syndromes may include hypercalcemia due to tumor secretion of PTHrP and syndrome of inappropriate secretion of antidiuretic hormone (SIADH).
6. Complications of treatment
7. Complications of surgery may affect cosmesis, speech, airway patency, and ability to swallow. Reconstructive flap techniques and prosthetics may minimize these problems. Neck dissection may result in shoulder weakness if resection or injury of the 11th cranial nerve occurs. After total laryngectomy, a tracheoesophageal puncture (TEP) may allow speech by diverting expired air into the esophagus to vibrate the remaining pharyngeal tissue or flap. An electrolarynx, a handheld device that serves as a vibratory source for phonation, may also be used to allow communication following laryngectomy.
8. Acute radiation toxicity may include severe painful mucositis, loss of taste sensation, and inability to swallow. Oral candidiasis complicating mucositis may be treated with topical agents (nystatin or clotrimazole) or systemic agents (fluconazole). A cocktail of equal volumes of diphenhydramine suspension, nystatin, viscous lidocaine, and aluminum hydroxide/magnesium hydroxide suspension may be used as a topical oral swish solution for mucositis. Some patients may prefer a solution of one teaspoon of baking soda and 1/2 teaspoon of salt in a quart of water for milder mucositis. Opiates are indicated for more severe pain. Skin toxicity in the radiation port should be treated with emollients such as Aquaphor or Biafine and wound dressings, as appropriate.
9. Late radiation effects include xerostomia, which may be addressed by frequent oral hydration, or pilocarpine. Pilocarpine may cause uncomfortable sweats, especially at higher doses. Artificial saliva is available but poorly accepted by most patients. Dental caries is a chronic toxicity that may lead to tooth loss. Good dental hygiene and use of fluoride preparations may minimize this complication. Osteoradionecrosis may be treated conservatively with antibiotics, surgical debridement, or hyperbaric oxygen therapy. Fibrosis of the neck tissues may result in trismus, lymphedema, and loss of range of motion. Exercises may be helpful in preventing trismus. Impaired swallowing due to weakness of pharyngeal constrictor muscles and aspiration may occur. Laryngeal edema may require tracheostomy for management and should prompt consideration of possible disease recurrence.
10. Chemotherapy toxicities vary according to the agents used. Chemotherapy given with radiation may increase the severity of mucositis. Cisplatin may cause nausea/vomiting, nephrotoxicity, peripheral neuropathy, ototoxicity, and myelosuppression. 5-FU may cause myelosuppression and mucositis. Taxanes may result in alopecia, myelosuppression, myalgias, and allergic reactions. Cetuximab is associated with acneiform rash, dry skin or skin fissuring, paronychial inflammation, and hypersensitivity infusion reactions. Minocycline may be helpful in managing the rash.

 IV. LIP AND ORAL CAVITY

1. Anatomy. Cancer of the lip and oral cavity is the most common site of malignancy in the head and neck representing 30% of total cancers. Sites contained within this group are cancers originating from the lip, floor of mouth, anterior two-thirds of the tongue, buccal mucosa, gingiva, hard palate, and retromolar trigone.
2. Presentation. Although this region is easily accessible, patients often present after a prolonged interval of symptoms and with advanced disease. Patients may present with symptoms such as nonhealing oral lesions, pain in the mouth or ear, trismus, and weight loss. A pertinent history should include assessment of tobacco use including chewing tobacco and alcohol consumption. Dental problems and a history of chronic mucosal irritation should also be noted. Determination of oral functional status (biting, chewing, swallowing, and speech) is essential.

 On physical examination, complete evaluation of the nares, oral cavity, oropharynx, hypopharynx, and larynx should be performed by clinical exam and fiberoptic endoscopy or mirror exam. Evaluation for trismus and tongue movement is also important. Fixation of the tongue (ankyloglossia) and trismus suggest an advanced lesion. Palpation with a gloved finger should be used to inspect the lips, buccal mucosa, oral tongue, retromolar trigone, and floor of mouth. The state of the patient’s dentition should also be noted. Cranial nerve evaluation should also be performed. The neck should be evaluated for lymphadenopathy. Level 1 neck nodes are located in the submandibular–submental region, level 2 nodes along the proximal third of the sternocleidomastoid muscle at the angle of the mandible, level 3 nodes along the middle third of the sternocleidomastoid muscle, level 4 nodes along the distal third of the sternocleidomastoid muscle, and level 5 nodes in the posterior triangle. Cancers of the lip and oral cavity tend to metastasize to level 1 and level 2 nodes first.

1. Staging. In addition to the history and physical examination, the staging evaluation should include an examination under anesthesia (EUA) and radiographic imaging. Computed tomography (CT) or magnetic resonance imaging (MRI) of the head and neck is necessary to obtain a better anatomical understanding of the extent of the cancer. A CT scan shows details of bone involvement, whereas MRI gives a better view of soft tissue involvement. Often these techniques are complementary. A panorex may also be helpful in examining for mandibular bony involvement. CT scan of the chest should be performed to rule out pulmonary metastasis. Fluorodeoxyglucose (FDG)-Positron Emission Tomography (PET)/CT is widely used in staging of patients with advanced disease and may aid in developing radiation ports.
2. Pathology. Squamous cell carcinoma is the leading histology of lip and oral cancers. Adverse pathologic features include depth of invasion, infiltrative borders, poorly differentiated tumors, and perineural and lymphovascular invasion. Sarcomatoid, spindle cell, and basaloid features may also portend a worse prognosis. Less common histologies include adenoid cystic carcinoma and mucoepidermoid cancer of the minor salivary glands. These will be discussed in more detail later in this chapter.
3. Natural history of disease. Squamous cell cancer of the lip and oral cavity presents most commonly as local or local–regional disease with relatively late spread to distant sites.
4. Field cancerization is an important concept in the natural history of head and neck cancer, especially oral cavity tumors. Because the exposure of the mucosa to carcinogens in tobacco is diffuse across the aerodigestive tract, invasive cancer may be surrounded by areas of dysplasia or carcinoma in situ. Patients with head and neck cancer are at an increased risk of development of second primary cancers in the head and neck, lung, and esophagus. The risk is approximately 3% to 4% per year and generally tapers at a lifelong risk of 20% to 25% in survivors of the first treated head and neck squamous cell carcinoma.
5. Leukoplakia and erythroleukoplakia are premalignant lesions of the oral mucosa, related to the epithelial injury due to tobacco and ethanol. Leukoplakia is a white patch of mucosa that cannot be scraped off. Erythroleukoplakia may appear red and velvety and more commonly demonstrates dysplasia or carcinoma in situ on biopsy. The risk of malignant transformation increases with duration of these lesions and is higher with erythroleukoplakia compared with leukoplakia.

 Treatment may include close observation or surgical resection, particularly if high-grade dysplasia is present. Early studies of retinoids such as isotretinoin (13 cis-retinoic acid) showed promising results in the treatment of leukoplakia. Isotretinoin (1.5 mg/kg/day by mouth for 3 months followed by 0.5 mg/kg/day) produced a response rate of 55%, with most patients maintaining their response over the course of 1 year. However, a large randomized trial failed to show a reduction in the risk of second cancers or recurrence of the primary cancer with isotretinoin in patients who had been treated with definitive radiation therapy for stage I and II SCCHN (J Natl Cancer Inst 2006;98:441). This trial did show that smoking cessation after radiation treatment of the SCCHN was associated with a significantly lower risk of second cancers and improved OS compared with continued smoking.

1. Treatment of lip and oral cavity SCC
2. stages I and II. Most patients are treated by surgery alone. Neck dissections are performed in patients with thick (>3 to 5 mm) or larger tumors. Radiation is an alternative to surgery in patients who decline surgery or are not surgical candidates.
3. stages III and IV. Most patients are treated by surgery followed by adjuvant therapy based on pathologic features. CRT is an alternative to surgery in patients who decline surgery or are not surgical candidates.
4. OROPHARYNX
5. Anatomy. Cancer of the oropharynx includes sites in the soft palate, palatine tonsils, posterior and lateral oropharyngeal walls, and the base of tongue. Its borders include the junction of the hard and soft palate, the tonsillar arch, and the circumvallate papillae on the tongue.
6. Presentation. Many of the features described earlier for cancers of the oral cavity also apply to cancers of the oropharynx.
7. Pertinent history should include an assessment of tobacco and alcohol use and comorbid diseases. Odynophagia, dysphagia, neck mass, otalgia, trismus, and weight loss should also be noted.
8. The physical examination includes an assessment of performance status, complete evaluation of the nares, oral cavity, oropharynx, hypopharynx and larynx, and neck, and the cranial nerves. An evaluation for trismus, status of dentition, and tongue movement and atrophy should be performed along with palpation of the tongue, tonsils, and soft palate. Lymph nodes in the neck should be examined with measurements of palpable nodes, noting their size, level, and whether they are fixed to underlying tissue. Primary tumors of the oropharynx tend to first metastasize to level 2 and 3 nodes.
9. Staging. Along with history and physical examination, the staging evaluation of patients with oropharynx cancers includes diagnostic imaging, EUA with biopsy of the primary lesion, and evaluation for distant metastasis and synchronous primaries. CT or MRI of the primary site and neck and CT of the chest should be performed. FDG-PET/CT is often performed. The staging of oropharynx cancer is defined by the size and extent of the primary tumor, extent of nodal disease, and presence or absence of distant metastasis.
10. Pathology. Squamous cell carcinoma is the histology found in more than 90% of cancers of the oropharynx. Less common pathologies include lymphomas involving Waldeyer’s ring (palatine and lingual tonsils, and adenoids), mucosal melanomas, and tumors arising in the minor salivary glands that lie in the mucosa, including adenocarcinomas, adenoid cystic carcinomas, and mucoepidermoid carcinomas. Distinction should be made between well-differentiated and poorly differentiated squamous cell carcinomas. Adverse pathologic features include increasing depth of invasion, infiltrative borders, poorly differentiated tumors, and perineural and lymphovascular invasion. Sarcomatoid differentiation or basaloid features may also portend a worse prognosis.

An increasing number of cancers of the oropharynx are found in younger patients who have little or no prior exposure to smoking (J Clin Oncol 2013;31:4550). Most of these patients are Caucasian males in their 40s or 50s who present with a level 2 or level 3 neck mass. These cancers are typically nonkeratinizing SCCs that are strongly positive for p16 expression (by immunohistochemical stain), a surrogate marker for HPV. HPV-related OPSCC often presents with small primary tumors, large necrotic neck nodes, and have an excellent prognosis with current multimodality therapy. However, smoking history as a continuous variable increases the risk for cancer recurrence (J Clin Oncol 2012;30:2102).

1. Natural history of disease. Squamous cell cancer of the oropharynx usually presents with locally advanced-stage disease. A significant proportion of patients who present with level two or three neck masses and unknown primary SCC are found on EUA with an operating room microscope and with directed biopsies to have HPV-related OPSCC. In smoking-related OPSCC, the effects of tobacco and alcohol on the mucosa increase the risk of second primary cancers due to field cancerization.
2. Treatment of OPSCC
3. Stages I and II. Patients may be treated with surgery that includes resection of the primary tumor and possibly at-risk neck nodes. Radiation provides clinical equipoise with surgery, and is an alternative in patients who decline surgery or are not surgical candidates.
4. Stages III and IV. Patients may be treated with surgery that includes resection of the primary tumor and grossly involved and at-risk neck nodes followed by adjuvant therapy based on pathologic features, CRT, or induction chemotherapy followed by CRT (Cancer 2013;119:766). It is not clear that there are any differences in overall disease control rates between these treatment approaches.

 VI. LARYNX AND HYPOPHARYNX

1. Anatomy. Cancers of the larynx and hypopharynx represent challenges in treatment because of their key involvement with speech and swallowing. As such, these sites have been associated with the most research on organ preservation, attempts to avoid total laryngectomy, while maintaining the best chance for cure. The boundaries of the hypopharynx are the level of the hyoid bone superiorly and the lower border of the cricoid inferiorly. Tumors in this area may be divided into those arising from the pyriform sinuses, the posterior wall of the hypopharynx, and the postcricoid area. Tumors of the larynx may be divided into those located predominantly above the true vocal cords (supraglottic), those arising from the true vocal cords (glottic), or those below the true vocal cords (subglottic). Cancers of the larynx are far more common than cancers of the hypopharynx.
2. Presentation. The presentation of cancers of the larynx and hypopharynx varies greatly with their primary site. Tumors of the supraglottic larynx or the pyriform sinus are often diagnosed only after cervical metastasis appears because of their greater access to lymphatics and vague symptoms of dysphagia or odynophagia. Conversely, glottic cancers present with hoarseness, often despite a small tumor size, and the tumors may remain localized to the primary site until thyroid cartilage invasion occurs. Cancers of the larynx and hypopharynx may cause airway obstruction resulting in stridor and requirement for immediate tracheostomy. Weight loss is also frequent at presentation.
3. Pertinent history should include tobacco and alcohol use, the existence of comorbid diseases, and symptoms of dysphagia, odynophagia, weight loss, dyspnea, and hoarseness. Unilateral paralysis of a vocal cord may result in speech that deteriorates with longer use of the voice and improves with rest. Patients may also become dyspneic with speech. Symptoms of aspiration should be sought. A history of gastroesophageal reflux should be noted.
4. Physical examination includes assessment of performance status, complete evaluation of the oral cavity, oropharynx, hypopharynx, and larynx with indirect examination or fiberoptic laryngoscopy, testing of cranial nerves, and palpation of the neck. Palpation and visualization of the base of tongue should be done to note whether there is superior extension of the tumor to this site. Pooling of saliva in the hypopharynx may interfere with the office examination and requires better visualization at the time of EUA and biopsy. Fixation of the true vocal cord should be noted, as this affects staging, and diagrams of the extent of the lesion are helpful.
5. Staging. The staging of cancers in the larynx and hypopharynx requires EUA with biopsy to determine the extent of the lesion and search for synchronous primary cancers. CT or MRI imaging is performed to define the extent of the primary disease and involved neck nodes. Chest CT and/or FDG-PET/CT are used to assess for distant metastases and second primary cancers. The tendency of the thyroid cartilage to display irregular calcification should be noted, as it may result in overestimating cartilage invasion on staging. In addition to size of the primary tumor, the staging criteria for the primary (T stage) include whether adjacent subsites of the hypopharynx (pyriform sinus, pharyngeal wall, and postcricoid region) or supraglottic larynx (suprahyoid epiglottis, infrahyoid epiglottis, aryepiglottic folds, arytenoids, and false vocal cords) are involved.
6. Pathology. Squamous cell carcinoma, or one of its variants, is the histologic description of more than 95% of tumors arising in the larynx and hypopharynx. Tumors of minor salivary gland histology (adenoid cystic, adenocarcinoma, and mucoepidermoid carcinoma) occur infrequently. The supraglottic larynx may be the site for neuroendocrine small cell carcinomas and should be recognized because of their tendency for distant spread and sensitivity to chemotherapy and radiation.
7. Stage-directed approach to therapy
8. Stage I to II. Early-stage disease is most likely to be encountered in glottic carcinomas owing to early symptoms of hoarseness. The primary approach may consist of surgical resection or radiation therapy with similar cure rates. In most cases, a larynx-conservation surgery approach is feasible, including a transoral endoscopic laser resection, open supraglottic, or open vertical hemilaryngectomy. These approaches permit preservation of speech but may be limited (particularly with the open approaches) by problems with aspiration, which can be problematic in patients with chronic pulmonary disease. Posttreatment voice quality is usually excellent with transoral surgery and radiation therapy, but may be less satisfactory with open approaches.
9. Stage III to IV. The traditional approach to locally advanced tumors of larynx and hypopharynx has been surgical resection with total laryngectomy or laryngopharyngectomy and adjuvant radiation therapy. However, CRT is also effective and allows preservation of speech and swallowing in the majority of patients.

 Interest in larynx preservation led to trials of chemotherapy and radiation in an attempt to avoid total laryngectomy and preserve anatomy and function. The Veterans Administration (VA) Larynx Trial compared laryngectomy and postoperative adjuvant radiation with induction chemotherapy followed by definitive radiation therapy for those patients whose tumors responded favorably to induction chemotherapy and total laryngectomy and adjuvant radiation for those patients whose tumors did not respond favorably to induction chemotherapy (N Engl J Med 1991;324:1685). Cisplatin and 5-FU were administered every 3 weeks, with primary tumor response assessment after the second cycle. Patients with tumors that responded favorably received an additional cycle of chemotherapy followed by definitive radiation, whereas patients whose tumors did not respond favorably underwent total laryngectomy followed by adjuvant radiation therapy. Salvage total laryngectomy was performed in patients with persistent or locally recurrent disease after radiation therapy. This treatment approach resulted in equivalent OS with induction chemotherapy and radiation therapy as compared with total laryngectomy and adjuvant radiation therapy and permitted 64% of the surviving patients in the nonsurgical treatment arm to retain their larynx.

 A European Organization for the Research and Treatment of Cancer (EORTC) trial in cancers of the pyriform sinus compared the results of surgical resection and adjuvant radiation therapy with a similar induction chemotherapy and radiation therapy strategy (N Engl J Med 2003;349:2091). Patients were randomized to surgery and adjuvant radiation therapy or induction chemotherapy with cisplatin and 5-FU followed by definitive radiation therapy. Patients with chemosensitive tumors as assessed after cycle 1 received a total of three cycles of chemotherapy followed by definitive radiation therapy with salvage surgery for nonresponders to chemotherapy or in those patients with persistent or recurrent disease following definitive radiation. As in the VA larynx trial, OS was equivalent between these two treatment approaches, and functional larynx preservation at 3 years was achieved in 42% (95% CI, 31% to 53%) of patients on the induction chemotherapy arm.

 RTOG 91-11 was an intergroup, three-arm randomized trial that compared induction chemotherapy followed by definitive radiation therapy (as given in the VA trial) to CRT to radiation therapy alone. The CRT arm received three cycles of high dose (100 mg/m²) bolus cisplatin given every 21 days concurrent with radiation therapy. Eligible patients included patients with stage III to IV laryngeal cancer who would require total laryngectomy as surgical management. Patients with T4 primaries were excluded if they had more than minimal thyroid cartilage invasion or more than 1-cm tumor extension onto the base of the tongue. The larynx preservation rate was significantly higher with CRT compared to induction chemotherapy followed by radiotherapy therapy and to radiation therapy only (83.6% vs. 70.5% vs. 65.7%, respectively). The 5-year OS were similar in the three arms (55%). Long-term (10-year) follow-up of the RTOG 91-11 trial showed that induction chemotherapy followed by radiation therapy and CRT had similar laryngeal-free survival, whereas deaths not due to larynx cancer or treatment were higher with CRT (30.8% vs. 20.8% with induction chemotherapy vs. 16.9% with radiation therapy alone) (J Clin Oncol 2013;31:845). Together, these trials demonstrate the feasibility of organ preservation in most cases of locally advanced cancers of the larynx and hypopharynx without adversely affecting survival.

 The TREMPLIN trial was a phase II randomized trial comparing induction chemotherapy with TPF followed by CRT with cisplatin or with cetuximab in favorable responders (J Clin Oncol 2013;31:853). Poor responders underwent salvage surgery. No significant differences in early laryngeal preservation or OS occurred in the two arms. Long-term follow-up of this trial is required to determine whether these results are maintained.

1. Natural history of disease. Local–regional control is a major challenge in the treatment of patients with cancer of the larynx and hypopharynx. The lack of symptoms in early pyriform sinus cancers can be contrasted with the frequent development of symptoms (hoarseness) with early glottic cancer. The effect of anatomy with confinement of many laryngeal cancers to the primary site due to surrounding thyroid cartilage contrasts with the advanced disease typically seen in hypopharynx cancers, which typically have submucosal spread and local lymphovascular spread. Although most recurrences of laryngeal and hypopharyngeal cancers occur within the first 3 years after treatment, continued vigilance is warranted for the development of metachronous primary head and neck cancers. All patients should be repeatedly counseled about the benefits of smoking cessation. Also, patients with cancers of the larynx and hypopharynx are at significant risk for subsequent development of lung cancer.

 VII. NASOPHARYNX CANCER

1. Anatomy. The borders of the nasopharynx include the choanae (anterior), the soft palate (inferior), and lateral walls, including the fossae of Rosenmuller and the eustachian tube orifices. Its sloping roof along the skull base (superior and posterior) lies in close proximity to the foramen lacerum and the carotid artery as it enters the cavernous sinus. Tumors may extend through the foramen ovale to access the middle cranial fossa and the cavernous sinus with access to the oculomotor (CN III), trochlear (CN IV), trigeminal (CN V), and abducens (CN VI) nerves. Optic nerve (CN II) and orbital invasion is possible in advanced cases. There is a rich lymphatic supply with retropharyngeal nodes, including the lateral retropharyngeal nodes (of Rouvière), representing an important route of spread.
2. Presentation. The presentation of nasopharyngeal cancer has many unique features. Symptoms at diagnosis may be related to the primary site, disease in the neck, or distant metastases. The epidemiology of this cancer is different from that of other head and neck sites. Causes of nasopharyngeal cancer include EBV infection, HPV infection, and smoking.
3. Pertinent history may include geographic, genetic, and environmental factors. The highest incidence of nasopharyngeal cancers is found in southern China and Southeast Asia. Genetic factors related to host response to EBV infection may explain the increased risk among people of Asian ancestry. Other risk factors have been implicated, including diet (consumption of salted fish and low intake of fresh fruits and vegetables) and smoking. Symptoms may include a painless neck mass, nasal obstruction, epistaxis, headache, persistent sinusitis symptoms, dysphagia, odynophagia, eustachian tube dysfunction with sterile middle ear effusion, or cranial neuropathies (particularly the abducens and trigeminal nerves). Trismus may indicate invasion of the pterygoid region.
4. Physical examination includes assessment of performance status, complete evaluation of the nares and oral cavity, and a thorough evaluation of the cranial nerves. Proptosis may indicate orbital invasion. Evaluation of the nasopharynx with fiberoptic endoscopy or examination under anesthesia with biopsy is appropriate. The status of dentition should be noted, as any needed restoration or extractions should precede the initiation of radiation therapy. Lymph nodes in the neck should be palpated and palpable nodes measured.
5. Staging. Along with history and physical examination, the staging evaluation of patients with nasopharynx cancers includes diagnostic imaging, including MRI and CT from the base of skull to clavicles, EUA, and Chest CT or FDG-PET/CT to look for distant metastases. MRI and CT are complementary and helpful for delineating disease extent due to early skull base involvement. The neck nodal staging system is different for nasopharyngeal carcinoma as compared with other mucosal sites of head and neck cancers. The staging for nasopharyngeal cancer is distinct from the other head and neck sites. T stage is subdivided into T0 (no evidence of primary tumor), T1 (no parapharyngeal extension), T2 (parapharyngeal extension), T3 (involvement of skull base of paranasal sinuses), and T4 (involvement of cranial nerves, hypopharynx, orbit, infratemporal fossa, or intracranial extension). The lymph node staging includes N0 (no regional lymph node metastasis), N1 (unilateral metastasis in cervical lymph nodes ≤6 cm above the supraclavicular fossa and/or unilateral or bilateral retropharyngeal lymph nodes ≤6 cm), N2 (bilateral cervical lymph nodes ≤6 cm), and N3 (lymph nodes >6 cm or extension to the supraclavicular fossa). Stage I is defined as T1N0M0, stage II as T1N1M0 or T2N0-1M0, and stage III as T1-2N2M0 or T3N0-2M0. Stage IV is subdivided into IVA (T4N0-2M0), IVB (T0-4, N3M0), and IVC (any T and N plus M1).
6. Pathology. Carcinomas represent 85% of nasopharynx tumors (less common are lymphoma, adenocarcinoma, melanoma, plasmacytoma, rhabdomyosarcoma, and others). Nasopharyngeal carcinoma is classified according to a World Health Organization (WHO) schema. WHO-Type 1 is keratinizing squamous cell carcinoma. WHO-Type 2 is nonkeratinizing squamous cell carcinoma, and WHO-Type 3 is undifferentiated carcinoma (lymphoepithelioma). EBV tumors are most closely associated with WHO Types 3 and 2 histologies. Nasopharyngeal carcinoma has recently been shown to also be more rarely associated with HPV infection.
7. Stage-directed approach to therapy
8. Early-stage disease is infrequently diagnosed in the Western world because of lack of symptoms and no screening programs due to rarity of the disease. Radiation therapy alone is the usual treatment for early-stage disease. Surgical resection or repeat radiation therapy may be considered for the rare local recurrence.
9. Advanced-stage disease is treated with CRT. The Intergroup 0099 trial demonstrated better OS with CRT compared with radiation therapy alone (J Clin Oncol 1998;16:1310). This randomized trial compared radiation therapy (70 Gy) alone with CRT (with cisplatin 100 mg/m² given every 21 days, total of three doses) and three cycles of adjuvant cisplatin and 5-FU given every 4 weeks after completion of CRT. The 3-year progression-free survival was 24% versus 69% (p <0.001), and 3-year OS was 47% versus 78% (p = 0.005) for radiation therapy alone versus CRT, respectively. This trial included all three WHO types. Other randomized trials confirmed the benefit of CRT over radiation therapy alone in populations enriched in EBV-driven tumors and in stage II disease. Randomized trials have also established that adjuvant chemotherapy does not improve outcomes after CRT (Lancet Oncol 2012;13:163) and that carboplatin was noninferior to cisplatin when administered concurrently with radiation therapy (Euro J Cancer 2007;43:1399).
10. Natural history of disease. Nasopharyngeal carcinoma is a disease with unique features. A younger age at presentation compared with that for other sites of head and neck cancers and a higher incidence in endemic geographic areas are seen. Most patients present with locally advanced disease, and for many decades the most common pattern of recurrence was local–regional failure. However, with the advent of combined CRT and advanced radiation techniques, distant failure is now more common, and the risk of distant metastasis is higher than with other sites. The role of genetic factors and EBV are well recognized but poorly understood. Viral titers assessed by polymerase chain reaction (PCR) that remain elevated or rise after therapy may identify a group at risk for disease recurrence.

VIII. LESS COMMON TUMORS OF THE HEAD AND NECK

1. Salivary gland cancers most commonly arise in the parotid gland, but may arise in the submandibular, sublingual, or minor salivary glands that line the mucosa of the upper aerodigestive tract.
2. Pathology. The histology of salivary gland carcinoma is varied. Perineural invasion, high-grade tumors, and nodal metastases are adverse prognostic features.
3. Mucoepidermoid carcinomas are the most common type arising in the parotid glands and are classified as low, intermediate, or high grade. Low-grade tumors respond well to surgical resection, whereas high-grade tumors are associated with more aggressive local invasion, and nodal and distant metastases.
4. Adenoid cystic carcinoma is the most frequent histology seen in the submandibular and minor salivary glands. Perineural invasion may lead to facial nerve (CN VII) paralysis and involvement of the skull base. It is also classified by grade and has a significant incidence of distant metastatic disease. Patients with distant metastasis to the lung have a much longer survival as compared with the more uncommon patients that develop metastasis to the liver or bones.
5. Malignant mixed tumors (carcinoma ex-pleomorphic adenoma) arise from a preexisting benign mixed tumor (pleomorphic adenoma).
6. Adenocarcinomas commonly arise from the minor salivary glands but may also arise in the major salivary glands. They have an aggressive behavior and a significant risk of distant metastasis. Low-grade polymorphous adenocarcinomas arise in the oral cavity and have an excellent prognosis with complete resection.
7. Acinic cell carcinomas usually arise in the parotid glands. They are typically low grade, slow growing tumors, but may invade adjacent structures. Unpredictably, a small number will behave very aggressively. These tumors can be bilateral. Late recurrences and distant metastases may occur.
8. Squamous cell carcinomas arising from the excretory duct of the salivary glands have an aggressive course with a poor prognosis despite aggressive therapy.
9. Metastatic regional disease to intraparotid nodes can occur from skin cancers arising from the face, scalp, or ears. These are primarily from squamous cell carcinoma, melanoma, and Merkel cell carcinoma.
10. Treatment. Management of salivary gland cancers is surgical resection. In the parotid gland, this may consist of total or superficial parotidectomy, depending on the location of the tumor and histology tumor type. When possible, the facial nerve may be preserved. High-grade tumors and low-grade tumors with a positive resection margin benefit from adjuvant radiation therapy. Recurrent or metastatic tumors may be treated with chemotherapy, including cisplatin, doxorubicin, 5-FU, and cyclophosphamide combinations. Recent reports have documented the expression of c-kit, her-2-neu, EGFR, and/or the androgen receptors in salivary gland cancers and case reports of tumor response to targeted therapy directed (J Clin Oncol 2006;24:2673).
11. Tumors of the nasal cavity and paranasal sinuses are rare tumors that include a variety of histologies. Risk factors may include occupational exposures to wood dust, shoe manufacture, nickel refining, and Thorotrast contrast media.
12. Squamous cell carcinoma is the most common type in the nasal cavity and paranasal sinuses, and the maxillary sinus is the most common primary site. Minor salivary gland tumors may also occur. Surgical resection and postoperative radiation therapy is the preferred treatment approach.
13. Esthesioneuroblastoma (olfactory neuroblastoma) arises from the olfactory neuroepithelium. Surgical resection and adjuvant radiation therapy is the preferred treatment approach. The benefit of the addition of chemotherapy to radiation therapy is unclear.
14. Sinonasal undifferentiated carcinomas (SNUCs) are high-grade epithelial malignancies that may occur with or without neuroendocrine differentiation. Ideal treatment is controversial and may include surgery and adjuvant radiation therapy, or CRT.

 IX. UNKNOWN PRIMARY

1. The patient with a neck mass may not have a primary site identified on initial inspection of the oral cavity and pharynx. The location (level) of the neck mass should direct close evaluation of the head and neck mucosal sites that are drained by that nodal group.
2. Fine needle aspiration for cytology of the neck mass should be pursued as the primary diagnostic procedure. Open biopsy should be pursued if a lymphoma is suggested. Evaluation of the thyroid, parotid, and any suggestive skin lesions should be performed. A mass in the supraclavicular fossa should prompt evaluation of possible primary sites below the clavicles.
3. If squamous cell carcinoma is suggested by the cytology, EUA with operative endoscopy should be used to try to identify the primary tumor site. Use of an operating microscope or surgical robot during the endoscopy might assist with identification of the primary tumor, particularly when small. If no primary is found, then bilateral or ipsilateral palatine tonsillectomy and ipsilateral lingual tonsillectomy should be performed, as these would be the most common sites for an occult primary, and the pathologist should perform serial step sectioning on the specimens. True occult primaries without an easily identifiable mucosal site are usually p16-positive oropharyngeal cancers.
4. If no primary site is found, several approaches are considered. If the neck mass is unresectable, then radiation therapy or CRT with a nasopharyngeal port, which will include the likely potential primary sites, may be used. If a nasopharyngeal primary is suggested by the cytology, CRT may be considered. If the neck mass is resectable, neck dissection may be pursued as primary therapy. If the pathology shows extracapsular extension or if multiple nodes are involved, postoperative CRT may be given, with some controversy as to whether a nasopharyngeal port or involved neck-only port is most appropriate. If the neck mass is solitary, small (N1), and without extracapsular extension, adjuvant radiation therapy may be held and the patient closely observed.

 X. MANAGEMENT OF THE NECK

1. Patients with clinically negative neck nodes that are at significant (≥20%) risk for occult disease may be treated effectively with selective neck dissection or radiation therapy. Clinically involved nodes may require both modalities, especially if there are multiple nodes involved or extracapsular extension.
2. Radical neck dissection consists of removing all five lymph node groups on one side of the neck, as well as the sternocleidomastoid muscle, the internal jugular vein, and the spinal accessory nerve (CN XI). Modified radical neck dissections remove all five lymph node groups but may spare one or more of the latter structures. In a selective neck dissection, only lymph node groups at the highest risk are excised, and the sternocleidomastoid, jugular vein, and CN XI are preserved.

SUGGESTED READINGS

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Al-Sarraf M, LeBlanc M, Shanker Giri PG, et al. Chemoradiotherapy versus radiotherapy in patient with advanced nasopharyngeal cancer: phase III randomized intergroup study 0099. J Clin Onol 1998;16:1310–1317.

Argiris A, Ghebremichael M, Gilbert J, et al. Phase III randomized, placebo-controlled trial of docetaxel with or without gefitinib in recurrent or metastatic head and neck cancer: an eastern cooperative oncology group trial. J Clin Oncol 2013;31:1405–1414.

Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers. J Clin Oncol 2013;31:4550–4559.

Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012;30:2102–2111.

Haddad R, O’Neill A, Rabinowits G, et al. Induction chemotherapy followed by concurrent chemoradiotherapy (sequential chemoradiotherpy) versus concurrent chemoradiotherapy alone in locally advanced head and neck cancer (PARADIGM): a randomized phase 3 trial. Lancet Oncol 2013;14:257–264.

Hitt R, Grau JJ, Lopez-Pousa A, et al. A randomized phase III trial comparing induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as treatment of unresectable head and neck cancer. Ann Oncol2014; 25: 216–225.

Laura SA, Licitra L. Systemic therapy in the palliative management of advanced salivary gland cancers. J Clin Oncol 2006;24:2673–2678.

Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med 2007;357:1695–1704.

Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med 2008;359:1116–1127.

Posner MR, Hershock DM, Blajman CR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer. N Engl J Med 2007;357:1705–1715.