Tobacco

In the late 1950s, a landmark case-control study by Dr. Ernst Wynder established the link between tobacco use and oral cavity cancer. A year later, a cohort study of over 180,000 men demonstrated an increased risk of death from HNSCC in cigarette smokers as compared with men who never smoked.¹² In 1964, the Advisory Committee to the Surgeon General on Smoking and Health published its report linking smoking to cancer.¹³ The strength and consistency of the association between smoking and HNSCC have been demonstrated in numerous case-control and cohort studies with significant relative risks or odds ratios in the 5- to 25-fold range.^{14, 15} Furthermore, a dose–response effect is consistently shown between the duration and dose of smoking with increasing risk of HNSCC and between the time since quitting and the decreasing risk of HNSCC. Other mucosal malignancies of the head and neck such as NPC and sinonasal malignancies have a weaker association with tobacco smoking.¹⁶

Although the risk of bronchogenic carcinoma appears to be less significant for cigar and pipe smokers than for cigarette smokers, these forms of tobacco use are also clearly associated with an increased risk of HNSCC.¹⁷ The pooling of saliva containing carcinogens in gravity-dependent regions may account for the site distribution of HNSCC based on consumption patterns; in the United States, floor of mouth (FOM), laryngeal, and hypopharyngeal cancers are almost exclusively found in smokers. Smokeless tobacco and related product users and pipe smokers often have a habitual position for the quid or pipe stem, and these products are also associated with cancer of the oral cavity. In South-Central Asia where the use of such products is common, the gingivobuccal region is the most common site for HNSCC.^{6, 18}

Although smoking rates are declining in the developed world, they are rising in developing countries. In 1965, 42.4% of the U.S. adult population was actively smoking, while in 2013 only 17.8% were current smokers.¹⁹ Although the reduction in cigarette smoking has been much greater in men over the past three decades, the rate of current cigarette use remains higher in men (20.5%) than in women (15.3%), and 26.1% of Native Americans continue to smoke.²⁰ Worldwide, striking variations in HNC sites and incidence are seen among different regions, cultures, and demographic groups and are due, in large part, to differing patterns of tobacco and other substance abuse. For instance, in South-Central Asia, “pano” (betel leaf, lime, catechu, and areca nut) is commonly chewed and is a strong risk factor independent of tobacco use for carcinoma of the oral cavity, one of the most common cancers in men and women in this region.^{10, 21}

Alcohol

Alcohol, too, is an important promoter of carcinogenesis in at least 30% of HNSCCs.^{10, 22} Furthermore, alcohol appears to have an effect on HNSCC risk independent of tobacco smoking, but these effects are consistently significant only at the highest level of alcohol consumption.²³ Although studies attempting to correlate the type of alcoholic beverage with specific cancer risks have been conflicting, most investigators believe that ethanol itself is the main causative factor. Nevertheless, it appears that the major clinical significance of alcohol consumption is that it potentiates the carcinogenic effect of tobacco. The synergistic relationship between smoking and alcohol results in a 30-fold increased risk of HNC.^{22, 24}

Infectious agents

Although various infectious agents have been suggested to play a role in head and neck carcinogenesis, current scientific evidence implicates only Epstein–Barr virus (EBV) and HPV as etiologic agents. Although herpes simplex viruses have been suggested as a risk factor for oral cavity cancer,²⁵ and Helicobacter pylori for laryngeal cancer,²⁶ confirmation is lacking.

Human papilloma virus

In contrast to non-oropharyngeal cancers, the incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased in recent decades, specifically among younger age groups,^27–31 given the rising incidence of oropharyngeal cancers associated with HPV infection.^{32, 33} HPV is associated with approximately 70% of OPSCC in the United States.³⁴ HPV may also play a role in the etiology of SCCs arising in the sinonasal tract.³⁵

HPVs are deoxyribonucleic acid (DNA) viruses with a unique affinity for human epithelia, and HPV-associated cancers arise from the tonsillar crypts without an overlying epithelial dyplasia. HPV has been well established as an etiologic agent in cervical and anal cancer,³⁶ and over the past decade, several investigators have indicated that infection with HPV is a significant risk factor for oropharyngeal carcinoma.^37–44 Over 120 different HPV types have been isolated, with low-risk types (e.g., HPV 6, 11) inducing benign hyperproliferation of the epithelium, leading to lesions such as papillomas and warts, and high-risk types (e.g., HPV 16, 18, 31, 33, 35) associated with carcinogenesis.⁴⁵ The prototypical oncogenic types 16 and 18 account for over 90% of HPV-related OPSCC, and are capable of malignant transformation of primary human keratinocytes from genital or upper respiratory tract epithelia.⁴⁶ This transforming potential is attributed to the two HPV oncoproteins, E6 and E7, that inactivate two human tumor-suppressor proteins, p53 and pRb, respectively.^{47, 48} These viral oncoproteins are not only necessary for transformation but also stimulate cellular proliferation, delay cellular differentiation, increase the frequency of spontaneous and mutagen-induced mutations, and promote focal and broad chromosomal instability in transfected cell lines.⁴⁹ Furthermore, in order to maintain a malignant phenotype, a transcriptionally active viral genome appears to be necessary.^50–53

The risk factors associated with HPV-associated OPSCC are distinct from HPV-negative tumors, and include oral sexual behaviors and marijuana use. Furthermore, a dose–response relationship has been identified between the risk of developing HPV-positive OPSCC with number of oral sex partners and joint years of marijuana use.⁵⁴ Although oropharyngeal cancer patients presenting without the classic tobacco exposures more commonly have HPV-16-associated tumors,³⁷ it is also possible that there may be synergistic interactions between the traditional oropharyngeal risk factors of tobacco and alcohol with HPV.⁴¹ The potential effect of HPV-16 immunizations in the prevention of cervical carcinomas may help prevent oropharyngeal cancers as well.⁴

EBV

The epidemiologic link between EBV and NPC is quite strong,^{42, 43} and is further supported by the identification of EBV DNA in premalignant nasopharyngeal lesions. Although World Health Organization (WHO) types II and III are overwhelmingly positive for EBV, the virus is also associated with well-differentiated (WHO type I) NPC.⁴⁶ Both serologic and mucosal swab evidence of EBV infection has been used to enhance screening for NPC in endemic areas.⁴² Evidence of EBV DNA in cervical lymph node metastases of unknown primary origin has been used to identify nasopharyngeal primaries. More recently, the detection of EBV DNA in peripheral blood (both cellular and cell-free component) has demonstrated prognostic significance for predicting survival and distant metastases and may become a biomarker to follow up on these patients.⁵¹

Genetic susceptibility

Since only a fraction of smokers develop cancer, variations in genetic susceptibility may be equally important in disease etiology. A genetic component to this disease is also supported by large family studies demonstrating a three- to eightfold increased risk of HNSCC in first-degree relatives of patients with HNSCC.^{53, 55} According to this hypothesis, inherited differences in the efficiencies of carcinogen metabolizing systems, DNA repair systems, and/or cell-cycle control/apoptosis systems influence risk of tobacco-induced cancers.^{56, 57} Identifying such at-risk individuals in the general population by use of biomarker assays would have a profound impact on primary prevention, early detection, and secondary prevention strategies. Three recent high-impact publications of genome-wide association studies have identified the same lung cancer susceptibility locus in separate populations.^{54, 58, 59} These studies will likely be followed in the near future by similar explorations of genome-wide HNSCC association studies and suggest that tailored prevention of tobacco-associated cancers may be a realistic goal.

Environmental tobacco smoke

In a study of 173 cases of HNSCC and 176 cancer-free controls, environmental tobacco smoke was associated with a more than twofold increased risk of HNSCC, and a dose–response relationship was also observed.⁶⁰ In a separate study of 44 nonsmokers with HNSCC and 132 cancer-free nonsmoker controls, environmental tobacco smoke was associated with a significantly increased risk of HNSCC, and this was particularly true for females and for those reporting exposure at work.⁶¹

Laryngopharyngeal reflux

Observational and anecdotal studies have long suggested that gastroesophageal reflux (GERD) may be associated with laryngeal cancer.^{62, 63} Furthermore, multiple studies have documented a high prevalence of gastric reflux into the laryngopharynx in patients with laryngeal cancer via 24-h pH probe monitoring.⁶⁴ A case-control study of 10,140 hospitalized patients and 12,061 outpatients with laryngeal and pharyngeal cancer and 40,561 hospitalized and 48,244 outpatient controls has been performed using U.S. Department of Veterans Affairs databases.⁶⁵ The diagnosis of GERD was associated with a significantly elevated risk of laryngeal cancer (OR, odds ratio = 2.4 and OR = 2.3 for hospitalized and outpatient groups, respectively) and of pharyngeal cancer (OR = 2.4 and OR = 1.9 for hospitalized and outpatient groups, respectively). However, a large Swedish cohort study of 66,965 patients with discharge diagnoses of heartburn, hiatal hernia, or esophagitis with a follow-up of 376,622 person-years concluded that there was no evidence of a causal association between GERD and either laryngeal or pharyngeal cancer.⁶⁶

Marijuana

Marijuana smoke has a four times higher tar burden and a 50% higher concentration of benzopyrene and aromatic hydrocarbons than does tobacco smoke. Although anecdotal evidence has long suggested that marijuana is a risk factor for HNSCC, few reports have found direct evidence of marijuana as an etiologic factor for HNSCC because most users of marijuana are also exposed to tobacco and alcohol.^{67, 68} A recent case-control study including 240 HNSCC patients and 322 cancer-free controls demonstrated a positive association of fivefold between marijuana use and HPV-related HNSCC, with a dose–response relationship.⁶⁹ However, a large retrospective cohort of 64,855 health maintenance organization (HMO) members found no association of marijuana use with tobacco-related cancers.⁷⁰ Problems of underreporting of marijuana use and limited sample size of heavy users limit conclusions regarding marijuana use and HNSCC risk.⁷¹

Diet

Epidemiologic evidence from case-control studies suggests that diets high in animal fats and low in fruits and vegetables may be risk factors for HNSCC.^{72, 73} Case-control studies have correlated salted fish consumption with NPC risk, which may be due to the high content of nitrosamine compounds in preserved foods.^{74, 75} Some evidence suggests vitamin A and beta-carotene may be responsible for the protective effect of diets high in fruits and vegetables, and carotenoid deficiency has been considered to be a risk factor for HNSCC and lung cancers.⁷⁶ It is not known, however, which of the more than 500 carotenoids are protective, what chemical interactions may occur, or what protective role other micronutrients in carotenoid-rich foods may play. Others have found that total intake of vitamins C and E are also protective.⁷³ Moreover, diets are complex and difficult to assess and validate; in particular, there are often inaccuracies in translating foods into constituent nutrients. It may be impossible to determine which of the vast array of compounds is most beneficial, and controlling for other dietary variables and confounding risk factors has remained a difficult methodological problem.

Occupation/air pollution

Although occupational exposures probably play a minor role overall in the development of HNSCC, they are major risk factors for malignancies of the sinonasal region.^77–79 The most important exposures occur in the metalworking, refining, woodworking, and leather/textile industries.^{77, 78} Indoor air pollution is a significant problem in much of the developing world where indoor stoves using biomass or fossil fuels are the primary method of cooking and heating. Although controversial, an expert committee of the National Academy of Sciences has concluded that there is sufficient evidence to consider asbestos as a significant independent risk factor for laryngeal cancer.⁸⁰

Radiation

No significant association has been demonstrated between ionizing radiation and the development of HNSCC. However, SCCs of the lip, like skin cancers, are associated with ultraviolet radiation exposure. Furthermore, exposure to gamma radiation is associated with thyroid cancers, sarcomas of the head and neck, salivary gland malignancies, and paranasal sinus cancers. Although therapeutic irradiation of HNC does not appear to induce second primary SCCs of the aerodigestive tract, it is associated with an increased risk of sarcomas of the head and neck.⁸¹ This is a particular concern for children requiring radiotherapy. Furthermore, environmental, medical diagnostic, and therapeutic radiation exposure to the head and neck are all significantly associated with salivary gland malignancies, with a dose–response relationship.^{82, 83} Mucoepidermoid carcinomas (MECs) appear to be the most common radiation-induced salivary malignancy.^{82, 83} Occupational studies have suggested that indoor exposure to radon gas or volatile chemicals may also increase the risk for HNSCC.⁷⁹

Ultimately, the public health goal is better prevention and early detection of these malignancies by reducing the use of tobacco and alcohol, preventive vaccination against high-risk oncogenic HPV, discovering and avoiding other causative agents, and identifying the genetically susceptible. Unfortunately, HNSCC screening has not been effective, likely due to the rarity of the disease and expertise required for examination.⁸⁴ However, in parts of the world where HNSCC accounts for a major portion of the cancer burden, prevention and screening programs have had some measure of efficacy where implemented.⁶

Lips

SCCs of the mucosal surface of the lips are the most common oral cavity cancers. An important distinction must be made with cancers of the skin surrounding the lips, which are considered cutaneous malignancies. Over 90% occur on the lower lip, usually on the exposed vermilion border, midway between the midline and the oral commissure.¹²³ Well-differentiated and verrucous cancers rarely metastasize. Poorly differentiated and spindle cell varieties tend to grow aggressively and metastasize commonly. Perineural infiltration of large nerves is indicative of aggressive disease and often requires combined therapies.

Considerations in the treatment of lip cancers include (1) oncological control of the disease, (2) a functional oral sphincter with oral competence, and (3) acceptable cosmetic outcome. These goals may be achieved with either primary radiation or surgery when the tumors are less than 2 cm in size or very superficial. Larger or deeply invasive lesions, however, are best treated with surgical resection and reconstruction, which allow for greater accuracy in evaluating the extent of tumor and nerve or lymphatic involvement. Frequently, adjacent precancerous changes are present, which can also be treated with surgery (lip shaving and advancement) to prevent recurrences or the development of second primary tumors.^{124, 125} For larger lesions, primary reconstruction with local, regional, and sometimes free-tissue flaps avoids defects that result from tissue loss with radiotherapy, provides for future reconstructive and treatment options, and decreases the risk of osteoradionecrosis of the mandible. Lesions demonstrating extensive infiltration, bone involvement, or lymphatic metastases should be managed with combined surgery and PORT.

Radiation therapy techniques for management of lip cancers include external irradiation, interstitial implants, and combinations of both. Local tumor control rates with irradiation exceed 80%,^{126, 127} with determinant survival at 5 years (including surgical salvage) in excess of 95%. Similar tumor control and survival rates are reported with primary surgical excision.¹²⁸ Regional metastasis decreases the survival rates to approximately 55%.^{129, 130} The 5-year survival rates for patients with carcinomas of the upper lip are lower than for those with similar lower lip lesions and range from 40% to 60%.¹³¹ Involvement of both lips and the lateral commissure is uncommon. The prognosis for commissure lesions is not as good as for cancers of other areas of the lip.

Tongue

Tongue cancers account for approximately 25% of oral cavity SCCs and most commonly arise in the anterior two-thirds of the tongue on the lateral or ventral surface. Infiltration of the underlying tongue musculature occurs early. The biologic aggressiveness of T1 and T2 (<4 cm) tongue cancers is noteworthy and is reflected in higher rates of occult regional metastases than those of similarly staged lesions arising from other oral sites. Occult nodal metastases are present in 30–40% of early lesions.¹³² Bilateral nodal involvement can occur with cancers of the tip or the midline of the tongue. Locoregional recurrence in patients with tongue cancer accounts for 60–70% of cancer deaths. Distant metastases account for 10–15% of deaths, and second primaries in the UADT account for approximately 20–40%.^{132, 133} The management of carcinomas of the tongue has been significantly influenced by an increased appreciation of the aggressiveness of seemingly small but deeply infiltrative lesions, the high rate of occult lymph node metastases, and improvements in soft tissue and bony reconstruction. Although surgical excision alone has been the mainstay of treatment, combined surgery and adjuvant radiation therapy to include the primary site and regional nodes is commonly used for advanced cancers (stages III and IV) and is being used increasingly for small stage II cancers that exhibit pathologic indicators of lymph node metastasis or perineural invasion (Figure 3). Postoperative chemoradiotherapy is indicated for adverse pathologic findings of perineural invasion, nodal ECS, or close surgical margins.¹³⁴

For stage I cancers, surgical excision is effective and expeditious, with excellent preservation of function. For stage II lesions that are infiltrative, hemiglossectomy or partial glossectomy achieves excellent tumor control rates and should be combined with dissection of neck nodes at risk (supraomohyoid dissection) to provide accurate information about staging and determine the need for PORT. Free-tissue transfer reconstruction can significantly offset the morbidity of hemiglossectomy.

Extension of cancer to the FOM or the mandible may necessitate partial mandibulectomy or segmental mandibular resection. Modern reconstructive techniques with vascularized composite bone and soft tissue free flaps, titanium metal prostheses, and dental implants have improved the functional and cosmetic results of major mandibular resections. An elective neck dissection is recommended for lesions with >4 mm of invasion owing to the risk of occult nodal disease.

For more advanced primary lesions (stages III and IV), surgery and postoperative external beam radiation are generally used. No prospective controlled trials have proved the superiority of combined therapy over surgery alone for disease without nodal metastases, but retrospective studies indicate improved locoregional control rates.^135–138 These improvements have generally been offset, in part, by an increased frequency of distant metastases and second primaries. Surgical management generally consists of partial glossectomy and neck dissection, with the mandible being spared unless directly involved. In instances with limited periosteal invasion, partial mandibular resections that spare mandibular continuity and maintain function can be performed. When tumors extend to the midline or involve the tongue base, subtotal or total glossectomy may be necessary. Continued advances in reconstructive techniques have improved the functional results of these aggressive resections. Provision for temporary tracheostomy and prolonged enteral nutrition should be made. Total glossectomy or sacrifice of both hypoglossal nerves frequently necessitates permanent feeding gastrostomy. Current experience indicates that total glossectomy can, in highly select patients, be accomplished without the need for laryngectomy, although prolonged or even permanent parenteral feeding will likely be required.¹³⁹ PORT is generally administered within 4–6 weeks of surgery. High-risk surgical margins or ECS can be treated to a high-dose or with concomitant chemoradiotherapy. For advanced oral cavity cancers, both ipsilateral and contralateral necks are irradiated, with the dosage determined by the extent of disease. Close surgical margins are often treated to high doses (66–70 Gy) because of the difficulty in eradicating even small amounts of tumor in the tongue after glossectomy. Even with combined therapy, estimated 2-year disease-free survival (DFS) and OS rates for advanced disease are about 50%. The 5-year survival rates range from 50% to 70% for stages I and II to 15–30% for stages III and IV.^140–144

Floor of mouth (FOM)

FOM cancers occur with a frequency similar to that of tongue cancer. Early spread to adjacent areas (gingiva and periosteum of the mandible) is common. The periosteum of the mandible is a natural barrier to invasion. Fixation of the tongue is a sign of deep invasion. The tumor may extend to or through the mylohyoid muscle, which serves as a natural barrier to direct spread below the hyoid bone. Lymph node metastases at presentation are seen in approximately 40% of patients. The occult metastatic rate increases with the T stage of the primary: T2 tumors have a 40% and T3 tumors a 70% occult metastasis rate.^{145, 146}

First-echelon nodes of lymphatic drainage include the submandibular and jugulodigastric lymph nodes (levels I and II). Evaluation for early mandibular involvement is facilitated by palpation. since fixation to the mandible indicates periosteal involvement and direct bone invasion is present in 50–60% of such tumors. This distinction is often aided with bone windows on CT.

Small cancers (T1, T2) are generally treated effectively by wide resection. Lateral FOM tumors can often be resected transorally and the resection defect closed with the advancement of adjacent mucosa, skin grafts, or secondary intention. Sialodochoplasty of the severed submandibular duct can be performed for superficial lesions. An elective selected neck dissection is performed for T1 tumors with more than 4 mm of invasion and for all T2-4 cancers. Bilateral neck dissections should be performed for anterior FOM lesions, as both necks are at risk for occult metastasis due to the nature of lymphatic drainage in this region. If nodal metastases are present, therapeutic neck dissection is indicated. Surgery remains the mainstay of treatment of early FOM malignancies, achieving excellent functional and curative results.

More advanced FOM cancers (T3, T4) are generally treated with resection combined with similar approaches to that described for oral tongue cancers in the prior section (Figure 4). Again, mandibular continuity-sparing procedures with cortical resections can often be employed. In these instances, we have found fasciocutaneous flaps to offer excellent FOM and tongue reconstructive potential. Large mucosal and soft tissue surgical defects are typically reconstructed with free-tissue transfers, and contemporary management of mandibular defects entails bony reconstruction with either a fibula or scapula free flap.

Treatment results are influenced by the size of the primary tumor, presence of lymph node metastases, degree of mandibular involvement, and adequacy of resection. The 5-year survival rates for stage I and II FOM carcinomas range around 80%.¹⁴⁶ Cancers that cross the midline or involve the tongue or the mandible are associated with 5-year survival rates of 50–60%.¹⁴⁷ Survival rates for more advanced lesions (stages III and IV) are less than 50%. The major advantage of combined treatment (radiation and surgery) in these patients is improved control of neck disease. Recurrence in the untreated, clinically negative neck is the most frequent site of failure in patients treated only with surgery.¹⁴⁸ For patients with multiple nodal metastases, induction chemotherapy (IC) is under study¹⁴⁹ as there is high risk for later development of distant metastases. Continuing surveillance for metachronous second primary cancers in the head and neck, esophagus, or lungs is advised.^{150, 151}

Gingival and buccal mucosa

Gingival cancers occur most commonly (80%) in the lower gingiva, posterior to the bicuspids. For both sites, trismus is an ominous sign indicating extension to the masseter or pterygoid muscles. Occult nodal metastases have been documented in as high as 30% of buccal cancers and elective neck dissection recommended in all but the earliest of cancers.¹⁵² Exophytic tumors tend to be papillary or verrucous in appearance and can be confused with benign hyperkeratosis.

Small, superficial gingival cancers can be effectively treated with surgical resection transorally with excellent preservation of function. Even larger lesions requiring partial maxillectomy or alveolectomy can be resected without external incision. For larger lesions (T3 and T4), segmental mandibulectomy and/or maxillectomy is required, and adjuvant radiation is frequently recommended (Figure 5). Elective neck dissection should be performed for advanced lesions of the mandibular gingival, as these lesions tend to have occult metastases. Limited data are available on the behavior of maxillary ridge and hard palate cancers, but these lesions can metastasize to the lateral neck nodes, and thus elective management of the neck is strongly encouraged, whether with neck dissection or neck irradiation.¹⁵³ Clinically positive neck nodes warrant neck dissection at the time of the resection of the primary tumor.

OS rates for gingival and buccal cancers depend on tumor size, bone involvement, and node metastases. Surgical results are clearly superior to those of radiation when bone involvement is present.^{152, 154}

Retromolar trigone

Cancers arising in the retromolar trigone are rarely confined to that gingiva, but often involve adjacent buccal mucosa, anterior tonsillar pillar, the FOM, and/or posterior gingiva. The risk of clinically positive and occult lymph node metastases is higher than with other gingival cancers. Frequent involvement of periosteum mandates partial (rim or marginal) mandibulectomy as part of the surgical management, even for small lesions. Primary radiation therapy is reserved for superficial lesions that cover a large surface area, such as extension to the soft palate or buccal mucosa, and remain mobile. Moderately advanced or deeply invasive lesions are best treated with surgical resection (mandibulectomy and neck dissection), followed by postoperative adjuvant therapy, as indicated.

Tonsil

The traditional treatment of stage I and II tonsillar neoplasms is radiation therapy as a single modality. Transoral wide local excision of small, superficial lesions may be locally effective, but does not address the high potential of occult lymph node metastasis. While surgery and primary radiation offer comparable locoregional control for small tumors, patients with HPV-negative tumors may more often require PORT.¹⁵⁸ For patients with early-stage HPV-positive tumors, TORS with neck dissection offers excellent local-regional control, without the need for adjuvant radiotherapy.¹⁵⁷ Surgical management of advanced cancers results in poor patient function and, therefore, combined chemotherapy and radiotherapy approaches are utilized (Figure 6). For patients with nodal disease (N1-2), the addition of PORT to TORS is associated with excellent oncological and functional outcomes, and spares the need for concurrent chemoradiotherapy. There is a growing rationale for avoiding XRT, particularly among patients with p16-positive (HPV-related) small tumors (T1–2) and small volume neck disease (N1), and this approach is currently under investigation in a multi-institutional clinical trial (ECOG 3311).

Alternatively, radiation for early tonsillar cancers offers the advantage of treating upper echelon lymph nodes along with the primary tumor. Treatment is usually unilateral unless extension to the tongue base or midline soft palate is present.¹⁵⁹ Ipsilateral treatment portals allow sparing of the contralateral mucosa and salivary glands. Modern treatment techniques, such as IMRT, permit conformal dose delivery which can reduce the potential morbidity of radiation treatment, particularly by reducing radiation-related xerostomia. Initial institutional reports have indicated encouraging treatment outcomes with the use of IMRT in oropharyngeal cancer patients;^160–164 this is discussed in greater detail in the section titled “Radiotherapy.”

Survival rates for patients with advanced (stage III/IV) tumors vary according to HPV/p16 expression status and smoking history. Patients with HPV-positive tumors and less than 10 pack-year smoking history (low-risk) treated with the combination of chemotherapy and radiotherapy have a 3-year survival rate of 93%; while a smoking history of more than 10 pack-years and HPV-/p16-negative tumor undergoing chemoradiation have a 3-year survival rate of 46.2%.⁸⁸ In general, surgery is rarely recommended for advanced tonsillar tumors unless the mandible is grossly invaded. When surgery is planned, postoperative concurrent therapy should be anticipated in the properly selected patient.

Tongue base

Cancers of the base of the tongue pose a more difficult therapeutic problem than do tonsillar carcinomas, particularly for HPV-negative malignancies. Most patients with HPV-negative tumors present with advanced primary site disease due to the silent nature of these tumors, resulting in frequent regional metastases, greater treatment morbidity, and poor patient survival. Due to the aggressive nature of HPV-negative tumors, most are treated with definitive radiation with or without chemotherapy, although a role for TORS is currently under clinical investigation. Owing to the rich network of lymphatics present in the base of the tongue, 75% of patients will present with stage III or IV disease (Figure 7). Understaging of the primary tumor is common because these cancers tend to be diffusely infiltrative beyond their clinical appearance.¹⁶⁵

The results of radiation therapy alone as definitive treatment of small primary tumors (T1, T2) are better for exophytic than for deeply invasive tumors.¹⁶⁶ Radiation alone is generally reserved for those patients without clinical nodal metastases, but can be combined with planned neck dissection for patients with clinically positive nodes that persist after the completion of radiation-based approaches.

Surgical management of early primary tongue-base tumors (T1–2) achieves results similar to those from radiation alone. Advances in robotic surgery have prompted the application of this technology in the management of tongue-base cancers, and is now a well-established approach in the HPV-positive population.¹⁶⁷ Elective neck dissection can serve as a staging procedure, thereby providing a rationale for adjuvant radiation therapy. To date, no prospective randomized trial data that compare surgery alone with combined surgery with either preoperative or postoperative radiation are available.

Radiation therapy is a standard approach for definitive treatment for the oropharynx which combines the goal of an oncological cure with organ preservation. The current XRT regimens are the results of several large randomized trials that have demonstrated favorable OS and DFS,¹⁶⁸ although permanent dysphagia and gastrostomy tube usage rates remain substantial.¹⁵⁶ Total radiation dosages and overall treatment times are regarded as important variables for oncologic response and for tissue toxicity. Several studies have shown that altered fractionation improved the locoregional rate, and a meta-analysis of 15 trials demonstrated a survival advantage with altered fractionation regimens.¹⁶⁹ Since cancers of the oropharynx are adjacent to several critical structures, the ideal dose distributions would tightly conform to the target area and spare the nonaffected surrounding tissue, which has led to the use of IMRT as a standard of care for HNSCC.¹⁷⁰

The classic pattern of relapse after RT in OPSCC has been locoregional recurrence, attributed to the development of radioresistent tumor cells that persist after treatment. To overcome this resistance, chemotherapy has been added to sensitize the tumor cells to the damaging effects of ionizing radiation. For patients with locally advanced oropharyngeal cancer, a pivotal randomized phase III trial by the French GORTEC group revealed an improvement in both progression-free survival (PFS) and 5-year OS for patients receiving combined modality therapy (42% and 51%) versus radiation therapy alone (22.4% and 15.8%) and improvement in locoregional control rates in the chemoradiation arm (66%) versus radiation therapy alone (42%). Despite these benefits, similar rates of distant metastases were observed in both arms (11%) and more significant side effects, including hematologic toxicities and grades 3 and 4 mucositis were observed in the chemotherapy arm.^{171, 172} These toxicities led to a higher rate of temporary gastrostomy tube usage in the combination arm compared to the radiation therapy alone arm. Taken together, these results suggest that the addition of chemotherapy concurrently to radiation therapy improves locoregional control, which translates into both a PFS and OS benefit for these patients, at the expense of more acute toxicities.

The risk of recurrence for locally advanced OPSCC following surgical resection has traditionally been high. For patients with high-risk features, including perineural invasion, multiple positive nodes, and advanced T stage, PORT has been shown to decrease locoregional recurrences. Furthermore, it has been shown that the addition of chemotherapy given concurrently with radiation can improve locoregional control rates in patients with high-risk features, particularly when surgical margins are positive or ECS is present.^{134, 173} Thus, patients who undergo surgical resection for OPSCC should be considered for adjuvant chemoradiotherapy when adverse pathological features are present. Whether this treatment paradigm is necessary for HPV-positive patients is currently under investigation.

Soft palate and pharyngeal wall

Cancers of the soft palate and pharyngeal wall are less common than other oropharyngeal neoplasms. Many soft palate and posterior wall cancers tend to be superficial. Advanced lesions with deep invasion have ready access to the prevertebral fascia, infratemporal fossa, and skull base and can be associated with extensive submucosal spread with clinical skip areas.

Radiation-based approaches as curative treatment are preferred in most cases, even for T3 primary tumors. Resection of most soft palate lesions is associated with severe functional disability. The rates of occult regional metastases are difficult to determine because elective irradiation of bilateral nodal groups is included as part of primary treatment and must include the retropharyngeal lymphatics. Clinically positive lymph nodes at presentation occur in 30% of patients.¹⁷⁴ Small primary tumors with positive nodes can be effectively treated with definitive radiation to the primary tumor and neck. Neck dissections should be performed if disease in the neck persists at 6 to 8 weeks following the completion of XRT. Pharyngeal wall cancers or palate cancers with extension to the tonsil and those cases with advanced regional metastases are usually treated with combined chemoradiotherapy approaches unless gross mandibular involvement is noted. Overall 5-year survival rates for soft palate and faucial pillar cancers are 60–70% and range from 80% to 90% for T1 and T2 lesions to 30–60% for stages III and IV lesions.¹⁷⁵

Supraglottic cancers

Important factors in selecting therapy for supraglottic cancers are tumor location, cord fixation, and pre-epiglottic extension. Tumors limited to the suprahyoid epiglottis are amenable to radiation with fields that encompass neck regions at risk of lymphatic metastases. In addition, some proponents of limited surgical interventions recommend endoscopic laser excision separate from management of the neck. Tumors involving the aryepiglottic folds, pyriform sinuses, or infrahyoid epiglottis tend to be more aggressive, are deeply infiltrative, and frequently involve the pre-epiglottic space. Radiation alone is less effective than surgery, resulting in more frequent local recurrences that require surgical salvage. The addition of systemic concurrent chemotherapy will positively impact the outcomes of patients with these tumors. Persistent postradiation edema of the supraglottic larynx is not uncommon and contributes to difficulty in detecting recurrence, which occurs in 40–50% of cases.^{202, 203} Most patients who have recurrence will ultimately require a salvage total laryngectomy.

In any patient undergoing partial laryngectomy, preoperative consent should be obtained for total laryngectomy in case the surgical findings dictate that more extensive surgery is needed. Approximately 20% of patients require prolonged tracheostomy, and this is usually related to edema secondary to PORT. The rates of persistent swallowing difficulties are low, however, and the need for completion laryngectomy for persistent aspiration ranges only from 0% to 5%.^{204, 205}

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