INTRODUCTION — Oropharyngeal squamous cell carcinomas (OPSCC) arise in the soft palate, tonsils, base of tongue, pharyngeal wall, and vallecula, the fold located between the base of tongue and the epiglottis (figure 1) [1].
The treatment of early squamous cell cancers of the oropharynx is reviewed here. The treatment of locally advanced oropharyngeal cancers, human papillomavirus (HPV) associated (ie, p16 positive) oropharyngeal cancer, and the management of metastatic and recurrent head and neck cancer is discussed separately.
●(See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx".)
●(See "Treatment of human papillomavirus associated oropharyngeal cancer".)
●(See "Treatment of metastatic and recurrent head and neck cancer".)
EPIDEMIOLOGY AND RISK FACTORS — Oropharyngeal squamous cell carcinomas (OPSCC) are relatively uncommon malignancies. The lifetime risk of developing oral cavity and oropharyngeal cancer is approximately 1 in 60 (1.7 percent) for males and 1 in 140 (0.71 percent) for females [2]. The five-year relative survival rate for all oropharyngeal cancers (including both human papillomavirus [HPV] associated and non-HPV associated tumors) is approximately 67 percent [2]. (See "Epidemiology and risk factors for head and neck cancer".)
Use of tobacco and alcohol were historically the principal risk factors for these cancers. Despite the decreasing prevalence of smoking, there is an increasing incidence of oropharyngeal cancers, particularly in younger, middle-age adults. This trend is related to an increase in oropharyngeal cancers caused by HPV infection; these cancers arise predominantly in the tonsillar area and the base of tongue.
Although most HPV associated oropharyngeal cancers present with locoregionally advanced disease, these tumors have a better prognosis than those related to tobacco and alcohol use. There are clinical trials investigating treatment deintensification in HPV associated oropharynx cancers. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Is there a role for treatment deintensification?'.)
STAGING — The eighth edition tumor, node, metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used to classify oropharyngeal carcinoma [3]. The eighth edition TNM staging system for clinical and pathologic staging distinguishes between human papillomavirus (HPV) associated (ie, p16 positive) oropharyngeal carcinoma (table 1 and table 2) and non-HPV associated (ie, p16 negative) tumors of the oropharynx (table 3 and table 4).
●Non-HPV associated stage I and II – Primary tumors ≤4 cm in greatest dimension without invasion into surrounding structures and with no clinical or radiographic evidence of lymph node involvement.
●HPV associated stage I – Primary tumors <4 cm in greatest dimension and either no regional lymph node metastasis or one or more ipsilateral lymph nodes, none larger than 6 cm.
●HPV associated stage II – T3 primary tumors (>4 cm in greatest dimension or with extension to the lingual surface of the epiglottis) with or without regional lymph node metastasis (ipsilateral, contralateral, or bilateral), none larger than 6 cm, OR primary tumors <4 cm with regional lymph node metastasis that are contralateral or bilateral, none larger than 6 cm.
GENERAL PRINCIPLES
Treatment approach — Patients with early (stage I and II) non-human papillomavirus (HPV) associated squamous cell carcinomas of the oropharynx can be treated with either primary surgery or definitive radiation therapy (RT) as a single modality. Definitive RT and primary surgery have yielded similar rates of local control and survival. The morbidity associated with each treatment approach is an important factor in making treatment decisions. (See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Nonsurgical versus surgical approaches'.)
For patients with early-stage HPV associated squamous cell carcinoma of the oropharynx, treatment may include surgery, RT, and chemotherapy, either as single modalities or in combination. The management of these patients is discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Initial treatment'.)
Surgical techniques — Minimally invasive techniques, such as transoral robotic surgery (TORS), have made resection of carefully selected early oropharyngeal cancers both feasible and well tolerated [4,5]. Another available option is transoral laser microsurgery (TLM), which uses an endoscope to view the pharynx through the mouth and a laser to excise the tumor. In most centers that perform minimally invasive surgery, TORS is used more frequently than TLM.
For patients who choose surgery, we suggest minimally invasive transoral surgery rather than more invasive surgical techniques [6]. Minimally invasive surgical approaches allow adequate visualization and exposure of oropharyngeal primary tumors without the morbidity of mandibulotomy and lip-split approaches. These approaches are most feasible for early tumor (T) stage tumors of the oropharynx (T1/T2) where function is likely to be preserved and become more challenging with advanced T stages where functional morbidity is likely. This is particularly true for those tumors with pterygoid and/or mandibular involvement or bilateral neck node involvement. (See "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx", section on 'Surgical techniques for the primary tumor' and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Surgical technique'.)
A study of the impact of TORS on overall treatment in patients with oropharyngeal cancer showed that with appropriate selection, TORS with neck dissection can yield good functional results [7]. In addition, TORS can also provide accurate staging of patients and can lead to appropriate selection of subsequent therapy. In this series, 42 patients were in the TORS group and were compared with 38 patients in the conventional chemoradiation group; 43 percent of the patients receiving initial surgery had a change in stage, and subsequent therapy was altered in 21 percent. This occurred at the primary site as well as the neck, and it was found to change staging in both directions. Survival was not compromised in the surgical group.
When TORS is applied to select patients with early-stage tumors, perioperative mortality is low and a majority can achieve negative resection margins. In a retrospective observational study of 2694 patients with clinically T1 or T2 oropharyngeal squamous cell carcinoma (OPSCC) treated with TORS between 2010 and 2015, 90-day mortality was 1.4 percent [6]. When compared with nonrobotic resection, TORS was associated with lower rates of positive resection margins (13 versus 20 percent), lower use of adjuvant chemotherapy (29 versus 36 percent), and improved five-year overall survival (85 versus 80 percent).
Randomized phase II studies have compared surgery versus definitive RT in patients with HPV associated OPSCC. These data are discussed separately. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Surgical resection'.)
Radiation therapy — The dosing of RT to the primary tumor and regional lymph nodes, and the optimal techniques for RT administration are discussed separately, as are the complications associated with RT. (See "General principles of radiation therapy for head and neck cancer" and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)
Management of the neck — The risk of occult neck metastases in a patient with early (T1/T2) oropharyngeal cancer and a clinically negative neck is relatively high. Thus, elective treatment of the neck is usually indicated. Elective treatment of the neck can be accomplished with either nodal dissection or RT. Patients undergoing primary surgery should be evaluated for appropriate ipsilateral or bilateral neck dissections to accurately stage the neck in the setting of a multidisciplinary tumor board discussion. Our approach is generally consistent with guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) [8,9].
Early tonsil cancers without soft palate or base of tongue involvement are considered lateralized primaries, and elective nodal treatment can involve either selective neck dissection (levels II to IV) in patients undergoing primary surgery (transoral or open) or ipsilateral neck RT in patients undergoing definitive RT.
However, it is important to address both sides of the neck for base of tongue, soft palate, and posterior pharyngeal wall primary tumors as these are considered midline structures, which can have bilateral lymphatic drainage. For patients with midline tumors managed with definitive RT, bilateral neck irradiation is recommended. For patients who initially undergo primary surgery of midline tumors, bilateral selective neck dissection including levels II to IV is recommended (figure 2) [10-12].
MANAGEMENT OF SPECIFIC TUMOR SITES
Soft palate — Patients with early cancer of the soft palate are usually treated with radiation therapy (RT) to the primary tumor and to the bilateral necks [9]. Retropharyngeal nodes should be included when irradiating soft palate primaries. Although locoregional control and survival with RT are comparable with surgery, surgery is generally associated with greater functional impairment, particularly velopharyngeal insufficiency [13]. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Selection of therapy: Surgery versus radiation'.)
If patients are treated with primary surgery for soft palate cancers, then it is essential that the tumor is amenable to margin-negative resection and that reconstruction with a free flap or obturator is performed unless the defect is not through and through. (See "Mandibular and palatal reconstruction in patients with head and neck cancer", section on 'Soft palate reconstruction'.)
For patients with stage I soft palate cancers, five-year locoregional control, cause-specific survival, and overall survival rates of 84, 89, and 52 percent, respectively, have been reported [14,15]. Similar rates have been published for patients with stage II disease (85, 87, and 61 percent, respectively).
Tonsillar cancer — Early tonsillar cancers can be treated with either primary surgery or RT, with similar outcomes [9,16]. The majority of cases of tonsillar cancer are now human papillomavirus (HPV) associated. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Selection of therapy: Surgery versus radiation' and "Epidemiology, staging, and clinical presentation of human papillomavirus associated head and neck cancer".)
With transoral approaches (robotic or laser), functional outcomes with both definitive RT and primary surgery are extremely good in carefully selected patients. In one series, reported five-year local control and cause-specific survival rates following initial RT were 88 and 100 percent for stage I disease and 84 and 86 percent for stage II disease [17]. (See "General principles of radiation therapy for head and neck cancer" and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)
Small tumors confined to the tonsil (ie, surrounded by normal tissue) can be treated with radical tonsillectomy. If primary surgery is used for tumors that extend beyond the tonsil itself, the pharyngeal wall and/or soft palate should be included in the resection.
More extensive but still early-stage tumors can be treated either with surgery or RT. When selecting between these two approaches, the multidisciplinary tumor board should weigh the treatment-related morbidity of either a primary surgery or definitive RT approach as it relates to the particular defect. For such tumors that are treated surgically, minimally invasive surgery, such as transoral robotic surgery (TORS), has largely replaced open surgical procedures (such as an anterior approach [a combined lip-splitting incision coupled with an anterior midline or lateral mandibulotomy] or a transhyoid approach). TORS avoids the morbidity associated with open surgical procedures and has been associated with significantly improved outcomes including high rates of local control [18-20]. Open surgical procedures are uncommon, except in the setting of salvage therapy. [21,22].
Base of tongue — Patients with primary squamous cell carcinomas arising at the base of tongue can be treated with either surgery (using minimally invasive approaches) or definitive RT. While RT is preferred in most patients with base of tongue tumors due to the anatomic midline location and propensity to involve cervical lymph nodes, carefully selected small tumors can be successfully treated with surgery if clinical expertise is available, negative margins can be obtained, and no other adverse features (eg, positive nodes, extranodal extension) are suspected that would warrant further adjuvant therapy. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Selection of therapy: Surgery versus radiation'.)
Patients with base-of-tongue tumors should also receive elective treatment to the bilateral neck. Base-of-tongue tumors are anatomic midline structures with bilateral lymphatic drainage, and the risk of occult lymph node metastasis is higher than for other oropharyngeal subsites, ranging from 21 to 45 percent [23]. Elective RT is recommended to the lymph node basins at risk for patients who are treated with primary RT, while lymph node dissection is recommended for patients who underwent surgical resection. (See "General principles of radiation therapy for head and neck cancer" and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)
Candidates for minimally invasive surgery must be carefully selected so that further adjuvant therapy (eg, RT with or without chemotherapy) can be avoided, if feasible. Patients treated with primary surgery who have positive margins will require postoperative chemoradiation. Similarly, patients with other adverse features (eg, many positive nodes, extranodal extension, bilateral nodal involvement) have a higher tumor stage and will require concurrent chemoradiation in addition to primary surgery. Treatment with triple modality therapy increases the morbidity and risk for long-term toxicity. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer".)
TORS has demonstrated excellent oncologic outcomes in base of tongue tumors. In one observational study of TORS in 410 patients with oropharyngeal cancer, two-year overall survival was 92 percent for the subset of those with base-of-tongue tumors [24].
Transoral laser microsurgery (TLM) may also improve local control and functional results for appropriately selected patients [25,26]. As an example, one study reported two-year local control and survival of 100 and 92 percent for T1 lesions and 87 and 91 percent for T2 lesions [26]. Compared with conventional open surgery, TLM minimizes the risk of fistula, flap failure, abscess, or osteoradionecrosis and is associated with a shorter hospital stay. Postoperative hemorrhage occurred in 5 to 10 percent of cases, but these data were obtained prior to the practice of ligating vessels, which lowers the risk of hemorrhage. [25,26].
ADJUVANT THERAPY — Patients with stage I and II oropharyngeal cancers are most commonly managed initially with either definitive radiation therapy (RT) or primary surgery (transoral with elective nodal dissection). While most patients do not receive further treatment, some require adjuvant therapy to reduce the risk of recurrent disease:
●Patients with residual disease after definitive RT are managed with salvage surgery.
●Patients initially treated with primary surgery should receive postoperative RT with concurrent, platinum-based chemotherapy for positive or closely resected margins and/or extranodal extension of lymph nodes. The management of tumors with these and other pathologic features that indicate a risk of recurrence, such as lymphovascular and perineural invasion, is discussed separately. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer" and "Overview of the treatment of locoregionally advanced head and neck cancer: The oropharynx".)
SURVEILLANCE — Regular posttreatment follow-up is an essential part of the care of patients treated for early-stage oropharyngeal cancer after potentially curative treatment. Further details are discussed separately. (See "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Head and neck cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Throat cancer (The Basics)" and "Patient education: Tongue cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Sites of disease – Oropharyngeal squamous cell carcinomas (OPSCC) can arise in the soft palate, tonsils, base of tongue, pharyngeal wall, and vallecula. (See 'Management of specific tumor sites' above.)
●Treatment of the primary tumor
•Non-HPV associated tumors – Early (stage I and II) non-human papillomavirus (HPV) associated tumors can be effectively treated with single-modality therapy, using either radiation therapy (RT) or transoral surgery. (See 'Treatment approach' above.)
•HPV associated tumors – For patients with early-stage HPV associated tumors, management may include surgery, RT, and chemotherapy, either as single modalities or in combination. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Initial treatment'.)
●Surgical approach - For patients with early-stage disease who choose surgery, we suggest minimally invasive transoral surgery rather than more invasive surgical techniques (Grade 2C). (See 'Surgical techniques' above and "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Surgical technique'.)
●Elective treatment of the neck – Elective neck treatment is indicated for all patients with early-stage (N0 by definition) oropharyngeal cancer. Patients undergoing primary surgery should be evaluated for appropriate ipsilateral or bilateral neck dissections to accurately stage the neck in the setting of a multidisciplinary tumor board discussion. (See 'Management of the neck' above.)
•If elective nodal dissection is planned, bilateral neck dissection is indicated for tumors on or near the midline; ipsilateral neck dissection is sufficient for lateralized primary tumors.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Carol R Bradford, MD, FACS, who contributed to an earlier version of this topic review.
