Treatment of locoregionally advanced (stage III and IV) head and neck cancer: The oral cavity

INTRODUCTION — The treatment of locoregionally advanced (stage III and IV (table 1)) squamous cell carcinoma of the oral cavity is discussed here.

An overview of the approach to oral cavity cancer and the treatment of early stage disease are presented separately, as is the management of patients with metastatic and recurrent disease:

●(See "Treatment of stage I and II (early) head and neck cancer: The oral cavity".)

●(See "Treatment of metastatic and recurrent head and neck cancer".)

●(See "Overview of treatment for head and neck cancer".)

ANATOMY AND STAGING — The oral cavity extends from the skin-vermilion junction of the lips to the junction of the hard and soft palate above and to the line of circumvallate papilla of the tongue below (figure 1). The anterior tonsillar pillars and glossotonsillar folds serve as the lateral boundaries between the oral cavity and oropharynx.

Specific sites of oral cavity cancer include the lip, floor of the mouth, oral tongue (anterior two-thirds of the tongue), lower alveolar ridge, upper alveolar ridge, retromolar trigone (retromolar gingiva), hard palate, and buccal mucosa.

The tumor, node, metastases (TNM) staging system of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) is used to classify lip and oral cavity carcinoma (table 1) [1]. (See "Overview of the diagnosis and staging of head and neck cancer".)

By definition, patients with stage III and IV disease have tumors greater than 4 cm in greatest dimension, invasion of adjacent structures, and/or evidence of lymph node involvement.

MANAGEMENT

Pretreatment evaluation — Delineation of the tumor size and extent of invasion, as well as potential involvement of regional lymph nodes, is essential prior to treatment in patients with oral cavity cancer. (See "Overview of the diagnosis and staging of head and neck cancer" and "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Pretreatment evaluation'.)

In addition, patients with locoregionally advanced disease should be evaluated for the presence of distant metastases. CT of the chest is a screen for lung metastases, and a PET/CT can be considered to rule out distant metastatic disease and potentially better characterize the primary tumor or neck nodes. Small, clinically indeterminate pulmonary nodules are often identified and should be followed.

All patients should be seen preoperatively by the surgeon, radiation oncologist, and medical oncologist for preoperative treatment planning. Assessment of comorbidity, speech and swallowing function, nutritional status, and dental and psychosocial evaluations are also important steps in treatment planning. (See "Treatment of human papillomavirus associated oropharyngeal cancer", section on 'Pretreatment evaluation'.)

Approach to therapy — Locoregionally advanced oral cavity cancers are aggressive malignancies with high rates of recurrence following definitive treatment with either surgery or radiation therapy (RT) alone [2]. Thus, a combined modality approach is generally indicated when permitted by the patient's overall condition.

Decisions about the optimal integration of surgery, RT, and chemotherapy for each patient should be made with multidisciplinary input. The management plan should take into account the likely functional consequences of treatment as well as the expertise of the treatment team.

There are limited randomized clinical trials to define an optimal strategy for patients with locoregionally advanced oral cavity cancers. Our approach is as follows:

●Resectable disease – For most patients with resectable disease, we suggest surgery as the initial therapy for locally advanced oral cavity cancers [3]. In most cases, simultaneous resection and reconstruction is feasible with acceptable functional outcomes. (See 'Resectable disease' below.)

For most patients with resected disease, adjuvant (eg, postoperative) RT or chemoradiation is the standard of care since these patients are at significant risk for local recurrence after surgery. (See 'Adjuvant RT or chemoradiotherapy' below.)

●Patients with technically unresectable disease or those who decline surgery – RT and/or chemoradiotherapy, with or without prior induction chemotherapy, is an alternative approach for patients who have a technically unresectable tumor (eg, due to carotid artery encasement, vertebral or brain invasion), are medically inoperable, or decline surgery. (See 'Technically unresectable disease' below.)

●Patients with borderline resectable or functionally unresectable disease – For select patients with good performance status (table 2) and either borderline resectable disease or those who are predicted to have an unacceptable functional outcome with initial surgery, we reserve the use of neoadjuvant (eg, preoperative) chemotherapy as initial therapy in an attempt to achieve surgical and functional preservation of important oral structures. The use of neoadjuvant chemotherapy should be determined using multidisciplinary input, as no survival advantage has been demonstrated with this approach [4-7] and data on long-term toxicity are limited [8]. Patients are encouraged to enroll in clinical trials, where available. (See 'Borderline resectable or functionally unresectable disease' below.)

TREATMENT OF THE PRIMARY TUMOR

Resectable disease — For patients with resectable disease, we suggest surgery as the initial therapy for patients with locoregionally advanced oral cavity cancer, although data comparing surgery with RT are limited [9,10].

Surgical technique — Oral cavity cancers can be accessed through a transoral approach or a combined transoral and transcervical approach. Traditional surgical techniques are generally used for locally advanced cancers. For these tumors, there is no advantage to minimally invasive approaches, such as transoral laser resection or robotic-assisted surgery, particularly given the complexity of the reconstruction that is often required.

Every attempt should be made to ensure negative resection margins, since there is an increased risk of treatment failure in patients with positive surgical margins, even when adjuvant RT or chemoradiotherapy is used [11]. If positive margins are identified, reresection is indicated when feasible. Adjuvant RT or chemoradiotherapy is indicated when positive surgical margins are identified.

Surgical procedures (eg, glossectomy, maxillectomy, mandibulectomy) can result in severe functional defects in speech and swallowing. The functional loss associated with these procedures may be mitigated by reconstruction and intense speech and swallowing rehabilitation. (See "Mandibular and palatal reconstruction in patients with head and neck cancer".)

Adjuvant RT or chemoradiotherapy — Adjuvant radiation therapy (RT) with or without concurrent chemotherapy is the standard of care for patients with resected locoregionally advanced oral cavity cancer since these patients are at significant risk for local recurrence after surgery [3]. The exception would be patients with a negative-margin resection of a thin primary lesion and a single metastatic lymph node without extranodal extension (ENE). (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity".)

For patients receiving adjuvant chemoradiation, we use cisplatin 40 mg/m² weekly as the chemosensitizer of choice, which is discussed separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy", section on 'Cisplatin'.)

Observation may be appropriate in such cases, particularly for patients with a marginal performance status. Randomized trials that included patients with oral cavity cancers have confirmed the benefit of adjuvant concurrent chemoradiation compared with adjuvant RT alone for high-risk patients with locally advanced head and neck cancer. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Chemoradiation versus radiation therapy alone'.)

Risk factors associated with a particularly increased risk of recurrence include ENE, positive resection margins, N2 or N3 nodal disease, nodal disease in levels IV or V, perineural invasion, or vascular invasion. Positive margins and ENE are absolute indications for chemoradiotherapy, and advanced nodal disease or perineural or vascular invasion may be a consideration for adding chemotherapy to RT. The presence of T3 or T4 disease, without any other high-risk features, is an indication for RT alone. (See "Adjuvant radiation therapy or chemoradiation in the management of head and neck cancer", section on 'Chemoradiation versus radiation therapy alone'.)

A phase III trial conducted in India attempted to determine the optimal approach to adjuvant RT in patients with locally advanced oral cavity cancer [12]. In that trial, 900 patients with predominantly gingival or buccal carcinoma were randomly assigned following surgery to RT alone (60 Gy in 30 fractions over six weeks), accelerated RT (60 Gy in 30 fractions over five weeks), or RT (60 Gy in 30 fractions over six weeks) in conjunction with chemotherapy (cisplatin 30 mg/m² weekly). For the entire study population, there was no difference in locoregional tumor control, disease-free survival (DFS), or overall survival (OS). However, in an unplanned post hoc analysis, there was a statistically significant improvement in all three outcome parameters, particularly OS, for high-risk patients (T3-T4, N2/N3, ENE) and for patients treated with either concurrent chemotherapy or standard fractionation versus the accelerated RT course. Treatment compliance was equivalent in all groups. Toxicity rates were equivalent in all three groups, although they trended towards more mucositis and dermatitis with six-days-per-week radiation.

Adjuvant RT is generally preferred over neoadjuvant RT for patients with locoregionally advanced oral cavity cancer. The administration of neoadjuvant preoperative RT can delay surgery and increases the risk of adjuvant complications.

Borderline resectable or functionally unresectable disease

Neoadjuvant chemotherapy — For select patients with good performance status (table 2) and either borderline resectable oral cavity squamous cell carcinoma (OCSCC) or those who are predicted to have an unacceptable functional outcome with initial surgery, we reserve the use of neoadjuvant (eg, preoperative) chemotherapy in an attempt at surgical and functional preservation of important oral structures. We offer three cycles of docetaxel, cisplatin, and fluorouracil (TPF (table 3)) to patients receiving neoadjuvant chemotherapy.

The choice of subsequent definitive therapy (surgery versus nonsurgical approaches) is determined by the response to neoadjuvant chemotherapy.

●Patients where neoadjuvant chemotherapy converts their disease from unresectable to resectable may subsequently be offered surgery followed by adjuvant RT or chemoradiation, as indicated.

●Patients whose disease remains unresectable despite neoadjuvant chemotherapy or those who are unlikely or unable to tolerate neoadjuvant chemotherapy due to performance status or comorbidities can receive definitive RT or chemoradiation as an alternative to surgery.

The use of neoadjuvant chemotherapy should be restricted to such highly selected cases with multidisciplinary input, as no survival advantage has been demonstrated with this approach [4-7] and data on long-term toxicity are limited [8]. Patients are encouraged to enroll in clinical trials, where available.

In patients with locoregionally advanced OCSCC, neoadjuvant chemotherapy may allow for surgical and functional preservation of important oral structures (such as the mandible or tongue), which can improve patient quality of life [4,6,13]. Although data for long-term toxicity are limited [8], observational studies also suggest that neoadjuvant chemotherapy does not increase overall perioperative complication rates [14].

However, in most randomized trials, neoadjuvant chemotherapy did not improve OS or DFS [4-6,10,13]. It is not known if longer courses of neoadjuvant TPF improve survival in these patients. Advances in patient selection and surgical techniques may also result in lower rates of mandibulectomy and adjuvant radiation without the need for neoadjuvant chemotherapy.

Data for various neoadjuvant chemotherapy regimens are as follows:

●Docetaxel, cisplatin, and fluorouracil (TPF) – In a phase III trial, 256 patients with advanced OCSCC were randomly assigned to either two cycles of TPF followed by surgery and adjuvant RT, or immediate surgery and adjuvant RT [5]. At median follow-up of 30 months, compared with immediate surgery, neoadjuvant chemotherapy did not improve OS (hazard ratio [HR] 0.98) or DFS (HR 0.97).

Similarly, in a randomized phase II trial of 68 patients with locoregionally advanced OCSCC, two cycles of neoadjuvant TPF followed by surgery and adjuvant chemoradiation did not improve DFS or OS compared with immediate surgery and adjuvant therapy [6]. However, mandibular preservation, the primary endpoint, was achieved in more patients treated with neoadjuvant TPF (47 percent; 16 of 34 patients) versus immediate surgery (0 percent; all 34 patients treated with segmental mandibulectomy). Of note, this study only included patients without mandibular disease involvement. Mandibulectomy was only indicated for surgical access, the need for which varies in clinical practice.

●Cisplatin plus fluorouracil – In a phase III trial, 195 patients with locoregionally advanced resectable OCSCC were randomly assigned to either three cycles of cisplatin plus fluorouracil followed by surgery, or immediate surgery [4,13]. Adjuvant RT was used for high-risk patients in both arms of the trial [4]. At median follow-up of 11.5 years, compared with immediate surgery, the addition of neoadjuvant chemotherapy to surgery did not improve ten-year DFS (49 versus 36 percent) or ten-year OS (47 versus 38 percent) [13]. Rates of locoregional relapse rates (30 versus 32 percent) and distant metastases (4 versus 9 percent) were also similar between the two treatment arms [13].

However, the use of neoadjuvant chemotherapy reduced the rates of mandibulectomy (31 versus 52 percent) and adjuvant radiation (33 versus 46 percent). However, most patients with resected locally advanced oral cavity tumors receive adjuvant radiation or chemoradiation in clinical practice [4]. (See 'Adjuvant RT or chemoradiotherapy' above.)

Is there a role for neoadjuvant immunotherapy? — Neoadjuvant (eg, preoperative) immunotherapy is not indicated for advanced OCSCC outside of a clinical trial. The use of neoadjuvant immunotherapy warrants further investigation, and randomized trials are ongoing.

The following studies have evaluated the feasibility of neoadjuvant immunotherapy in OCSCC:

●In an open label phase II trial, 29 patients with ≥T2 OCSCC were randomly assigned to a very brief course of neoadjuvant nivolumab with or without ipilimumab [15]. A minority of patients (24 percent) experienced grade 3 or greater toxicity, and none required delay of surgery. Despite the short time to surgery, pathologic downstaging was noted in approximately half, with complete or near complete responses in four patients (14 percent). The extent of surgery was not modified by neoadjuvant treatment and progression-free survival and OS data have not been reported.

●Another open label phase II trial included 36 patients with advanced stage HPV-negative HNSCC, most with advanced stage OCSCC (22 patients, 61 percent) [16]. Using a single dose of pembrolizumab prior to surgery, no grade 3 or greater toxicity or surgical delays were observed. Some degree of pathologic tumor response was noted in 44 percent of patients and pathologic downstaging was observed in seven patients (19 percent).

Technically unresectable disease

Definitive RT or chemoradiation, potentially preceded by induction chemotherapy, are alternatives for patients who have a technically unresectable tumor (eg, carotid artery encasement, vertebral or brain invasion), are medically inoperable, or decline surgery.

●A combined modality approach utilizing both chemotherapy and RT is appropriate for patients who are not surgical candidates but whose overall condition will tolerate the potential increase in toxicity. Approaches that may be used include induction chemotherapy followed by definitive concurrent chemoradiotherapy or RT and immediate concurrent chemoradiotherapy. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy".)

●RT without chemotherapy is appropriate for patients who are not surgical candidates and whose medical condition will not tolerate the increased toxicity associated with induction chemotherapy or concurrent chemoradiation.

●Patients who are ineligible for RT are treated with systemic therapy using a similar approach to those with metastatic disease. (See "Treatment of metastatic and recurrent head and neck cancer".)

For patients where a nonsurgical approach was originally undertaken because of either the low probability of surgical cure or the morbidity associated with resection, complete resection or neck dissection may be indicated as a salvage procedure for residual disease. However, the risks of salvage surgery are substantial, and the oncologic outcomes are generally poor.

MANAGEMENT BY ORAL CAVITY SUBSITES

Lip — Although squamous cell carcinomas are the most frequent histologic type of lip cancer, these tumors generally are more related to skin cancers than to other oral cavity cancers. Because they are readily visible, most lip cancers are diagnosed at early stages, with T3 and T4 tumors representing a very small proportion of cases [17,18]. (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Lip (squamous cell carcinoma)'.)

Occasionally, definitive RT may be functionally and cosmetically preferable to surgical resection. In cases with bone or nerve invasion, resection with adjuvant RT is indicated [19].

Floor of mouth — Locally advanced cancer of the floor of mouth is typically treated with surgical resection to achieve negative margins, followed by adjuvant RT with or without concurrent chemotherapy. The combination of surgery and adjuvant RT has been associated with better local control than either modality alone, as surgical resection alone (with 1 to 2 cm margins) for stage III and IV disease (table 1) results in five-year OS of only 46 and 26 percent [20,21].

Cancer of the floor of mouth has a high rate of mandibular invasion and cervical lymph node metastases. Furthermore, anterior floor of mouth cancers often involve the geniohyoid tubercle and genioglossus muscle anteriorly. Thus, surgery will frequently require segmental mandibulectomy as a marginal resection of bone is generally not possible in the coronal plane.

Oral tongue — The oral tongue is the most common subsite for oral cavity cancer. Cancer of the oral tongue has been associated with a worse prognosis compared with other oral cavity subsites in some but not all series [22,23]. Typically, five-year disease-specific survival rates of 39 and 27 percent have been achieved for stage III and IV disease, respectively [24].

Partial glossectomy is commonly required for locoregionally advanced disease. Total glossectomy is occasionally required in cases where bilateral lingual arteries are involved by cancer. In those cases, total laryngectomy may also be required to prevent aspiration. The addition of adjuvant RT or chemoradiotherapy, appears to improve disease control compared with surgery alone [25].

Primary treatment with concurrent chemoradiotherapy or sequential therapy may be preferred when total glossectomy is indicated, given the overall poor prognosis and functional loss associated with surgery. Patients considering this option should be aware of the potential trade-off between oncologic and functional outcome. (See 'Technically unresectable disease' above.)

Lower alveolar ridge and retromolar trigone — The surgical approach to resection of locoregionally advanced oral cavity cancer involving the lower alveolar ridge depends upon the status of the teeth. Patients with good dentition are often candidates for marginal resection of the mandible, which can be performed transorally. In contrast, edentulous patients and those with loose teeth involved by cancer require segmental resection of the mandible to ensure adequate clearance of disease.

Similarly, locally advanced retromolar trigone lesions typically require segmental mandibulectomy followed by adjuvant RT [26,27]. Resection of the ascending ramus of the mandible including the pterygoid muscles is important to ensure eradication of disease. Microvascular reconstruction with a fibular free tissue transfer provides optimal functional and cosmetic rehabilitation. (See "Treatment of stage I and II (early) head and neck cancer: The oral cavity", section on 'Lower alveolar ridge and retromolar trigone'.)

Upper alveolar ridge and hard palate — Hard palate cancers are rare. Locally advanced lesions typically involve the underlying bone, and primary surgery is used more commonly than definitive RT [28]. Resection is generally well tolerated. These patients can be reconstructed with either an immediate surgical obturator or microvascular-free tissue transfer.

Buccal mucosa — Buccal mucosa cancers have a high tendency to recur locoregionally and systemically. Consequently, patients with buccal mucosa cancers have a worse survival rate compared with patients with cancer in other oral cavity subsites [29].

Exposure of a buccal mucosa cancer can be difficult via a transoral approach, which makes it difficult to obtain clear radial margins in an en bloc fashion. Furthermore, the thin distance between the buccal mucosa and the buccal space permits early invasion to deep structures or to anterior cheek skin. Exenteration of the buccal space, parotid, and skin may be needed to maximize oncologic outcome for deeply invasive tumors, although this is achieved with a considerable cost to cosmesis.

Cancer of the buccal mucosa can be treated with definitive RT. However, deeply invasive cancers should be managed with surgery and adjuvant RT or chemoradiation. Regardless of the method of treatment, there is a high risk of severe, irreversible trismus. Aggressive reconstruction and rehabilitation is required to optimize functional outcomes. (See "Management of late complications of head and neck cancer and its treatment", section on 'Trismus'.)

SUPPORTIVE CARE MEASURES — Prophylactic tracheostomy is often required for locoregionally advanced oral cavity cancers undergoing surgery, except for cancers of the upper alveolar ridge and hard palate. The tracheostomy can usually be removed within a couple of weeks of surgery and prior to adjuvant therapy. In some cases, tracheostomy is maintained during adjuvant RT or chemoradiotherapy.

A feeding tube is usually required after surgery. A nasogastric feeding tube is feasible if the impact on swallowing is expected to be minimal and of relatively short duration. A gastrostomy tube is advised for patients who have lost significant weight before surgery and for those whose swallowing will be severely compromised. (See "Gastrostomy tubes: Uses, patient selection, and efficacy in adults".)

MANAGEMENT OF THE NECK — Patients with stage III and IV oral cavity cancer either have clinically involved lymph node(s) in the neck or are at significant risk of subclinical nodal involvement due to the size and extent of the primary tumor. Thus, treatment of the neck is indicated [3]; this usually includes unilateral or bilateral neck dissection with adjuvant RT to the neck, when indicated.

Although there is disagreement regarding some details, our approach is generally consistent with guidelines from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) [30,31]. An important difference is that we recommend adjuvant neck RT to patients with a single pathologically positive lymph node. While the NCCN allows for RT in this population, ASCO limits RT in this scenario to patients with high-risk features such as perineural invasion, lymphovascular space invasion, or a T3/4 primary.

The extent of neck dissection remains controversial. Elective lymph node dissection for clinically N0 tumors should include at least 18 lymph nodes. Limiting the extent of dissection reduces surgical morbidity, particularly if level V is excluded (figure 2). A selective dissection including levels I to III, a supraomohyoid neck dissection, is typically sufficient for clinically N0 oral cavity cancer, as level IV and V nodes are rarely involved without clinical disease at other levels [32-36]. This dissection includes the submandibular gland but preserves the spinal accessory nerve, the internal jugular vein, and the sternocleidomastoid muscle. Some cancers of the oral tongue, however, involve level IV lymph nodes without disease being present in levels I to III, a phenomenon known as "skip metastases" [33]. Level IV lymph nodes are included for therapeutic dissection of clinically positive nodes.

While patients with clinically involved regional lymph nodes may benefit from a complete modified neck dissection, selective neck dissection has been demonstrated to be oncologically sound in patients with advanced oral cavity cancer.

Contralateral metastases, and hence the need for bilateral neck treatment, are more likely when tumors approach or cross the midline [37]. In addition, ventral oral tongue and floor of mouth cancers are at very high risk for bilateral nodal involvement. If adjuvant RT is planned for the ipsilateral neck, some groups advocate RT to the contralateral clinically undissected N0 neck rather than neck dissection. Bilateral neck dissection combined with bilateral neck RT has a high risk of significant and devastating lymphedema, although surgical sparing of the jugular vein is the most important aspect of preventing edema in patients undergoing a bilateral neck dissection [38].

For patients receiving definitive RT, irradiation of the neck should follow the same indications as for neck dissection.

For patients initially treated with RT or chemoradiotherapy, management of the neck can be complex. A general discussion of the management of the neck in this situation is presented separately. (See "Management of the neck following definitive radiotherapy with or without chemoradiotherapy in head and neck squamous cell carcinoma".)

COMPLICATIONS — Both surgery and RT can have a profound effect on the quality of life, given the role of the oral cavity in speech, mastication, and swallowing. Thus, careful patient selection and surgical planning is required for all locoregionally advanced oral cavity cancer patients. The use of a multimodality approach in locally advanced oral cavity cancers increases the risk of serious complications.

Potential direct surgical complications include infection, bleeding, aspiration, wound breakdown, flap loss, and fistula [39].

Irradiation of the oral cavity and neck may result in mucositis, skin reaction, xerostomia, loss of taste, necrosis of soft tissues and bone, and dysphagia. Late toxicities may include skin and soft tissue atrophy and fibrosis; osteoradionecrosis; xerostomia; trismus; hypothyroidism; esophageal stricture; aspiration; vascular obstruction of the internal carotids; late progressive scarring and fibrosis; and second, radiation-induced, cancers. (See "Management and prevention of complications during initial treatment of head and neck cancer" and "Management of late complications of head and neck cancer and its treatment".)

Recovery from xerostomia after irradiation of the oral cavity, even with modern conformal techniques, is more limited than with other head and neck sites because of higher doses of irradiation to the submandibular glands and larger volumes of oral mucosa and the minor salivary glands in the treatment fields [40]. Xerostomia also exacerbates other late complications, such as difficulty swallowing, impaired speech, and dental caries [41].

Osteoradionecrosis of the mandible is a particularly feared consequence of high-dose radiation to the oral cavity, and one of the primary reasons that surgery is often preferred to definitive RT [42].

The adoption of newer reconstructive techniques may decrease functional deficits from radical surgery involving the oral cavity [43,44]. However, these reconstructive techniques do not restore motor or sensory function. This is acceptable for smaller defects (eg, hemiglossectomy reconstructed with radial forearm free flap) where the remaining normal tissue can compensate well. On the other hand, larger defects (eg, total glossectomy reconstructed with rectus free flap) may result in permanent debilitating functional loss. (See "Mandibular and palatal reconstruction in patients with head and neck cancer".)

PROGNOSIS — The Surveillance, Epidemiology and End Results (SEER) Cancer Statistics review for the years 1975 to 2007 reports a five-year relative survival for locally advanced oral cavity and oropharyngeal cancer of 54.7 percent, in contrast to 82.5 percent for early-stage disease [45]. Although stage IVA patients have worse outcomes than stage III patients, it has been suggested that the subset of stage IVA patients with pT4N0 disease may have similar outcomes to stage III patients [46].

Lymph node involvement is the single most important prognostic factor for outcome in oral cavity cancer [47]. In addition to the presence or absence of lymph node metastasis, other factors include the number and size of positive lymph nodes, the presence of extranodal extension, and the ratio of positive lymph nodes to total number of excised lymph nodes [48-50]. With regard to the primary lesion, higher histologic grade, the presence of perineural invasion and increasing size have been correlated with worse outcomes [51,52].

POSTTREATMENT EVALUATION AND SURVEILLANCE — Regular posttreatment follow-up as well as tobacco and alcohol cessation is an essential part of the care of patients after potentially curative treatment of oral cavity cancer, both to detect recurrent disease and to diagnose second malignancies that may develop, as well as to treat or prevent the consequences of functional issues. Patients should be educated about possible signs and symptoms of tumor recurrence, including hoarseness, pain, dysphagia, bleeding, and enlarged lymph nodes. (See "Second primary malignancies in patients with head and neck cancers".)

In general, the intensity of follow-up is greatest in the first two to four years, since approximately 80 to 90 percent of all recurrences will occur within this timeframe. Because of the higher risk of recurrence and second primary malignancy in those who continue tobacco use, many schedule more frequent surveillance visits for these patients and also continue surveillance beyond five years.

All patients treated for advanced stage oral cavity cancer will require intensive functional rehabilitation in addition to cancer surveillance. Patients should be counseled in smoking cessation and referred for dental, speech, hearing, and swallowing evaluation. (See "Overview of treatment for head and neck cancer" and "Speech and swallowing rehabilitation of the patient with head and neck cancer".)

Posttreatment surveillance of patients with head and neck cancer, including screening for treatment-related complications, is reviewed 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 5^th to 6^th 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 10^th to 12^th 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 topic (see "Patient education: Tongue cancer (The Basics)" and "Patient education: Mouth sores (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Anatomy of oral cavity tumors – Oral cavity squamous cell carcinomas (OCSCCs) include tumors originating in the lip, floor of mouth, oral tongue, lower alveolar ridge, upper alveolar ridge, retromolar trigone, hard palate, and buccal mucosa (figure 1). (See 'Anatomy and staging' above.)

●Approach to therapy – Locally advanced oral cavity cancer typically requires multimodality treatment due to the relatively high risk of locoregional recurrence and disease-related mortality. All patients should be seen preoperatively by the surgeon, radiation oncologist, and medical oncologist for preoperative treatment planning. (See 'Approach to therapy' above.)

●Resectable disease – For most patients with locoregionally advanced OCSCC and resectable disease, we suggest surgical resection of the primary tumor and neck dissection, followed by adjuvant radiation therapy (RT) or chemoradiotherapy, as the initial treatment, rather than RT or chemotherapy (Grade 2B). (See 'Resectable disease' above.)

•Management of the neck – The optimal extent of the neck dissection is partially influenced by the extent of the primary tumor. Tumors that approach or cross the midline, and oral tongue and floor of mouth cancers are treated with bilateral neck treatment. For patients receiving definitive RT, irradiation of the neck should follow the same indications as for neck dissection. (See 'Management of the neck' above.)

•Indications for adjuvant RT or chemoradiation – Most patients with locoregionally advanced OCSCC remain at significant risk for local recurrence after surgery. We recommend adjuvant RT with or without concurrent chemotherapy (Grade 1B). (See 'Adjuvant RT or chemoradiotherapy' above.)

-We recommend adjuvant chemoradiotherapy over adjuvant RT alone for patients with positive surgical margins and extranodal extension (Grade 1B). We use cisplatin 40 mg/m² weekly for chemosensitization during adjuvant chemoradiation.

●Technically unresectable disease – Definitive RT or chemoradiation, potentially preceded by induction chemotherapy, are options for patients who have technically unresectable disease (eg, carotid artery encasement, vertebral or brain invasion), are medically inoperable, or decline surgery. (See 'Technically unresectable disease' above.)

●Borderline resectable or functionally unresectable disease – For select patients with good performance status (table 2) and either borderline resectable disease or those who are predicted to have an unacceptable functional outcome with initial surgery, we reserve the use of neoadjuvant (eg, preoperative) chemotherapy in an attempt at surgical and functional preservation of important oral structures. (See 'Borderline resectable or functionally unresectable disease' above.)

•We offer three cycles of docetaxel, cisplatin, and fluorouracil (TPF) (table 3) to patients receiving neoadjuvant chemotherapy.

•Patients where neoadjuvant chemotherapy converts their disease from unresectable to resectable may subsequently be offered surgery followed by adjuvant RT or chemoradiation, as indicated.

•Patients whose disease remains unresectable despite neoadjuvant chemotherapy, or those who are unlikely or unable to tolerate neoadjuvant chemotherapy due to performance status or comorbidities, can receive definitive RT or chemoradiation as an alternative to surgery.