Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

7. Oral Cavity

Anshu K. Jain • Nicole M. Hsu • K. S. Clifford Chao

Oral Cavity Cancer – Highlights

Key Recent Clinical Studies

Sher et al. (IJROBP 2011) showed that 2-year locoregional control rates and overall survival rates for oral cavity squamous cell carcinoma were 91% and 85%, respectively, with adjuvant IMRT, and 64% and 63%, respectively, with definitive IMRT. No grade 3 xerostomia was seen. (PMID 21531515)

Gomez et al. (IJROBP 2009) demonstrated that postoperative IMRT showed impressive 2- and 3-year locoregional control rates of 84% and 77%, respectively, with 80% of patients having stage III or IV disease. Late complications were low. (PMID 18707827)

New Target Delineation Contours

FIGURE 7-7. CTV1, CTV2, and CTV3 delineation in a patient with left mandibular squamous cell carcinoma post left hemimandibulectomy, left neck dissection, tracheotomy, and reconstruction with fibular free flap, pathologically T4aN0, who received postoperative IMRT.

1. ANATOMY

• The oral cavity consists of the upper and lower lips, gingivobuccal sulcus, buccal mucosa, upper and lower gingiva (including alveolar ridge), hard palate, floor of the mouth, and anterior two-thirds of the tongue.

• The lips are the anterior border of the oral cavity. The vermilion border is the site of transition between facial skin and oral mucous membrane. Sensory nerves to the upper lip are provided by the infraorbital branch of the maxillary nerve (V2), while lower lip sensation is provided by the mental nerve (V3).The labial arteries are branches from the facial artery and provide the main blood supply to the lips.

• The upper and lower alveolar ridges are covered by the gingiva and contain the alveoli (sockets) of the teeth. Lateral to each alveolar ridge is the gingivobuccal sulcus, the transition from the alveolus to the buccal mucosa. Medially, the upper alveolus transitions to the hard palate while the lower alveolus transitions to the floor of the mouth. The upper alveolar ridge extends posterosuperiorly to the maxillary tuberosity and the lower alveolar ridge continues posteriorly to the retromolar trigone, which is the mucosa overlying the ascending ramus of the mandible. The retromolar trigone is a small triangular region that is continuous with the buccal mucosa laterally and the anterior tonsillar pillar medially. Sensory innervation of the upper alveolus and maxillary teeth is provided by the alveolar nerves (V2), as well as the greater palatine and nasopalatine nerves. The lower alveolus and mandibular teeth receive sensory innervation from various branches of the mandibular nerve (V3). The blood supply to the alveolar ridges is provided by the branches of the internal maxillary artery.

• The tongue is a muscular organ composed of intrinsic and extrinsic muscles which are separated within the midline by a fibrous lingual septum. The sulcus terminalis, situated posterior to the V-shaped configuration of the circumvallate papillae, separates the oral tongue (anterior two-third) from the base of the tongue (posterior one-third). Four extrinsic muscles (genioglossus, hyoglossus, styloglossus, and palatoglossus) serve to move the position of the tongue. The hypoglossal nerve (CN XII) provides motor innervation to all the musculature of the tongue except to the palatoglossus, which is innervated by a pharyngeal branch of the vagus nerve (CN X). The general sensory nerve of the oral tongue is the lingual nerve, a branch of the mandibular nerve (V3). The chorda tympani provides specialized taste sensation to the oral tongue. It branches from the facial nerve, before the latter exits the stylomastoid foramen, and joins the lingual nerve to provide special sensory fibers to the anterior two-third of the tongue. It also provides parasympathetic innervation to the tongue and submandibular and sublingual glands via the submandibular ganglion. The base of tongue receives both general and special taste sensation innervation from the glossopharyngeal nerve (CN IX). The primary blood supply to the tongue comes from the lingual artery.

• The floor of the mouth is bounded by the lower gingiva anteriorly and laterally, and extends posteriorly to the insertion of the anterior tonsillar pillar into the tongue (Fig. 7-1). The floor of the mouth is divided into halves by the lingual frenulum and is covered by a mucous membrane with stratified squamous epithelium. A muscular sling, composed of the genioglossus, mylohyoid, and hyoglossus, supports the contents of the floor of the mouth space. The sublingual glands lie just below the mucosa superomedial to the mylohyoid muscle and adjacent to the lingual surface of the anterior mandible. The sublingual space is continuous with the submandibular space at the posterior margin of the mylohyoid. The submandibular glands consist of a larger superficial portion that lies primarily in the submandibular space inferior to the mylohyoid muscle and a smaller, deep portion located superior to the mylohyoid in the sublingual space. The submandibular duct (Wharton’s duct) arises from the deep portion of the gland, courses between the sublingual gland and genioglossus muscle, and opens in the anterior floor of the mouth just lateral to the lingual frenulum. The lingual nerve provides sensory innervation to the floor of mouth. While the hypoglossal nerve provides motor innervation to the tongue, not to the muscles in the floor of mouth, it is important to note its location, as it runs just inferior to the hyoglossal fascia. The lingual artery, a branch of the external carotid artery, supplies blood to the floor of the mouth.

• The hard palate extends from the posterior aspect of the upper alveolar ridge to the soft palate and serves as the roof of the mouth separating the oral and nasal cavities. The bony portion of the hard palate is composed of the palatine process of the maxilla and the horizontal plate of the palatine bone, and is covered by tightly adherent periosteum and mucosa. The incisive foramen, which is located immediately posterior to the maxillary incisors, transmits the nasopalatine nerve (V2) from the floor of the nasal cavity as well as the nasopalatine artery, a branch of the sphenopalatine artery, supplying the oral mucosa covering the hard palate. The greater and lesser palatine foramina are located at the posterolateral aspect of the hard palate directly anterior to the junction of the hard and soft palate; these foramina transmit the greater and lesser palatine vessels and nerves.

• The buccal mucosa is the mucous membrane overlying the internal surface of the lips and cheeks, extending from the posterior portion of the lips medially to the upper and lower alveolar ridges and posteriorly to the pterygomandibular raphe and retromolar trigone. The papillae of the parotid duct (Stensen’s Duct) open into the vestibule of the mouth at the level of the second maxillary molar after exiting the parotid gland and piercing through the buccal fat, buccopharyngeal fascia, and buccinator muscle. The masseter muscle lies posteriorly and laterally to the buccinator muscle. The blood supply comes from the facial artery. Sensory innervation to the buccal mucosa is provided by the second and third branches of the trigeminal nerve (V2 and V3), and the facial nerve provides motor innervation to the buccinator muscle.

FIGURE 7-1. Muscles, glands, and vessels of floor of mouth and medial aspect of mandible. (A) Sublingual and submandibular glands. The tongue has been excised. (B) Structures related to the medial surface of the mandible. The optic ganglion lies medial to the mandibular nerve (CN V3) and between the foramen ovale superiorly and the medial pterygoid muscle inferiorly. (From Agur AMR, Dalley AF. Grant’s Atlas of Anatomy, 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2009:681.)

2. NATURAL HISTORY

• Oral cavity cancers typically begin as exophytic masses, ulcers, or patches of thickened white or red areas within the mouth which persist for more than 2 weeks. These lesions may be asymptomatic or may be painful and may bleed easily. Due to the close proximity of the oral mucosa to the underlying bone throughout many areas within the oral cavity, such as the alveolar ridge, early bone invasion is not uncommon. A graphic illustrating oral cavity cancer spread is shown in Figure 7-2.

• Lip cancers are often detected at an early stage with no cervical metastasis because of their prominent, visible location.

• Oral tongue cancers mainly originate from the lateral and ventral surfaces of the tongue and are often diagnosed in early stages. Advanced lesions may grow into the adjacent structures within the oral cavity or oropharynx, such as the anterior tonsillar pillar, floor of the mouth, and base of the tongue. In addition, as there are no distinct planes between the intrinsic muscles of the tongue, a diffusely infiltrating pattern of tumor growth may develop. Perineural invasion of the lingual or hypoglossal nerves can also occur. Studies have shown that tumor thickness of >4 mm, and not just T stage, correlates with increased risk of occult cervical metastasis as well as with reduced survival.1,2

• Floor of the mouth cancers mostly originates within 2 cm of the anterior midline. There is early invasion into the submucosa, with extension into the sublingual glands as well as into the genioglossus and geniohyoid muscles. The muscular sling of the floor of mouth, composed of the genioglossus, mylohyoid, and hyoglossus muscles, serves as a barrier to the spread of disease in the early stages. As the tumor growth progresses, there can be invasion into the muscles of the floor of mouth, oral tongue, and lower alveolar ridge. Small and early lesions may extend into the periosteum, but mandible invasion occurs late in the course of the disease. Perineural invasion into the lingual or hypoglossal nerves can lead to the loss of sensation along the dorsal surface of the tongue, as well as deviation of tongue protrusion, fasciculations, and muscular atrophy. Submandibular ducts may become obstructed. Approximately one-third of patients have cervical lymph node involvement, with the submandibular nodes most commonly involved.

FIGURE 7-2. Patterns of spread. (A) Coronal view: The invasion of oral tongue cancer into floor of mouth and alveolar ridges. (B) Sagittal view: The invasion of oral tongue cancer into extrinsic floor of mouth musculature and posterior tongue. The primary cancer (oral cavity) invades in various directions, which are shown as color-coded vectors (arrows) representing stages of progression: Tis, yellow; Tl, green; T2, blue; T3, purple; T4A, red; and T4B, black. (From Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:53. Modified from Agur AMF, Dalley AF, eds. Grant's Atlas of Anatomy, 12th edition. Philadelphia: Lippincott Williams & Wilkins, 2009.)

• Retromolar trigone cancers typically are diagnosed only in advanced stages. The mucosa is tightly adherent to the underlying mandible, allowing for malignant tumors to infiltrate the periosteum of the mandible at an early stage. Invasion of the underlying mandible may be an early or late manifestation. The lingual nerve enters the mandible just posteromedial to the retromolar trigone and may become involved with the tumor relatively early. Lower lip paresthesia may be an indication of perineural invasion at the level of the mandibular foramen. Lesions commonly spread to the adjacent buccal mucosa, anterior tonsillar pillar, and lower alveolus. Retromolar trigone lesions have an overall metastasis rate of approximately 45%.3

• Buccal mucosa lesions typically develop on the lateral walls, often adjacent to the third mandibular molar. Advanced lesions can invade the muscles of mastication and may eventually penetrate laterally to the skin or superiorly to the infratemporal fossa. Advanced lesions may also extend into the parotid gland causing obstructive sialadenitis and facial nerve dysfunction.

3. DIAGNOSIS AND STAGING SYSTEM

3.1. Signs and Symptoms

• Lesions of the lip are typically nonhealing blisters or ulcers on the vermilion or cutaneous skin. Sclerotic or nodular lesions may penetrate deeper into the soft tissue.

• Oral tongue carcinomas may present as an exophytic mass or ulceration. Irritation and the sensation of a lump are the most frequent symptoms in tongue cancer. Pain is typically localized, but lingual nerve involvement can present with referred otalgia via the auriculotemporal nerve. More advanced lesions, including base-of-tongue extension, may cause referred otalgia via Jacobson’s nerve (CN IX). Speech and swallowing may be affected in advanced lesions. Bleeding may occur.

• Floor of the mouth lesions often present early as a lump. Bleeding, loose teeth, halitosis, a painful mass in the submandibular region, change in speech, restricted tongue mobility or fixation, and loss of sensation along the dorsal surface of the tongue, as well as deviation of tongue protrusion, fasciculations, and muscular atrophy can be seen in advanced lesions.

• Alveolar lesions are typically ulcerative, while hard palatal lesions can present as a submucosal nodule or an ulcerative mass. These lesions are often asymptomatic in the early stages, but can become painful as the disease advances. Ill-fitting dentures, bleeding, and halitosis can be associated with progress of the disease. Tumor extension from the lower alveolar ridge can invade the inferior alveolar nerve, causing paresthesia of the mandibular teeth and chin. Direct bony infiltration of the hard palate can extend up into the nasal cavity or maxillary sinus, and may invade the greater palatine nerve causing paresthesia of the palate.

• Retromolar trigone lesions can produce local pain and referred pain to the external auditory canal and preauricular area. Trismus may be seen if the lesion invades the medial pterygoid muscles. Hyperesthesia may indicate perineural invasion.

• Buccal mucosa tumors often have associated leukoplakia. Obstruction of Stensen’s duct may cause swelling and/or inflammation of the parotid gland. Extension into the pterygoids, masseter, or buccinator muscles may cause trismus. Intermittent bleeding can be seen during mastication.

3.2. Physical Examination

• The extent of disease in oral cavity lesions is determined by visual examination and palpation. It is imperative to remove dentures and oral appliances for a thorough evaluation. Topical anesthesia may be required for examination.

• Bimanual palpation determines the extent of induration and degree of fixation to the periosteum. Large lesions bulge into the submental or submandibular space. The submandibular duct and gland, as well as the parotid duct and gland, are evaluated by bimanual palpation.

3.3. Imaging

3.3.1. Floor of the Mouth

• On axial imaging, the floor of the mouth is seen as a fat-containing space lying between the paired bellies of the genioglossus and geniohyoid muscles. The mylohyoid muscle is best seen on coronal sections because it extends from the mylohyoid line of the mandible to the hyoid.

• The sublingual spaces are usually symmetric. The submandibular space is separated from the floor of the mouth by the mylohyoid muscle and is located in the suprahyoid part of the neck. The sublingual space communicates with the submandibular space at the posterior extent of the mylohyoid. Because these spaces contain glandular and fat tissue, they are easily distinguished from adjacent muscles on both CT and MRI. The lingual vessel bundle is easily identified in these spaces with contrast. The hypoglossal and lingual nerves are normally difficult to identify.

• The hyoglossus muscle is visible on axial and coronal images coursing within the glandular and fatty tissue of the sublingual space.

• The small space between the digastric muscles next to their insertion on the mandible is the submental space. The submandibular space contains the submandibular gland, facial vessels, and lymph nodes, which are normally small (<5 mm). Floor-of-the-mouth lesions can obstruct the ducts, leading to submandibular ductal dilatation and subsequent gland swelling/inflammation which should be distinguished from gland invasion on imaging.

3.3.2. Oral Tongue

• It is difficult to differentiate the zone between the floor of the mouth and the ventral surface of the oral tongue in axial images. Coronal or sagittal sections of MRI or CT are better in evaluating floor-of-the-mouth invasion. Careful imaging may also aid in identification of extension across the midline lingual septum. In the sagittal plane of MRI, various intrinsic muscle bundles and fat tissue can easily be seen. The styloglossus muscle interdigitates with the hyoglossus muscle within the posterior aspect of the tongue.

• The muscles and spaces medial and lateral to the styloglossus muscle are potential places of tumor spread toward the skull base from the floor of the mouth and tongue base.

• Although CT and MRI cannot detect microscopic spread beyond the visible margins of the tumor, they are critical in helping to map the gross tumor boundary before surgical management or radiation therapy.

3.3.3. Retromolar Trigone

• CT is the choice of imaging because a detailed study of bony structures, soft tissues, and regional nodes is required. Spread to the lingual muscles can be recognized better on MRI than on CT. Occult spread anteriorly along the attachment of the mylohyoid muscle may be visible on CT or MRI when not palpable or visible by clinical examination. Supplemental MRI may be useful when looking for perineural spread and determining extension into the nasal cavity or soft palate.

3.4. Staging

• In 2010 the American Joint Committee on Cancer issued new TNM classification guidelines for Lip and Oral Cavity cancers.4 One significant change from the 6th edition is that T4 lesions have been subdivided into T4a and T4b for moderately and very advanced disease, respectively. The reader is encouraged to consult the new AJCC staging manual for details.

4. RISK FACTORS FOR NODAL METASTASIS

• Clinically detected nodal metastases on admission vary according to T stage and subsites of the oral cavity (Table 7-1). The incidence and distribution of metastatic disease in clinically negative and positive neck nodes also change according to subsites of cancer in the oral cavity. The distribution of pathologically positive neck nodes after electively modified neck dissection in patients with carcinomas in the oral tongue, floor of the mouth, or retromolar trigone is shown in Tables 7-2 through 7-4.

• There are several factors influencing contralateral nodal metastasis in oral cavity cancer (Table 7-5). Except for lesions arising from the tip of the tongue or extending across the midline, metastatic disease usually occurs in the ipsilateral cervical lymph nodes.5

• Byers et al.6 reported the incidence of nodal metastasis by T stage and subsite in oral cavity cancer after elective nodal dissection (Table 7-6).

• Lymphatics from the upper lip drain to the ipsilateral preauricular, intraparotid, submandibular, and submental lymph nodes. Lower lip lymphatics drain to the submental and submandibular nodes, as well as to the upper and middle jugular nodal groups. Upper lip has primarily ipsilateral drainage while lower lip can have ipsilateral or contralateral drainage.

• Lymphatic drainage from the buccal surface of the upper and lower alveolar ridges is to submental and submandibular lymph nodes, and the lingual surface drains to upper jugular and lateral retropharyngeal lymph nodes.

• There is variable lymphatic drainage of the oral tongue based on the location within the tongue. Primary lymphatic drainage in the oral tongue is to the subdigastric and submandibular lymph nodes. Rouviere and Tobias7 described the lymphatic trunks that bypass this primary lymphatic drainage and go directly to the midjugular lymph nodes, which probably accounts for the relative frequency of metastatic lymph nodes in these locations (Fig. 7-3).

• Lymphatics in the anterior aspect of the floor of mouth may drain to both the ipsilateral and contralateral submental and submandibular lymph nodes, whereas the posterior aspect drains to the ipsilateral upper jugular lymph nodes. The incidence of bilateral lymph node involvement is relatively high for floor of mouth cancers because many lesions are near or cross the midline.5,6

• Lymphatic drainage of the buccal mucosa is primarily to the submental and submandibular lymph nodes.

5. GENERAL MANAGEMENT

• A variety of therapeutic measures is available for managing localized carcinomas of the oral cavity, including surgery, radiation therapy, laser excision, and combinations of these methods. Deng et al. recently reviewed various treatment options and outcomes for a variety of oral cancers.8 It is worth noting that RTOG conducted a phase III trial (9901) to determine whether injection of granulocyte macrophage colony stimulating factor (GM-CSF) would ameliorate radiation-induced mucositis in oral cancer treatment. The report by Ryu et al.9 indicated little benefit for GM-CSF in these patients.

5.1. Lips

• Surgical excision is the preferred modality as the oncologic, functional, and cosmetic outcomes are typically excellent in early-stage disease. A combination of surgery with postoperative irradiation is used for T3 and T4 disease or recurrent disease after primary surgical management.

5.2. Alveolar Ridge and Retromolar Trigone

• Treatment for T1 and T2 lesions of the alveolus is primarily surgical, but radiation therapy must be added if bony invasion, nodal metastases, or perineural invasion is present.

• If the lesion invades the periosteum or bone, marginal/segmental maxillectomy/mandibulectomy is required to obtain negative surgical margins.

• Radiation therapy is the preferred treatment modality for early disease of the retromolar trigone, as surgical resection of these tumors can be technically challenging and may lead to significant morbidity.

FIGURE 7-3. Lymphatic drainage of the tongue. (A) Superior view of the dorsum of the tongue. (B) Lateral view of the head and neck. Lymph drains to the submental, submandibular, and superior and inferior deep cervical lymph nodes, including the jugulodigastric and jugulo-omohyoid nodes. Extensive communications occur across the midline of the tongue. (From Moore KL, Dalley AF. Clinical Oriented Anatomy, 4th ed. Baltimore, MD: Lippincott Williams & Wilkins, 1999.)

• Advanced T3 and T4 retromolar trigone lesions often require a composite resection, including partial mandibulectomy and neck dissection, combined with irradiation.

5.3. Oral Tongue

• Management of carcinoma of the oral tongue is difficult and controversial and depends on the primary lesion’s size, location, and growth pattern and the nodal status in the neck.

5.3.1. T1 and T2 Tongue Lesions

• Although surgery or irradiation is effective in controlling small cancers, transoral surgical resection for small, well-defined lesions involving the tip and anterolateral border of the tongue can be effective management without risk of functional morbidity, particularly in aged and feeble patients.5

• Radiation therapy (60 to 65 Gy in 6 to 7 weeks) is preferred for small, posteriorly situated, ill-defined lesions inaccessible for transoral surgical excision.

• Superficial, exophytic T1 and T2 lesions with minimal muscular invasion are amenable to successful treatment with irradiation (70 Gy in 7 weeks).

• For moderately advanced, medium-sized T2 tumors involving the adjacent floor of the mouth, surgical treatment includes partial glossectomy, possible partial mandibulectomy, and neck dissection. As an alternative to surgery, comprehensive irradiation (70 to 75 Gy in 7 to 8 weeks) with progressively decreasing fields to the primary site and neck nodes can be used, and surgery is reserved for salvage therapy of residual or recurrent disease.

5.3.2. T3 and T4 Tongue Lesions

• Advanced disease with deep muscle invasion, often associated with cervical lymph node metastases, is unlikely to be cured with irradiation alone.

• These lesions are best managed by combined irradiation (50 to 60 Gy in 5 to 6 weeks) and surgery.

• Wide local excision is the treatment of choice for well-circumscribed lesions that can be excised transorally with at least 1 cm margins.

• Wide local excision of lesions of the posterior part of the mobile tongue is difficult; however, with the advancements in transoral robotic surgery (TORS), resection of these lesions may be possible. Reconstruction may be needed for large defects as they can result in serious functional deficits in swallowing and speech. External irradiation combined with interstitial implant may also be used for such patients.

• The extent of surgery for larger lesions is usually hemi or total glossectomy.

• Postoperative irradiation is recommended for larger lesions, close or positive margins, and perineural invasion. It is also recommended for patients with initially positive surgical margins, who later have negative surgical margins on re-excision.10,11

• Treatment results for carcinoma of the oral tongue are summarized in Table 7-7.

5.4. Floor of Mouth

• When the tumor is small or limited to the mucosa, it is highly curable by surgery or irradiation alone.

• Very small superficial lesions can be treated with interstitial implant (60 to 65 Gy) or intraoral cone (45 Gy over 3 weeks) alone.

• T1 and early T2 lesions must be treated with external-beam irradiation and various boost techniques, such as interstitial implant (45 Gy external plus 25 Gy implant) or intraoral cone (45 Gy external plus 20 Gy intraoral cone).

• In floor of mouth lesions that are tethered or fixed to the mandible, resection of the inner table is often recommended, which results in reasonable speech and swallowing.

• Postoperative irradiation is usually recommended because of the negative prognostic factors associated with radiation.

• For advanced lesions as the result of bone invasion, wide local excision of tumor along with segmental resection of the mandible is often followed by reconstruction of the floor of the mouth and mandible.

• For very advanced disease involving the floor of the mouth, tongue, and mandible, and for massive neck disease, the chance of cure with any aggressive treatment is low and often associated with formidable complications; a course of irradiation should be strongly considered.

• For extensive, infiltrative T3 and T4 lesions with marked involvement of the adjacent muscle of the tongue and mandible, radical surgery followed by plastic closure and postoperative irradiation is the procedure of choice.

• For advanced T3 and T4 lesions, external-beam irradiation is given through large opposing lateral portals with equal loading covering the primary lesion and nodal areas to a dose of approximately 45 Gy in 4.5 to 5 weeks, followed by two- or three-step reduced fields to a total dose of 70 to 74 Gy.

• The treatment results for floor of mouth carcinoma are summarized in Table 7-8.

5.5. Hard Palate

• Surgical management is the preferred method of treatment for carcinomas of the hard palate. Small T1 and T2 lesions are treated with wide local excision; involvement of the periosteum requires a partial or subtotal maxillectomy.

• For larger T3 and T4 lesions, combined therapy of surgery and irradiation is needed. Small defects can be reconstructed with local advancement flaps, while larger defects typically require palatal prostheses.

5.6. Buccal Mucosa

• Primary surgery is effective for small, superficial T1 lesions without involvement of the commissure. The procedure excises the malignancy and can address adjacent leukoplakia.

• Intermediate T2 lesions and those involving the commissure can be managed surgically or with irradiation, which can produce a high cure rate with good functional and cosmetic results.

• For T1 and most T2 lesions without nodal involvement, results with irradiation are best when photon or electron beam therapy is combined with interstitial implant or intraoral cone therapy.

• For T3 and T4 tumors with deep muscular invasion, cure rates after radiation therapy are poor. These lesions are usually treated with radical surgery, reconstruction, and postoperative irradiation.

• For moderately advanced lesions, with or without positive nodes, appropriate radiation therapy must include the primary site and regional lymph nodes. This is best achieved with external-beam irradiation through ipsilateral and anterior wedged-pair fields for a tumor dose of 55 to 60 Gy in 6 weeks, followed by boost irradiation that spares the mandible, and an interstitial implant, intraoral cone, or electron beam irradiation for an additional 20 Gy.

• Table 7-9 summarizes the treatment results for carcinoma of the buccal mucosa.

5.7. Management of Neck Nodes

• The management of a clinically and radiographically negative (N0) neck in early oral cavity carcinoma is controversial. In patients with early, small lesions resected with adequate margins and thickness of <2 mm without poor prognostic factors, no further elective treatment is typically required if the neck is clinically and radiographically negative. However, for patients with an oral cavity carcinoma with a risk of occult metastases of >20%, many consider elective treatment to the regional lymphatics necessary, even if they have a clinically and radiographically negative (N0) neck.

• The neck should be treated in patients who have resected primary lesions of the oral tongue >4-mm thick or poor prognostic factors such as perineural or perilymphatic invasion.

• Any form of bilateral neck dissection has worse cosmetic results than produced by a moderate dose of irradiation (45 to 50 Gy).

• If neck dissection reveals only one positive node with no extracapsular extension, we usually recommend no radiation therapy to the neck.10 If neck dissection shows more than one node, and especially metastases at more than one nodal station or extracapsular extension of a single or multiple nodes, a course of postoperative irradiation to the neck is indicated.

• In patients with clinically or radiographically positive neck nodes (by CT scan with contrast), the treatment of choice for the neck is ipsilateral neck dissection followed by bilateral postoperative neck irradiation.

• Contralateral prophylactic neck dissection is a serious disservice to the patient.30

5.8. Chemotherapy

• Clinical trials for advanced tumors evaluating the use of chemotherapy preoperatively, before radiation therapy, as an adjuvant therapy after surgery, or as a part of combined modality therapy have not clarified the appropriate treatment scheme.

• A recent randomized, multicenter trial enrolling 198 patients with a resectable stage T2–4 (>3 cm), N0 to N2, M0 untreated, squamous cell carcinoma of the oral cavity showed that neoadjuvant chemotherapy was unable to improve survival but had a role in reducing the number of patients who underwent mandibulectomy (31% vs 52%) or radiation therapy (33% vs 46%).31

• A meta-analysis of 63 randomized prospective trials published between 1965 and 1993 showed an 8% absolute survival advantage in the subset of patients receiving concomitant chemotherapy and radiation therapy.32 Patients receiving adjuvant or neoadjuvant chemotherapy had no survival advantage in this meta-analysis.

• Rosenthal et al.33 reported results from a Phase II RTOG trial (0024) using postoperative paclitaxel in high-risk head and neck patients, 35% of whom had oral cavity cancer. With a median follow-up of 3.3 years, 2-year disease-free survival was 60%.

• The 18 ongoing trials may further clarify the role of concomitant chemotherapy and radiation therapy in the management of oral cavity cancer.

6. INTENSITY-MODULATED RADIATION THERAPY IN ORAL CAVITY CANCERS

6.1. Target Volume Determination

• If chemotherapy has been delivered before radiation, the targets should be outlined on the planning CT according to their prechemotherapy extent.

• Lymph node groups at risk in the oral cavity include the following:

(a) Submandibular nodes (surgical level lb): all cases.

(b) Upper deep jugular (junctional and parapharyngeal) nodes: all cases (on the neck side ipsilateral to the primary tumor).

(c) Subdigastric (jugulodigastric), midjugular, lower neck, and supraclavicular nodes (levels II–IV): all cases, bilaterally.

(d) Posterior cervical nodes (level V): all cases, on the neck side where there is evidence of jugular nodal metastasis.

(e) Retropharyngeal nodes: all cases, if there is evidence of jugular nodal metastasis.

• Suggested target volume determination for oral cavity carcinoma is summarized in Table 7-10.

• Suggested target volume doses for chemoradiation and definitive IMRT without chemotherapy in oral cavity cancer are given in Table 7-10, as a footnote.

6.2. Target Volume Delineation

• In patients receiving postoperative IMRT, clinical target volume 1 (CTV1) encompasses the residual tumor and the region adjacent to it but not directly involved by the tumor, the surgical bed with soft-tissue invasion by the tumor, or the extracapsular extension by metastatic neck nodes. CTV2 primarily includes the prophylactically treated neck.

• In patients receiving definitive IMRT, CTV1 is defined as gross tumor (primary and enlarged nodes) plus a 5 to 20 mm margin based on clinical and radiologic justification. CTV2 includes the region adjacent to CTV1 (i.e., ipsilateral upper neck of the involved tumor site). Prophylactically treated neck (classified as CTV2 in postoperative IMRT) is termed as CTV3.

• CTV1 and CTV2 delineation in a patient with clinically T3N2bM0 squamous cell carcinoma of the retromolar trigone who received definitive IMRT is shown in Figure 7-4. The patient presented with an ulcerative right-sided mass in the retromolar trigone. The lesion was not fixed to the mandible. There were also multiple, palpable level II and III lymph nodes on physical examination. Biopsy revealed a squamous cell carcinoma of the retromolar trigone. The patient was treated with definitive IMRT.

• CTV1 and CTV2 delineation in a patient with pathologic T2N2bM0 squamous cell carcinoma of the tongue receiving postoperative IMRT is shown in Figure 7-5. The patient presented with an ulcerative 2 × 3 cm lesion on the left side of his tongue. On physical examination, there were multiple, palpable level II lymph nodes on the right side of the neck. The patient underwent hemiglossectomy with right-modified neck dissection. Pathology specimen revealed a squamous cell carcinoma. Two of 13 lymph nodes were positive without extracapsular extension. The patient was treated with postoperative IMRT.

• Figure 7-6 shows the target delineation for a 52-year-old woman with squamous cell carcinoma of the right oral cavity, staged as pT1N1 post lateral partial glossectomy and right neck dissection. She was found to have perineural invasion.

• Target contours for a 74-year-old woman with left mandibular squamous cell carcinoma are shown in Figure 7-7. She was staged as pT4aN0 post left hemimandibulectomy, left neck dissection, tracheotomy, and reconstruction with fibular free flap.

6.3. Suggested Target and Normal Tissue Doses

• See Chapter 4 for suggested target and normal tissue doses.

6.4. Intensity-Modulated Radiation Therapy Results

• A total of 15 patients with oral cavity carcinoma were treated with IMRT between February 1997 and December 2000 at Washington University34; 2 patients were treated postoperatively, and 13 patients were treated with definitive IMRT. The T stages were T1 (3 patients), T2 (5 patients), T3 (3 patients), and T4 (4 patients). The N stages were N0 (5 patients), N1 (2 patients), and N2 (8 patients) (according to the American Joint Committee on Cancer staging system: stage I [2 patients], stage II [2 patients], stage III [2 patients], and stage IV [9 patients]). We observed five locoregional recurrences, and distant metastasis developed in one patient.35,36 All patients are alive except two who died of the cancer. A gastrostomy tube was temporarily placed in two patients during treatment. No grade 3 or 4 late complications were seen. Radiation Therapy Oncology Group grades 1 and 2 xerostomia were observed as a late sequelae in five and three patients, respectively.

• Claus et al.37 reported results of eight patients with oral cavity cancer who were treated with IMRT. The majority of patients had recurrent tumor and in-field relapses within 4 months after the end of the IMRT, with a median overall survival of 7 months. Acute toxicity as the result of radiation was acceptable. Dysphagia and pain were the predominant acute toxicities. In regard to late complications, no myelitis, carotid rupture, or cranial nerve palsy was observed. Osteoradionecrosis of the mandible developed in one patient, and feeding-tube dependency occurred in one patient. No fatal late complications were observed in this group.

FIGURE 7-4. Clinical target volume (CTV) delineation in a patient with T3N2bM0 retromolar trigone carcinoma who received definitive IMRT. CTV1 (gold-yellow line); CTV2 (red line); CTV3 (dark blue line); gross tumor volume (GTV) (yellow line); oral cavity (OC) (magenta line); spinal cord (SC) (green line).

FIGURE 7-5. CTV delineation in a patient with T2N2bM0 oral tongue carcinoma who received postoperative IMRT. CTV1 (red line); CTV2 (dark blue line); right parotid (P) gland (rust line); left parotid gland (aqua line); spinal cord (SC) (green line).

FIGURE 7-6. Target delineation for a 52-year-old woman with squamous cell carcinoma of the right oral cavity, staged as pT1N1 post lateral partial glossectomy and right neck dissection.

• Sher et al.38 reported the results of 42 patients with oral cavity squamous cell carcinoma treated with postoperative or definitive IMRT between 2004 and 2009. Thirty of these patients were treated postoperatively and 12, definitively. Sixty-four percent of patients were stage III or higher. Two-year rates of local control were 91% and 64% for adjuvant and definitive IMRT, respectively. Two-year survival rates were 85% and 63% for adjuvant and definitive IMRT, respectively. Only one patient developed osteoradionecrosis, while 35% experienced grade 2 or 3 late dypshagia.

• Pederson et al.39 reported results on concurrent chemotherapy and IMRT on 21 patients treated between 2001 and 2004. With a median follow-up of 60 months, there were two locoregional failures and two distant failures. Locoregional control at 5 years was 90% and overall survival at 5 years was 76%. Three patients experienced osteoradionecrosis.

• Gomez et al.40 reported the results of 35 patients treated postoperatively with IMRT between 2000 and 2006. Approximately 80% of patients had stage III or IV disease. Median follow-up was 28 months. The 2- and 3-year locoregional control rates were 84% and 77%, respectively, and overall survival rates were 70% and 64%, respectively. Osteoradionecrosis was present in two patients.

FIGURE 7-7. Target contours for a 74-year-old woman with left mandibular squamous cell carcinoma. She was staged as pT4aN0 post left hemimandibulectomy, left neck dissection, tracheotomy, and reconstruction with fibular free flap.

• A retrospective study of 284 patients, including 70 with oral cavity cancer and 125 with oropharyngeal cancer treated with IMRT, most of whom presenting T3 or T4 disease, was done by Yao et al.41 They found that with 22.8 months of median follow-up, 3-year locoregional recurrence-free survival, distant metastasis-free survival, and overall survival were 92.5%, 84.1%, and 68.95%, respectively. Multivariate analysis showed that N-stage and T-stage were strongly associated with distant metastasis.

• Sparing of the contralateral submandibular gland (CSG) in relation to xerostomia was studied by Wang et al.42 in 52 patients treated with IMRT, half of them with lowered dose to the CSG. Recovery of salivary flow and lower grade xerostomia were seen in the CSG-spared cohort, which was related to the mean V30 Gy to the gland.

• A previous longitudinal study from the same group43 showed dose dependent volume losses in the parotid and submandibular glands following RT.

• Little et al.44 treated 78 patients with stage II–IV oropharynx or nasopharynx disease with IMRT plans sparing parotid and also minor salivary and submandibular glands (SMG). They found that keeping mean dose to the oral cavity and contralateral SMG at <40 Gy and <50 Gy, respectively, resulted in lower reported xerostomia.

• A note of caution was raised by Damast et al.45 They found that four patients with stage III or IV oral tongue disease previously treated at outside institutions with selective radiation targeting came to MSKCC with marginal recurrences. They noted that comprehensive IMRT would have covered the areas of recurrence; they advise against selective targeting.

• Cvek et al.46 did a Phase I dose escalation trial using hyperfractionated accelerated IMRT with concomitant boost to 70 to 75 Gy in head and neck tumors, about half of which were in the oral cavity. These patients all had very bulky, advanced stage IV disease and were deemed inoperable and ineligible for concurrent chemotherapy due to comorbidities. Grade 3 mucositis was 51% in the oral cavity; recovery time for all patients was ≤9 weeks, and 1-year overall survival was 51%.

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