Steven J. Frank, Anesa Ahamad, and K. Kian Ang
ANATOMY
Nasal Cavity
The nasal cavity extends from the hard palate inferiorly to the base of the skull superiorly. It is above and behind the vestibule and is defined anteriorly by the transition from skin to mucous membrane and posteriorly by the choanae, which open directly into the nasopharynx.1 The nasal cavity consists of four subsites: the nasal vestibule, the lateral walls, the floor, and the septum.
The nasal vestibule is the triangular space located inside the aperture of the nostril as a slight dilatation that extends as a small recess toward the apex of the nose. It is defined laterally by the alae; medially by the membranous septum, the distal end of the cartilaginous septum, and columella; and inferiorly by the adjacent floor of the nasal cavity. It is lined by skin containing hairs and sebaceous glands; therefore, tumors at this location are often those that arise from the skin, usually squamous cell cancers2 but may occasionally be basal cell carcinoma3 sebaceous carcinoma,4 melanoma,5 or non-Hodgkin lymphoma.6
The lateral walls correspond with the medial walls of the maxillary sinuses and consist of thin bony structures that have three shell-shaped projections (superior, middle, and inferior conchae or turbinates) into the nasal cavity. The floor extends from the vestibule to the nasopharynx above the hard palate of the maxilla. The septum divides the nasal cavity into right and left halves.
Paranasal Sinuses
The paranasal sinuses are named according to the bones in which they are located: the ethmoid, maxilla, sphenoid, and frontal.
Ethmoid Sinuses
The ethmoid sinuses are composed of several small cavities, the ethmoid air cells, within the ethmoid labyrinth located below the anterior cranial fossa and between the nasal cavity and the orbit. They are separated from the orbital cavity by a thin, porous bone, the lamina papyracea, and from the anterior cranial fossa by a portion of the frontal bone, the fovea ethmoidalis. They are in close proximity to the optic nerves laterally and the optic chiasm posteriorly. The ethmoid sinuses are divided into anterior, middle, and posterior groups of air cells. The middle ethmoid cells open directly into the middle meatus. The anterior cells may drain indirectly into the middle meatus via the infundibulum. The posterior cells open directly into the superior meatus.
Maxillary Sinuses
The maxillary sinuses, the largest of the paranasal sinuses, are pyramid-shaped cavities located in the maxillae. The lateral walls of the nasal cavity form the base and the roofs correspond to the orbital floors, which contain the infraorbital canals. The floors of the maxillary sinuses are composed of the alveolar processes. The apices extend toward and frequently into the zygomatic bones. Secretions drain by mucociliary action into the middle meatus via the hiatus semilunaris through an aperture near the roof of the maxillary sinus. Ohngren’s line is a theoretical plane dividing each maxillary sinus into the suprastructure and infrastructure; it is defined by connecting the medial canthus with the angle of the mandible.
Sphenoid Sinus and Frontal Sinuses
The sphenoid bone forms a midline inner cavity that communicates with the nasal cavity through an aperture in its anterior wall. It is directly apposed superiorly to the pituitary gland and optic chiasm, laterally to the cavernous sinuses, anteriorly to the ethmoid sinuses and nasal cavity, and inferiorly to the nasopharynx. The paired, typically asymmetric frontal sinuses are located between the inner and outer tables of the frontal bone. They are anterior to the anterior cranial fossa, superior to the sphenoid and ethmoid sinuses, and superomedial to the orbits. They usually communicate with the middle meatus of the nasal cavity.
EPIDEMIOLOGY
Cancers of the nasal cavity and paranasal sinuses are relatively uncommon. Fewer than 4,500 cases are diagnosed each year in the United States, an incidence of 0.75 per 100,000.7 Cancers of the maxillary sinus are twice as common as those of the nasal cavity; cancers of the ethmoid, frontal, and sphenoid sinuses are extremely rare. They generally develop after the age of 40 years, except for esthesioneuroblastoma, which has a unique bimodal age distribution8and occurs twice as often in men than in women.9 These tumors are most common in Japan and South Africa.
The etiologic factors vary by tumor type and location. Adenocarcinomas of the nasal cavity and ethmoid sinus have been reported to occur more frequently in carpenters and sawmill workers who are exposed to wood dust,10,11,12Synthetic wood, binding agents, and glues may also be involved as cocarcinogens.13 Squamous cell carcinomas of the nasal cavity have been seen more often in nickel workers.14 Maxillary sinus carcinomas have been associated with radioactive thorium-containing contrast material (Thorotrast) used for radiographic visualization of the maxillary sinuses in the past. Occupational exposure in the production of chromium, mustard gas, isopropyl alcohol, and radium also may increase the risk of sinonasal carcinomas.
Cigarette smoking is reported to increase the risk of nasal cancer, with a doubling of risk among heavy or long-term smokers and a reduction in risk after long-term cessation. After adjustment for smoking, a significant dose–response relationship has also been noted between alcohol consumption and risk of nasal cancer.15
NATURAL HISTORY
Nasal Vestibule
Nasal vestibule carcinomas can spread by direct invasion of the upper lip, gingivolabial sulcus, premaxilla (early events), or nasal cavity (late events), as shown in Figure 42.1. Vertical invasion may result in septal (membranous or cartilaginous) perforation or alar cartilage destruction. Lymphatic spread from nasal vestibule carcinomas is usually to the ipsilateral facial (buccinator and mandibular) and submandibular nodes. Large lesions extending across the midline may spread to the contralateral facial or submandibular nodes. The incidence of nodal metastasis at diagnosis is approximately 5%.16,17 Without elective nodal treatment, approximately 15% of patients develop nodal relapse. Hematogenous metastases are rare.
FIGURE 42.1. Computed tomography scans of a nasal vestibule squamous cell carcinoma that has spread by direct invasion of the upper lip (arrow in A) and gingivolabial sulcus and premaxilla (arrow in B and C).
Nasal Cavity and Ethmoid Sinuses
The pattern of contiguous spread of carcinomas varies with the location of the primary lesion. Tumors arising in the upper nasal cavity and ethmoid cells can extend to the orbit through the thin lamina papyracea and to the anterior cranial fossa via the cribriform plate, or they may grow through the nasal bone to the subcutaneous tissue and skin. Lateral wall primaries invade the maxillary antrum, ethmoid cells, orbit, pterygopalatine fossa, and nasopharynx. Primaries of the floor and lower septum may invade the palate and maxillary antrum. Perineural extension (typically involving branches of the trigeminal nerve) is seen most often with adenoid cystic carcinomas.
Lymphatic spread of nasal cavity primaries is uncommon, although spread to retropharyngeal and cervical lymph nodes is possible. In a series of 51 patients reported by the University of Texas MD Anderson Cancer Center,18 only 1 patient had palpable subdigastric nodes at diagnosis. Of the 36 patients who did not receive elective lymphatic irradiation, 2 (6%) experienced subdigastric nodal relapse. Hematogenous dissemination is rare. In the MD Anderson Cancer Center series, for example, distant metastasis to bone, brain, or liver occurred in only 4 of 51 patients.18
The olfactory region is the site of origin of esthesioneuroblastoma and, occasionally, adenocarcinomas. Esthesioneuroblastoma is a tumor of neural crest origin first reported by Berger and Luc in 1924 as esthesioneuroepithelioma olfactif19; other names include olfactory neuroblastoma and esthesioneurocytoma. Esthesioneuroblastoma constitutes approximately only 3% of all intranasal neoplasms. About 250 cases have been reported between 1924 and 1990.20 The tumor typically is composed of round, oval, or fusiform cells containing neurofibrils with pseudorosette formation and diffusely increased microvascularity.21
Esthesioneuroblastoma may be mistaken for any other “small round-cell tumor,” that is, a group of aggressive malignant tumors composed of small and monotonous undifferentiated cells that includes Ewing’s sarcoma, peripheral primitive neuroectodermal tumor (also known as extraskeletal Ewing’s), rhabdomyosarcoma, lymphoma, small cell carcinoma (undifferentiated or neuroendocrine), and mesenchymal chondrosarcoma. The clinical presentations of these entities often overlap, but clinicopathologic features and immunohistochemical staining may help in distinguishing among them.
The route of contiguous spread of esthesioneuroblastomas is similar to that of ethmoid carcinomas. Lymph node involvement and distant metastasis are uncommon at diagnosis.22,23
Maxillary Sinuses
The pattern of spread of maxillary sinus cancers varies with the site of origin. Suprastructure tumors extend into the nasal cavity, ethmoid cells, orbit, pterygopalatine fossa, infratemporal fossa, and base of skull (Fig. 42.2A–C). Invasion of these structures gives lesions of the suprastructure a poorer prognosis. Their treatment is also associated with greater morbidity as a consequence of craniofacial resection or radiation of intracranial and ocular structures. Infrastructure tumors often infiltrate the palate, alveolar process, gingivobuccal sulcus, soft tissue of the cheek, nasal cavity, masseter muscle, pterygopalatine space, and pterygoid fossa (Fig. 42.2D–J).
The maxillary sinuses are believed to have a limited lymphatic supply24 and a correspondingly low incidence of lymphadenopathy at diagnosis.25,26 Only 6 of the 73 patients (8%) in the MD Anderson Cancer Center series had palpable lymphadenopathy at diagnosis. The incidence of nodal spread, however, varies with the histologic type (17%, or 5 of 29 patients with squamous cell or poorly differentiated carcinomas vs. 4%, or 1 of 27 for patients with adenocarcinoma, adenoid cystic carcinoma, or mucoepidermoid carcinoma). The incidence of subclinical disease, as reflected in the rate of nodal relapse in patients who did not receive elective neck treatment, also varies with histologic type (38%, or 9 of 24 patients with squamous cell or poorly differentiated carcinomas vs. 8%, or 2 of 26 patients with adenocarcinoma, adenoid cystic carcinoma, or mucoepidermoid carcinoma). The cumulative incidence of nodal involvement (gross and microscopic) for patients with squamous cell and poorly differentiated carcinomas is about 30%. The risk of regional recurrence after treatment is 20% to 30% or higher, depending on the extent of disease and elective neck treatment.27 Ipsilateral subdigastric and submandibular nodes are most often involved. Hematogenous spread is uncommon.
CLINICAL PRESENTATION
Nasal Vestibule
Carcinomas of the nasal vestibule usually present as asymptomatic plaques or nodules, often with crusting and scabbing. Advanced lesions may extend beyond the vestibule and may cause pain, bleeding, or ulceration. Large ulcerated lesions may become infected, leading to severe tenderness that requires anesthesia for complete clinical assessment.
FIGURE 42.2. The pattern of spread of maxillary sinus cancers. A–C: Suprastructure tumors are shown, with arrows indicating the involvement of the nasal cavity and ethmoid cells (A), the orbit (B), and the base of skull (C). D–J: Advanced tumor is shown, with arrows indicating alveolar process destruction with loosening of a tooth (E) and abutment of the orbital floor without frank intraorbital invasion (F). The patient had a maxillectomy and orbital floor resection with an anterolateral thigh (ALT) flap (arrow in G), and titanium mesh reconstruction of the orbital floor (H, I, and J).
Nasal Cavity
Nasal cavity tumors present with symptoms and signs of nasal polyps (e.g., chronic unilateral discharge, ulcer, obstruction, anterior headache, and intermittent epistaxis), hence delaying the diagnosis. Additional symptoms and signs develop as the lesion enlarges: medial orbital mass, proptosis, expansion of the nasal bridge, diplopia resulting from invasion of the orbit, epiphora due to obstruction of the nasolacrimal duct, anomaly of smell or anosmia from involvement of the olfactory region, or frontal headache due to extension through the cribriform plate.
The common presenting symptoms of esthesioneuroblastomas are nasal obstruction and epistaxis. Spaulding et al.28 found that anosmia could precede diagnosis by many years. Other symptoms are related to contiguous disease extension into the orbit (proptosis, visual-field defects, orbital pain, epiphora), paranasal sinuses (medial canthus mass, facial swelling), or anterior cranial fossa (headache) or are due to inappropriate antidiuretic hormone secretion.28
Ethmoid Sinuses
The presenting symptoms and signs of ethmoid sinus tumors are central or facial headaches and referred pain to the nasal or retrobulbar region, a subcutaneous mass at the inner canthus, nasal obstruction and discharge, diplopia, and proptosis. In one study of 34 patients with ethmoid sinus cancers treated at MD Anderson Cancer Center between 1969 and 1993,29 nasal cavity symptoms (nasal obstruction, epistaxis, discharge) were reported in 25 patients (74%), orbital symptoms (diplopia, orbital pain, vision loss, proptosis, inner canthus mass, tearing) in 12 (35%), headache in 6 (18%), and hyposmia or anosmia in 5 (15%).
Maxillary Sinuses
Maxillary sinus cancers usually are diagnosed at advanced stages. Symptoms and signs are facial swelling, pain, or paresthesia of the cheek induced by disease extension to the premaxillary region, epistaxis, nasal discharge and obstruction related to tumor spread to the nasal cavity, ill-fitting dentures, alveolar or palatal mass, unhealed tooth socket after extraction from spread to the oral cavity, and proptosis, diplopia, impaired vision, or orbital pain due to orbital invasion.30
DIAGNOSTIC WORKUP
The recommended pretreatment physical, diagnostic, and staging evaluations are listed in Table 42.1.
TABLE 42.1 PRETREATMENT EVALUATION FOR TUMORS OF THE NASAL CAVITY AND PARANASAL SINUSES
Physical Examination
Inspection and palpation of the orbits, nasal and oral cavities, and nasopharynx can provide preliminary determination of tumor extent. Bimanual palpation is important in assessing contiguous extension of nasal vestibule lesions and in identifying buccinator and submandibular nodal involvement. Careful examination of cranial nerves is required. Fiberoptic nasal endoscopy after mucosal decongestion and topical analgesia allows assessment of local extent and facilitates biopsy of tumor involving the nasal cavity or nasopharynx.
Radiographic Evaluation
Imaging has a crucial role in the staging of sinonasal tumors. Magnetic resonance imaging (MRI) and computed tomography (CT) scans are complementary.31 MRI is superior at detecting direct intracranial or perineural or leptomeningeal spread.32 T2-weighted MRI can be helpful in distinguishing tumor (low signal) from obstructed secretions (bright).33 CT is superior for detecting early cortical bone erosion or extension through the cribriform plate or orbital walls.
Certain features provide clues as to the nature of the tumors in this region. Slowly progressive lesions tend to deform instead of destroy bony structures. Intermediate-grade tumors can cause sclerosis of adjacent bone. Lymphomas tend to permeate bone without frank destruction, and carcinomas and sarcomas infiltrate and destroy adjacent bone.
Biopsy
Transnasal biopsy is preferred for tumors arising from or extending into the nasal cavity or nasopharynx. Some paranasal sinus tumors may be more easily sampled using transoral procedures or an open Caldwell-Luc approach.
Laboratory Studies
Complete blood counts and serum chemistries can be used to screen for the presence of distant metastases. Abnormalities of these tests can be further investigated as necessary.
STAGING
The seventh edition of the American Joint Committee on Cancer’s (AJCC) AJCC Cancer Staging Manual tumor-node-metastasis (TNM) classification includes staging for cancers of the maxillary sinus, ethmoid sinus, and the nasal cavity.34 Significant updates from the sixth edition affect classifications of T4 lesions and hence stage IV disease. Specifically, T4 lesions are now considered either T4a (moderately advanced local disease) or T4b (very advanced local disease), which leads to stratification of stage IV disease as either IVA (moderately advanced local or regional disease, IVB (very advanced local or regional disease), or IVC (distant metastatic disease). Definitions of anatomic stage prognostic groupings and TNM classifications are given in Table 42.2.
PATHOLOGIC CLASSIFICATION
Most nasal vestibule cancers are squamous cell carcinomas; the remaining tumors are basal cell or adnexal carcinomas. Most cancers of the nasal cavity and paranasal sinuses are also squamous cell carcinomas, although minor salivary gland neoplasms (adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma) account for 10% to 15% of lesions in these locations. Melanoma accounts for 5% to 10% of nasal cavity malignancies but is rare in the paranasal sinuses. Neuroendocrine carcinomas of the sinonasal region (including small cell carcinoma, esthesioneuroblastoma, and sinonasal undifferentiated carcinomas), lymphomas, sarcomas, and plasmacytomas are even less common.
PROGNOSTIC FACTORS
Patient-specific factors (primarily prognostic for survival) include age and performance status. Disease-specific factors (primarily prognostic for locoregional control) include location, histology, and locoregional extent (reflected in TNM stage), and perineural invasion. Extensive local disease involving the nasopharynx, base of skull, or cavernous sinuses markedly increases surgical morbidity as well as the risk of subtotal surgical excision. Tumor extension into the orbit may require enucleation, but minimal invasion of the floor or medial wall may be dealt with through resection and reconstruction, sparing the globe.
GENERAL MANAGEMENT
Nasal Vestibule Tumors
Nasal vestibule tumors can be treated definitively with surgery, primary radiation therapy, or postoperative (adjuvant) radiation therapy when indicated because of tumor size or positive surgical findings. For small superficial tumors, standard treatment approaches are surgery or primary radiation therapy. Depending on the location and size of the primary tumor, radiation can be delivered as external beam radiation therapy, brachytherapy, or a combination of the two. Primary radiation therapy may be preferable for nasal vestibule carcinoma for better cosmetic outcome, although surgery can yield high control rates with excellent cosmetic results for selected small superficial tumors. Adjuvant radiation is indicated for cases involving positive surgical margins, positive lymph nodes, or perineural invasion. Cartilaginous invasion is not a contraindication for radiation therapy because fractionated treatment carries a low risk of necrosis.35 For large invasive tumors with extensive tissue destruction and distortion, the combination of surgery and radiation therapy, with the radiation given either before or after surgery, is the mainstay of treatment. However, some clinicians favor primary radiation with salvage surgery for this situation.36 Cosmesis can be enhanced by having experienced prosthodontists design aesthetically satisfactory custom-made nasal prostheses after radical surgery. Patients who are older or who have poor performance status can be treated with radiation therapy alone. No role for systemic chemotherapy has been established for tumors of this type.
Nasal Fossa Tumors
Either surgery or primary radiation therapy can produce similarly high control rates for early-stage nasal fossa lesions. The choice of treatment modality is generally guided by the size and location of the tumor as well as the anticipated cosmetic outcome. Posterior nasal septum lesions or locally advanced lesions are generally treated surgically, but small anterior-inferior septal lesions (≤1.5 cm) can be treated effectively with interstitial brachytherapy (iridium-192 [192Ir] implant). For lateral wall lesions extending to the nasal ala, primary external beam radiation therapy may produce the best cosmetic results.
TABLE 42.2 2010 AMERICAN JOINT COMMITTEE ON CANCER STAGING SYSTEM FOR CANCER OF THE NASAL CAVITY AND PARANASAL SINUSES
Paranasal Sinus Tumors
Surgery can produce excellent control rates for T1 and T2 tumors and is generally the mainstay of treatment. The combination of surgery and postoperative radiation therapy is the treatment of choice for patients with more advanced but resectable disease who are medically fit to undergo surgery. Maxillary sinus and ethmoid sinus tumors often present as locally advanced disease (large T3 or T4) and are commonly managed with surgery and postoperative radiation therapy. Ethmoid sinus carcinomas can be treated with radiation alone or with concurrent chemotherapy to avoid structural or functional deficits.37 Surgery generally involves medial maxillectomy and en blocethmoidectomy; a craniofacial approach is required if tumor extends superiorly to the ethmoid roof or olfactory region.38,39 Primary radiation therapy, with or without concurrent chemotherapy, can be considered for patients who are not fit to undergo surgery owing to significant comorbid conditions or poor performance status, or for patients who decline radical surgery.
For patients presenting with Kadish stage A esthesioneuroblastoma, either surgery or radiation therapy ultimately yields locoregional control rates exceeding 90%.8 Single-modality therapy has also been used for lesions involving the nasal cavity and one or more paranasal sinuses (stage B), as has surgery followed by adjuvant radiation therapy. However, the optimal therapy for stage B lesions is not clear because of the heterogeneity of these tumors. Surgery with adjuvant radiation is generally used for disease that extends beyond the nasal cavity and paranasal sinuses (stage C). Overall, local therapy with surgery and postoperative radiation therapy yields excellent results at 5 years with regard to both overall survival (93.1%) and local control (96.2%).36 Elective nodal irradiation is not generally recommended because the incidence of nodal relapse is <15%. Distant metastasis is uncommon (10%) even among patients presenting with locally advanced disease.
CHEMOTHERAPY: NEOADJUVANT AND CONCOMITANT
Neoadjuvant chemotherapy (i.e., chemotherapy given before surgery) can reduce tumor volumes, which may allow a less extensive surgical resection than would be possible otherwise. Similarly, chemotherapy given before primary radiation therapy can also reduce tumor volumes and facilitate radiotherapy planning by increasing the distance between tumor borders and critical organ structures such as brain, chiasm, optic nerve, or spinal cord. Investigations are ongoing to determine whether the response (or lack of same) to neoadjuvant chemotherapy can help in the choice of definitive treatment. For example, if neoadjuvant chemotherapy produces a complete response, then primary radiation therapy, with or without chemotherapy, can be considered; a less-than-complete response would prompt surgical excision of the lesion followed by adjuvant radiation therapy.
Concurrent chemoradiation therapy can also be used for patients with medical conditions that preclude surgery if those patients have good performance status. Depending on the patient’s performance status and renal function, single-agent cisplatin or carboplatin can be used concurrently with external beam radiation for locally advanced, unresectable squamous cell carcinoma. Neoadjuvant chemotherapy or concurrent chemoradiation with etoposide and cisplatin or carboplatin can be used to treat sinonasal undifferentiated carcinoma, neuroendocrine carcinoma, or small cell carcinoma. Chemotherapy is not used routinely for esthesioneuroblastoma, and its role in the management of this disease is under investigation. Chemotherapy may have a role in the management of Kadish stage C disease, and although responses to chemotherapy have been reported, they are usually of limited duration.40 Concurrent chemotherapy during radiation may be considered for inoperable cases.
PALLIATION
Symptoms of incurable sinonasal cancer are particularly distressing. Multidisciplinary input is required even for very advanced cases, as palliation may involve limited surgery, radiation therapy, chemotherapy, investigational studies, or best supportive care. The morbidity of each modality must be balanced with the potential benefits in symptom control and improved quality of life. Particular attention is required to address the control of pain and discomfort as a first priority, and the impact of disfigurement and dysfunction, which is often present.
Chemotherapy can be given as single-agent therapy in investigational settings. If radiation therapy is given, large doses per fraction are usually given to reduce the duration of treatment. However, if concurrent chemotherapy is added, treatment with 2-Gy fractions should be considered to avoid severe acute effects. Radiation or chemotherapy is often effective in reducing tumor bulk and relieving symptoms associated with disfiguring masses, proptosis, discomfort or neuropathic pain, headache, epistaxis or other bleeding, nasal obstruction or discharge, and trismus.
RADIATION THERAPY TECHNIQUES
Tumors of the Nasal Cavity
Nasal Vestibule Tumors
Target Volumes
For small, well-differentiated lesions that are ≤1.5 cm in diameter, small fields with a 1- to 2-cm margin are appropriate. The initial target volume for all poorly differentiated tumors and well-differentiated primary tumors larger than 1.5 cm without palpable lymphadenopathy should include both nasal vestibules with at least 2- to 3-cm margins around the primary tumor (wider margins for infiltrative tumor) as well as bilateral facial, submandibular, and subdigastric nodes. When lymph node involvement is present at diagnosis, the lower neck is also irradiated. For larger nasal vestibule lesions, the lower half of the nose and the upper lip are treated as well as the regional lymphatics, including the facial lymphatics and upper neck nodes. For postoperative radiation therapy, the initial target volume includes the operative bed plus a 1- to 1.5-cm margin and the elective nodal regions.
Treatment Techniques
External Beam Radiation. Thin superficial nasal vestibule lesions can be treated with orthovoltage x-rays or electrons with skin bolus, whereas thicker lesions are generally treated with electrons. In definitive therapy, the target volume is treated to a dose of 66 to 70 Gy, with a small reduction in the treatment fields after 50 Gy to boost the dose to the gross disease. For patients presenting with palpable neck adenopathy, the entire neck is treated with at least a subclinical dose of 50 Gy, and the gross disease plus a 1- to 2-cm margin is then treated with an additional 16 to 20 Gy. A technique for external beam irradiation using electrons is illustrated in Figure 42.3. The patient lies supine, immobilized with the neck slightly flexed by using a custom mask to align the anterior surface of the maxilla parallel with the top of the couch. For larger nasal vestibule lesions, the lower half of the nose and the upper lip are treated with an anterior appositional field using 20-MeV electrons and 6-MV photons weighted 4 to 1. Skin collimation is used to minimize scatter irradiation to the eye and reduce the penumbra of the beam and reduce the field size required. Custom beeswax bolus material is prepared to allow a relatively flat surface contour onto which the electron beam is incident, avoiding inhomogeneity due to oblique incidence and surface irregularity. A bolus is also used to fill the nares to avoid the dose perturbation from the air cavity with electron beams. In photon treatments, the bolus is removed to spare the skin unless the overlying skin is involved. An intraoral Cerrobend-containing stent is used to displace the tongue posteriorly and partially shield the upper alveolar ridge.
When indicated, the right and left facial lymphatics are irradiated with appositional fields; these require an approximately 15-degree gantry rotation to the respective side with 6-MeV electron fields, each abutting the appositional primary lesion portal and the upper neck fields. The medial border is matched to the lateral border of the anterior primary field. The anterior border extends down from the oral commissure to the middle of the horizontal ramus of the mandible, whereas the posterior border extends from the upper edge of the anterior field to just above the angle of the mandible. The inferior border splits the horizontal ramus of the mandible and is matched to the upper neck field. The junctions are moved twice during the course of treatment to reduce dose heterogeneity. The submandibular and subdigastric nodes are treated with lateral parallel-opposed photon fields. For patients with involved nodes, these upper neck fields are matched inferiorly to an anterior portal treating the middle and lower neck nodes.
For definitive treatment, the external beam radiation schedule for lesions up to 1.5 cm in diameter for which a combination of electrons and photons is used is typically 50 Gy in 25 fractions followed by a boost of 10 to 16 Gy in 5 to 8 fractions (prescribed at the 90% isodose line). Larger lesions to be treated by external beam radiation alone receive 50 Gy in 25 fractions plus a boost of 16 to 20 Gy in 8 to 10 fractions. The schedule for elective nodal irradiation is 50 Gy in 25 fractions. Palpable nodes are given a boost to a total dose of 66 to 70 Gy in 33 to 35 fractions, depending on the size. For postoperative treatment, the volume is reduced off the undissected nodal regions after 50 Gy (25 fractions) to deliver an additional 6 Gy to the surgical bed. At 56 Gy, a final “cone down” is done to include a 4-Gy dose to the preoperative tumor bed, for a total dose of 60 Gy. If the excision was limited or positive margins are present, the final cone-down dose is 10 Gy for a total dose of 66 Gy.
FIGURE 42.3. Nasal vestibule squamous cell carcinoma. A: Arrows indicate tumor expanding the columella. B,C: Arrows indicate invasion downward into the upper gingivobuccal sulcus on computed tomography (CT) imaging. D: Arrow shows setup for electron-beam phase of therapy with custom lead skin collimation in situ. E: Arrow shows the beeswax bolus in situ. F: Dosimetry to 50 Gy resulting from an appositional electron beam with beeswax bolus (arrow) to compensate for surface obliquity. The primary tumor, facial, and level II nodes were treated to 50 Gy. This was followed by 25 Gy administered by an interstitial low-dose-rate iridium needle implant at 0.55 Gy per hour. G: Dummy wires are inserted into each hollow tube. Each tube has a ball anchor at the distal end of the needles, which is pushed snugly against the skin and sutured to the skin. Note the placement of transverse “moustache” needles. H,I: Orthogonal x-ray (anteroposterior, lateral) films taken to document the placement of the needles. CT-based planning was performed. J,K: Live sources in situ.
Brachytherapy. Brachytherapy for small lesions is accomplished by using a 192Ir wire implant or, in selected cases, by using an intracavitary 192Ir mold. Hollow needles for after loading are inserted under general anesthesia, which allows good exposure of the tumor and protects the airway in the event of bleeding from the vascular Kiesselbach plexus on the anterior nasal septum or from posterior hemorrhages originating from larger vessels near the sphenopalatine artery, behind the middle turbinate. Implantation of a T2 squamous cell carcinoma of the columella is shown in Figure 42.3. The recommended doses for low-dose–rate brachytherapy have evolved empirically and range from 60 to 65 Gy delivered during 5 to 7 days.
Brachytherapy can be used instead of an external beam boost for patients with T1 or T2 nasal vestibule tumors after initial larger-field radiation therapy. After delivery of 50 Gy, the patient is assessed and if the tumor volume has been substantially reduced, a boost of 20 to 25 Gy may be administered in about 2 days by using low-dose–rate brachytherapy.
High-dose–rate brachytherapy has also been used to deliver the boost. A custom mold of the nasal vestibule is fabricated and tumor is marked in the mold. Two to four plastic tubes are inserted in the mold alongside the tumor at 1-cm intervals. For tumors of the lateral part of the vestibule, two catheters are placed on the inner aspect of the nasal vestibule. For medially localized tumors, catheters are placed on both sides of the vestibule. After external beam radiation to 50 Gy in 5 weeks, high-dose–rate brachytherapy is delivered in week 6. The dose is typically 3 Gy per fraction, given twice a day, to a total dose of 18 Gy specified at the center of the tumor. With a median overall treatment time (external beam radiation plus brachytherapy) of 36 days, this technique has been reported to yield 2-year local control rates of 86% and ultimate locoregional control rates of 100%.41
FIGURE 42.4. Intensity-modulated radiotherapy for adjuvant radiotherapy for an adenoid cystic carcinoma of the ethmoid sinus, anterior skull base, nasal cavity, and medial orbit following endoscopic anteroposterior ethmoidectomy with resection of tumor, left maxillary antrostomy with disease removal, bilateral sphenoidotomy, and frontal sinusotomy with anterior approach to the anterior skull base including a left lateral rhinotomy and medial maxillectomy and extradural resection of anterior cranial base. A,B: Preoperative computed tomography scans with tumor indicated by white arrow. C: Transverse section at the level of the orbit that show sharp dose gradient at the interface of the clinical target volume and the optic nerves and chiasm. D,E: Cumulative dose volume (y-axis) histogram.
TABLE 42.3 TARGET VOLUMES FOR INTENSITY MODULATED RADIATION THERAPY OF SINONASAL CANCERS
Nasal Fossa Tumors
Target Volume
The technique for primary or postoperative external beam irradiation of nasal cavity tumors depends on the depth of the neoplasm. For tumors located <3.5 or 4.0 cm from the skin of the apex of the nose, electrons can be used, as 20 MeV electrons will provide coverage up to 5 cm in depth. A margin of at least 1 cm deep to the posterior edge must be included in the full-dose volume. The technique is as previously described for nasal vestibule carcinoma. CT-based treatment planning is necessary for accurate target localization and dose calculation.
Intensity-modulated radiation therapy (IMRT) is recommended for tumors of the nasal cavity in which the target volume is more than 5 cm deep or for tumors of the ethmoid sinus (Fig. 42.4). This technique delivers the desired dose to the target volume while minimizing the dose to critical organs such as cornea, lens, lacrimal glands, retina, optic nerve, optic chiasm, brain, and brainstem. For postoperative radiation therapy, the primary clinical target volume (CTV) descriptions are given in Table 42.3. The CTV1 consists of the primary tumor bed with a 1.0- to 1.5-cm margin. A boost subvolume consisting of high-risk regions (sites of positive margins, gross macroscopic residual tumor) to be treated to higher doses may be outlined. The CTV2 includes the entire operative bed. For ethmoid sinus tumors, this might include the frontal sinus, maxillary sinus, and sphenoid sinus. The bony orbit is part of the operative bed when orbital exenteration is performed because of tumor invasion. For lesions involving the ethmoid sinuses or olfactory region, the CTV should also include the cribriform plate. A third CTV may be delineated to encompass the tract of cranial nerve V2 to the foramen rotundum if perineural invasion is present. For primary radiation therapy given as IMRT, the CTV1, consisting of the gross tumor volume plus a margin of 1 to 2 cm, receives the full dose of 66 to 70 Gy. For patients receiving neoadjuvant chemotherapy, target volume definition is based on the extent of disease before chemotherapy.
For three-dimensional (3D) conformal radiation therapy, the initial target volume for postoperative radiation consists of the surgical bed with 1- or 2-cm margins, depending on the surgical pathology findings and the proximity of critical structures. The boost volume consists of areas at greatest risk of recurrence, such as close or positive resection margins or regions of perineural invasion, with 1- to 2-cm margins.
For small anteroinferior septal lesions, brachytherapy can be accomplished by using a single-plane implant of the lesion with 2-cm margins. Elective neck irradiation is not given routinely even for patients with large tumors or esthesioneuroblastoma.
Setup and Field Arrangement
For target volumes <5 cm deep, an electron technique similar to that described for nasal vestibule carcinomas is used. Treatment devices include lead skin collimation to obtain a sharp penumbra as well as bolus material in the nasal cavity, in postoperative defects, and on skin scars. An intraoral stent is used to depress the tongue, provide a patent airway, and aid in immobilization. Tungsten internal eye shields may be used if the target volume approaches the orbits (see Fig. 42.3).
For 3D-conformal therapy or IMRT, the patient is immobilized in a supine position with the head positioned such that the hard palate is perpendicular to the treatment couch. Scars are marked with thin radio-opaque wires, bolus and other devices are positioned, and transverse CT images are obtained from the vertex to the upper mediastinum. For IMRT, rigid immobilization is necessary, including use of special head and shoulder thermoplastic masks that extend down to the upper thorax. The shoulders can be additionally depressed and fixed by using wrist straps tethered to a footboard. Target volumes are delineated as previously described.
For IMRT, multiple gantry angles are used based on beam-optimization algorithms. An example of a 10-field noncoplanar arrangement with two vertex beams is shown in Figure 42.4. The beam angle selections are based on the same principles as for 3D-conformal therapy:
1. Preference for the shortest path to the target;
2. Avoidance of direct irradiation of the critical structures (e.g., avoid beam entry through the contralateral eye after ipsilateral exenteration); and
3. Use of as large a beam separation as possible.
Inverse planning is usually done and multiple iterations may be necessary to ensure that the following are accomplished:
1. Targets are covered;
2. Normal tissue constraints are respected; and
3. Dose is relatively homogenous.
Dose calculations should include heterogeneity corrections because of the significant amounts of air and bone in the sinuses. Radiation oncologists must work closely with physicists and dosimetrists. It is important to realize that the criteria for accepting or rejecting the plan may not be evident from the dose–volume histogram.
For 3D-conformal radiation therapy, anterior oblique wedge-pair photon fields are appropriate for lesions located in the anterior lower half of the nasal cavity. Opposed-lateral fields can be used to treat tumors at the posterior part of the nasal fossa, provided the ethmoid cells are not involved. The optic pathway can be excluded from the radiation fields with this setup. For primaries of the upper nasal cavity and ethmoidal air cells, a three-field setup allows coverage of the ethmoid cells while sparing the optic apparatus. CT-based treatment planning is necessary to select beam and wedge angles (usually 45 to 60 degrees) and the relative loading of the fields, as well as to evaluate the dose to critical structures such as brain, brainstem, and optic structures.
Proton beam therapy techniques for treating nasal fossa tumors are rapidly evolving and include both passive scattering and discrete spot scanning beams. Theoretically, the advantage of proton therapy derives from the unique physical properties of protons that allow deposition of most of the particle’s energy at the end of its range. Descriptions of the various techniques by which proton therapy can be delivered are beyond the scope of this chapter. Nevertheless, with optimization of dosimetry, the conformality and heterogeneity within the target volumes provided by proton therapy should be equivalent to what can be achieved with either electron or photon therapy, with the added advantage of minimizing the unnecessary dose or “dose bath” from IMRT to the surrounding normal tissue structures.
Dose Fractionation Schedule
The dose schedule for low-dose–rate brachytherapy is 60 to 65 Gy during 5 to 7 days. The external beam regimen for primary radiation therapy is 50 Gy in 25 fractions followed by a boost of 16 to 20 Gy in 8 to 10 fractions, depending on the size of the lesion. Postoperative radiation therapy consists of 50 Gy to elective tissue, 56 Gy to the operative bed, and 60 Gy to the tumor bed, with an optional boost to close or positive surgical margins, all given at 2 Gy per fraction. Dose regimens for intensity-modulated therapy, whether with photons or protons, are summarized in Table 42.3.
Tumors of the Paranasal Sinuses
Target Volume
Because maxillary cancers are usually diagnosed at a locally advanced stage and surgery is the primary therapy, most patients receive postoperative radiation therapy. Delineation of target volumes is based on physical examination, pretreatment imaging, intraoperative findings (tumor extension relative to critical structures such as orbital wall, cribriform plate, cranial nerve foramina, and ease of resection), and pathologic findings (such as positive margin or perineural invasion).
IMRT is the preferred treatment method as it generally yields better dose distribution in terms of both tumor coverage and sparing of normal tissues than can be achieved with 3D-conformal radiation therapy. IMRT is rapidly becoming the standard of care technique for external beam therapy for sinonasal malignancies.42,43 Proton therapy may offer additional advantages over IMRT in terms of further reducing the dose to normal tissues while achieving equivalent doses to the target volume. The CTV1 consists of the primary tumor bed with 1.0- to 1.5-cm margin of normal tissue. The CTV2 encompasses the operative bed, including the bony orbit after orbital exenteration and the ethmoid, frontal, or sphenoid sinuses if explored during surgery. A third CTV may be delineated to encompass the tract of cranial nerve V2 to the foramen rotundum if perineural invasion is present. A CTV for high-risk areas (CTVHR; see Table 42.3) may also be outlined to cover, for example, gross macroscopic residual tumor or positive margins to which a higher dose may be delivered.
For primary radiation therapy using IMRT, the prescription doses are 66 to 70 Gy to the gross tumor volume (the prechemotherapy volume for those receiving systemic treatment), plus a 1- to 1.5-cm margin of normal-appearing tissue (CTV1), 59 to 63 Gy to other secondary clinical target volumes such as the rest of the involved sinus and wider region around the primary target, and 54 to 57 Gy to the tracts of nerves (if perineural invasion is present) and to elective nodal regions. An example of an IMRT plan for primary definitive radiation therapy of a T4N0 squamous cell carcinoma is shown in Figure 42.5.
For postoperative radiation therapy using a 3D-conformal technique, the initial target volume consists of the operative bed with 1- to 2-cm margins. The boost field consists of the primary tumor bed and areas at higher risk of recurrence, such as positive resection margins or perineural invasion. Radiation is administered to the neck after node dissection if multiple nodes are involved or extracapsular extension is present. Elective radiation of ipsilateral submandibular and subdigastric nodes is given for patients with squamous cell or poorly differentiated carcinoma. An example of an intensity-modulated proton plan for postoperative radiation therapy is shown in Figure 42.6.
FIGURE 42.5. Intensity-modulated radiotherapy (IMRT) for definitive radiotherapy for T4N0 squamous cell carcinoma of the maxillary sinus. A,B: Pretreatment photographs showing skin of cheek involvement. C,D: Magnetic resonance image (MRI) scans with tumor indicated by white arrow. E,F: MRIs following induction chemotherapy showed progressive disease involving left maxilla, left nasoethmoid region, extending inferiorly into the premaxillary soft tissues. G–I: IMRT plan with sections showing coverage of the target volumes. The patient was treated using concomitant boost fractionation. The primary plan delivered 57 Gy and a concomitant boost plan administered an additional 15 Gy. G and H also show avoidance of the normal tissues, as listed in the key and illustrated further in the cumulative dose–volume histogram in L. J,K: The skin reaction during final week of radiotherapy. M,N: MRI and patient photo at follow-up, showing healed skin with hyperpigmentation. The tumor was in complete remission at the last visit 7 months after therapy.
Setup and Field Arrangement
Patients undergoing treatment of paranasal tumors are immobilized in a supine position with the head slightly hyperextended to bring the floor of the orbit parallel to the axis of the anterior field. An intraoral stent is used to open the mouth and depress the tongue out of the radiation field. After palatectomy, the stent can be designed to hold a water-filled balloon to obliterate the large air cavity in the surgical defect to improve dose homogeneity. An orbital exenteration defect can also be filled directly with a water-filled balloon to decrease the dose delivered to the temporal lobe. Marking of the lateral canthi, oral commissures, external auditory canals, and external scars facilitates target volume delineation. The planning CT scan should include the entire head to allow the use of vertex beams. The principles of target delineation and plan evaluation for IMRT of maxillary sinus cancer are the same as those described for nasal cavity and ethmoid tumors.
For 3D-conformal radiation, a three-field technique consisting of an anterior and right and left lateral fields is used for tumors involving the suprastructure or extending to the roof of the nasal cavity and ethmoid cells. The lateral fields may have a 5-degree posterior tilt and 60-degree wedges. The relative loading varies from 1:0.15:0.15 to 1:0.07:0.07 depending on the tumor location and photon energy. For the initial target volume, the superior border of the anterior portal is above the crista galli to encompass the ethmoids and, in the absence of orbital invasion, at the lower edge of the cornea to cover the orbital floor. The inferior border is 1 cm below the floor of the sinus and the medial border is 1 to 2 cm (or more if necessary) across the midline to cover contralateral ethmoidal extension. The lateral border is 1 cm beyond the apex of the sinus or falling off the skin. The superior border of the lateral portals follows the floor of the anterior cranial fossa, the anterior border is behind the lateral bony canthus parallel to the slope of the face, the posterior border covers the pterygoid plates, and the inferior border corresponds to that of the anterior portal. The boost volume encompasses the tumor bed while sparing the optic pathway.
Anterior and ipsilateral wedge-pair (usually 45-degree wedges) photon fields are used for tumors of the infrastructure with no extension into the orbit or ethmoids. If necessary, the lateral portal can have a 5-degree inferior tilt to avoid beam divergence into the contralateral eye. Lateral-opposed photon fields are preferred for tumors of the infrastructure spreading across midline through the hard palate. If necessary, the fields can be slightly angled (5-degree inferior tilt from the ipsilateral side and 5-degree superior tilt from the contralateral side) to avoid irradiating the contralateral eye. The use of a half beam with the isocenter placed at the level of the orbital floor and the upper half of the fields shielded further reduces exposure of the eyes by beam divergence.
The eyes and the optic pathway are of particular concern. With 3D-conformal techniques, the cornea can generally be shielded (to avoid keratitis) in patients with limited involvement of the medial or inferior orbital wall. If the tumor invades the orbital cavity without necessitating orbital exenteration, care should be taken to avoid irradiating the lacrimal gland to prevent xerophthalmia. It is important to keep the dose to the contralateral optic nerve as well as the optic chiasm below 54 Gy in 27 fractions to prevent bilateral blindness.
FIGURE 42.6. Proton therapy for recurrent adenoid cystic carcinoma (ACC) of the right hard palate. The patient had a palatectomy with radial forearm free flap reconstruction followed by postoperative external beam radiation therapy with IMRT to 60 Gy in 30 fractions. One year later, the ACC recurred with enhancement in right V1 and V2, involvement of the right cavernous sinus, and an enhancing mass in the infratemporal fossa and pterygopalatine fossa. Salvage surgery involved a right total maxillectomy with orbital preservation, pterygomaxillary space dissection and resection, and an extracranial dissection of vidian nerve and cranial nerve 5, V2. With evidence of skull base and cavernous sinus involvement after surgery he was treated with postoperative chemoradiation with IMPT and cisplatin to a dose of 66 Gy(RBE) in 33 fractions. No evidence of disease was present at 6 months after salvage therapy. The figure represents the axial, sagittal, and dose–volume histogram (DVH) of the IMPT plan. (DVH for the IMPT plan, from left to right on the graph: red, spinal cord; green, whole brain; black, brainstem; pink, left parotid; white, left eye; brown, right cochlea; dark green, left lens; sky blue, right parotid; brown, oral cavity; violet, optic chiasm; red, right eye; green, mandible; light green, left optic nerve; soft pink, right lens; dark green, right optic nerve; yellow, CTV or CTV3; blue, CTV2; orange, CTV1.)
Treatment of the Neck
For squamous and undifferentiated carcinoma, elective neck irradiation is recommended.47 Ipsilateral upper neck treatment is delivered by using a lateral appositional electron field (usually 12 MeV). With conventional radiation techniques, careful matching is required to prevent hot or cold spots. The superior border of the field slopes up from the horizontal ramus of the mandible anteriorly to match the inferior border of the primary portal posteriorly, leaving a small triangle over the cheek untreated. The anterior border is just behind the oral commissure, the posterior border is at the mastoid process, and the inferior border is at the thyroid notch (above the arytenoids). The nodal volume can also be covered by using IMRT with sparing of the parotid gland. Alternatively, the primary tumor bed and the upper neck can be treated with IMRT with the isocenter above the arytenoids and matched to a separate unmodulated lower neck field. This allows the laryngeal structures to be spared by using a larynx block.
If the maxillary sinus is being treated with conventional non-IMRT techniques, the central axes of the primary (sinus) fields and the opposed-lateral upper neck fields all are placed in the plane of the inferior border of the maxillary fields (i.e., usually 1 cm below the floor of the maxillary sinus). An independent collimator jaw is used to shield the caudal half of the maxillary fields and the cephalad half of the neck field. The junction between the primary and the neck fields can be moved during the course of treatment to reduce dose heterogeneity in this region. Portals are reduced after 42 Gy, and treatment to the posterior neck continues with abutting electron fields to the desired dose. The middle and lower neck is irradiated with an anterior appositional photon field matched to the inferior border of the opposed-lateral upper neck fields.
Dose Fractionation Schedule
Table 42.3 summarizes the dose regimens for IMRT. With 3D-conformal techniques, the dose for postoperative radiation therapy at 2 Gy per fraction is 50 Gy for elective nodal treatment, 56 Gy to the operative bed, 60 Gy to the tumor bed if resection margins are negative, and 66 Gy if margins are positive. For primary radiation therapy, the total dose to the primary tumor at 2 Gy per fraction is 66 to 70 Gy. The contralateral optic nerve and chiasm are excluded from the field after a dose of 50 to 54 Gy. When the tumor invades structures adjacent to the optic chiasm, a dose of up to 60 Gy to the chiasm may be acceptable because of the higher probability of control and the relatively low risk of visual impairment,36 after clear discussion with the patient.
FOLLOW-UP AND RECURRENCES
Salvage is possible for some persistent or recurrent lesions. In particular, recurrent cancers of the nasal vestibule remain curable with salvage surgery after primary radiation or occasionally with salvage radiation after primary surgery. Regional recurrences can be treated successfully with neck dissection with or without postoperative radiation depending on the pathologic features. Treatment options are limited for tumors that recur after combined-modality therapy, although a few highly selected patients may qualify for reirradiation with curative intent. Cumulative doses of radiation to neural tissues (spinal cord, brainstem, brain, optic structures) are the main limitation to reirradiation.
Most oncologists recommend a second baseline physical examination together with CT, MRI, or positron emission tomography with CT for patients with nasal cavity or paranasal sinus tumors at 3 months after treatment. Common practice is to repeat clinical examination and imaging when indicated every 4 months for the first 3 years after treatment, every 6 months for the fourth and fifth years after treatment, and annually thereafter. In addition to monitoring possible tumor recurrence, these follow-up visits are critical for identifying and managing side effects of treatment.
RESULTS OF TREATMENT
The results of treatment have improved from the 1960s through the 1990s, with overall survival rates increasing progressively from 33% ± 18% in the 1960s to 42% ± 15% in the 1970s, 54% ± 15% in the 1980s, and 56% ± 13% in the 1990s (P <.001).48 In a systematic review of published series spanning 40 years, Dulguerov et al.48 demonstrated progressive improvements in outcome for all treatment modalities (surgery, surgery with radiation, and radiation). However, a more recent review of the experience at the University of California, San Francisco showed no significance differences in 5-year overall survival rates or local control rates by decade of treatment (1960s through 2000s; overall survival, 46% to 56%; local control 55% to 62%) or by radiation technique (conventional, 3D conformal, or IMRT; overall survival 47% to 57%; local control 59% to 65%). However, the incidence of severe (grade 3 or 4) side effects declined significantly over time from 50% in the 1960s to 16% in the 2000s.49
Tumors of the Nasal Cavity
Nasal Vestibule Tumors
Findings from several retrospective studies of radiation therapy for nasal vestibule tumors3,17,36,41,50–58 suggest that either brachytherapy or external beam radiation therapy can produce cure rates of up to 90% for small (<2-cm) lesions (Table 42.4).3,17,41,50–53,55–57 For 2- to 4-cm lesions, external beam radiation can control 70% to 80% of tumors. Although nodal spread of disease is relatively rare for lesions smaller than 2 cm, up to 40% of patients with larger primary tumors have metastases to the cervical nodes at presentation. With the use of appropriate radiation techniques and fractionation schedules, severe and late complications after radiation therapy are uncommon (see Table 42.4).
An analysis by the Groupe Europeen de Curietherapie of 1,676 carcinomas of the skin of the nose and nasal vestibule treated by brachytherapy or external beam irradiation revealed an overall local control rate of 93%.3 Local control depended on tumor size (<2 cm, 96%; 2–3.9 cm, 88%; ≥4 cm, 81%), tumor site (external surface, 94%; vestibule, 75%), and status (new, 95%; recurrent, 88%). Local control was independent of histology for tumors <4 cm, but for those >4 cm, basal cell carcinomas were more often controlled than were squamous cell carcinomas. Complications were rare (necrosis, 2%). The local control rate with surgery was approximately 90%.
Nasal Fossa Tumors
Documentation of treatment outcomes for nasal fossa tumors, like nasal vestibule tumors, comes mostly from retrospective studies.18,59–61 Results are best for lesions confined to the nasal septum, which are generally small and well controlled with primary radiation therapy. Locoregional control rates range from 60% to 85%, and the rate of isolated regional recurrence for patients who did not receive elective nodal irradiation is approximately 5%. The most common complications after radiation therapy are soft tissue necrosis, visual impairment, and nasal stenosis, seen in 5% to 11% of patients (Table 42.5).18,59,60,61 Ang et al.18 at MD Anderson Cancer Center reported better primary disease control and survival rates for patients with tumors located in the septum (86%) versus patients with tumors on the lateral wall or floor of the nasal fossa (68%). In that study no patients with nasal septum carcinomas who underwent elective nodal irradiation had nodal relapses, whereas two of eight patients who did not undergo nodal irradiation experienced recurrence in the ipsilateral subdigastric nodes. Distant metastasis was more common among patients with lateral wall and floor disease, and ultimately survival rates were best among patients with nasal septum tumors. However, other groups59,61 found no differences in results for tumors at various sites within the nasal cavity. Results of treatment for early-stage tumors are equally good after radiation therapy or surgery. Indeed, T1 lesions in particular can be well controlled with either modality, and in one study were associated with a 5-year overall survival rate of 91%.62
An analysis of 783 patients with nasal cavity cancer included in the Surveillance, Epidemiology, and End Results (SEER) database from 1988 through 199863 revealed squamous cell carcinoma to be the most common tumor type (49.3%), followed by esthesioneuroblastoma (13.2%). More than half of the cases presented with a small primary tumor (T1), and only 5% had positive nodes at diagnosis. Overall mean survival time was 57 months and the 5-year survival rate was 40.3%. On multivariate analysis, male sex, increasing age, T status, N status, and poorer tumor grade all adversely affected survival (P <.05). Radiation therapy, given to 50.5% of patients, also independently predicted poorer survival (P = .03), probably because those patients had had poor prognostic features such as perineural invasion, positive margins, or poor performance status (medically unfit for surgery). Five-year survival rates by tumor type, T status, and N status are shown in Table 42.6.63 Five-year survival rates also correlated with extent of tumor dedifferentiation, being 75.3%, 61.9%, 47.6%, and 36.8% for well-, moderately, poorly, and undifferentiated cancers, respectively.
TABLE 42.4 LOCAL AND REGIONAL CONTROL RATES OF NASAL VESTIBULE CARCINOMAS TREATED BY DEFINITIVE RADIOTHERAPY
TABLE 42.5 TREATMENT OUTCOMES FOR NASAL FOSSA TUMORS
TABLE 42.6 TREATMENT RESULTS FOR NASAL CAVITY CANCER FROM THE SURVEILLANCE, EPIDEMIOLOGY AND END RESULTS DATABASE FOR 1988 THROUGH 1998A
TABLE 42.7 OVERALL TREATMENT RESULTS OF ESTHESIONEUROBLASTOMA
Esthesioneuroblastoma
Either surgery or primary radiation therapy as single-modality therapy can produce locoregional control rates exceeding 90% for tumors are confined to the nasal cavity (Kadish stage A).8 Single-modality therapy has also been used for lesions involving the nasal cavity and one or more paranasal sinuses (stage B), as has surgery followed by adjuvant radiation therapy. However, the optimal therapy for stage B lesions is not clear because of the heterogeneity of these tumors. Disease that extends beyond the nasal cavity and paranasal sinuses (stage C) seems to be best treated with a combination of surgery and radiation, and the role of chemotherapy, if any, is being investigated. Elective nodal irradiation is not generally recommended because the incidence of nodal relapse is <15%. Distant metastasis is uncommon (10%) even among patients presenting with locally advanced disease.
Among 783 nasal cavity cancers identified from the SEER database, 103 (13.2%) were esthesioneuroblastomas; the median survival time for patients with these tumors was 88 months and the overall 5-year survival rate was 63.6%.63 Tables 42.748,64–68 and 42.88 summarize the results of treatment. The prognosis for patients with stage A disease is excellent. Overall, 30% of patients with stage B tumor died of the disease. About 60% of patients with stage C tumors died of the disease, primarily because of failure to control the primary tumor. As noted above, distant metastasis is uncommon (10%) even in locoregionally advanced disease.
Spaulding et al.28 reported results for 25 patients treated at the University of Virginia Medical Center from 1959 through 1986 who were followed for 2 years after therapy. Treatment approaches had gradually evolved during that period, with progressive introduction of craniofacial resections, complex field megavoltage radiation, and, for stage C disease, the addition of chemotherapy. Therefore, patients were assigned to two groups, based on treatment era, for comparative analysis. Although this series is relatively small, it revealed two interesting findings on this rare disease: first, that extensive craniofacial resection does not seem to confer a major advantage over wide local excision for patients with stage B lesions, and second, that the addition of chemotherapy to craniofacial resection and radiation therapy for patients with stage C tumors may yield higher disease-specific survival rates.
A larger series of 72 patients with sinonasal neuroendocrine tumors treated at MD Anderson Cancer Center between 1982 and 200264 included a spectrum of histologies: esthesioneuroblastoma (31 patients), sinonasal undifferentiated carcinoma (SNUC, 16 patients), neuroendocrine carcinoma (18 patients), and small cell carcinoma (7 patients). The overall survival rates at 5 years were 93.1% for patients with esthesioneuroblastoma, 62.5% for those with SNUC, 64.2% for neuroendocrine carcinoma, and 28.6% for small cell carcinoma (P = .0029; log-rank test). The local control rates at 5 years also were superior for patients with esthesioneuroblastoma (96.2%) compared with patients who had SNUC (78.6%), neuroendocrine carcinoma (72.6%), or small cell carcinoma (66.7%) (P = .04). The corresponding regional failure rate at 5 years were 8.7% for patients with esthesioneuroblastoma, 15.6% for SNUC, 12.9% for neuroendocrine carcinoma, and 44.4% for small cell carcinoma, and distant metastasis rates were 0% for esthesioneuroblastoma, 25.4% for SNUC, 14.1% for neuroendocrine carcinoma, and 75.0% for small cell carcinoma. Moreover, local therapy alone produced excellent local and distant control rates for esthesioneuroblastoma. Among 8 patients treated for esthesioneuroblastoma since 2000 with surgery and adjuvant IMRT to 60 Gy (1 with stage B disease and 7 with stage C [5 of whom had intracranial extension]), there were no local recurrences and one nodal recurrence was salvaged surgically. All eight patients were alive with no evidence of disease at the last follow-up.
TABLE 42.8 PATTERN OF FAILURE AND RESULTS OF SALVAGE TREATMENT OF ESTHESIONEUROBLASTOMA BY STAGE AND TREATMENT
Tumors of the Paranasal Sinuses
Five-year outcomes from studies reported since 1998 continue to illustrate that local control after treatment of paranasal sinus tumors remains problematic30,42,46,47,67–78 (Table 42.9). For patients with carcinoma of the maxillary sinuses, the combination of surgery and radiation yields 5-year local control and survival rates ranging from 44% to 80%. These rates are better than those achieved with either surgery or radiation therapy alone. For radiation therapy alone, the 5-year local control rates range from 22% to 39% and the 5-year overall survival rates from 22% to 40%. Findings from a large multicenter retrospective analysis of 418 patients with ethmoid sinus adenocarcinoma indicated that the size of the lesion (T4) the extent of nodal involvement (N+), and the presence of brain extension were the most significant prognostic factors for overall survival.79 Although the authors concluded that surgery followed by postoperative radiation therapy remains the treatment of choice, they did note that 51% of the patients developed recurrences, 74% of which were local.
A 1991 review of outcomes after treatment of 73 patients with maxillary sinus carcinomas at MD Anderson Cancer Center reported 5-year local and regional control rates according to pathologic T category as follows: for T1 and T2 tumors, 91% local and 71% regional control; for T3, 77% local and 80% regional; and for T4, 65% local and 93% regional.30 Five-year regional control rates according to N category were 84% for N0 disease and 82% for N1 or N2 disease. The most common histologic subtypes were squamous cell carcinoma (48%) and adenoid cystic carcinoma (27%); 5-year local and regional control rates were 62% (local) and 86% (regional) for squamous cell tumors and 82% (local) and 94% (regional) for adenoid tumors. Perineural invasion and nodal disease at presentation were poor prognostic factors. An update of this report published in 200747 showed that increasing the radiation portals to cover the skull base for patients with perineural invasion reduced the risk of local recurrence and that adding elective nodal irradiation for patients with squamous or undifferentiated tumors improved the rates of nodal control, distant metastasis, and recurrence-free survival.
IMRT has emerged as the standard of care for tumors of the paranasal sinuses with low toxicity and high local control rates.42,62,73,78 Madani et al.73 reported the largest series to date, in which 105 patients (most of whom [56%] had ethmoid sinus tumors) were treated with IMRT. At a median follow-up time of 40 months, the 5-year actuarial local control and overall survival rates were 70.7% and 58.5%. In multivariate analysis, invasion of the cribiform plate was found to predict worse local control (P <.001) and lower overall survival (P <.001).
The extent of neuroendocrine differentiation of sinonasal carcinomas also influences the patterns of failure. In one study, the 5-year actuarial rates of local, regional, and distant failure according to tumor histology were as follows: esthesioneuroblastoma 4% local failure, 9% regional failure, and 0% distant failure; neuroendocrine carcinoma 27% local, 13% regional, and 12% distant; sinonasal undifferentiated carcinoma 21% local, 16% regional, and 25% distant; and small cell carcinoma 33% local failure, 44% regional failure, and 75% distant failure.64
Future Directions in Radiation Therapy
IMRT has rapidly become the standard of care in external beam therapy for sinonasal malignancies.42,43,62,73 Nevertheless, proton beam therapy may confer further benefits for nasal and paranasal sinus tumors, and investigators at MD Anderson Cancer Center have demonstrated the clinical feasibility of intensity-modulated proton therapy for this purpose (see Fig. 42.6). The additional advantages of this technique over photon-based IMRT are its ability to limit the radiation “dose bath” to normal critical tissue structures and allow escalation of dose to the target. Well-designed clinical trials in a cooperative group setting will be necessary to provide the evidence required for widespread adoption of proton therapy over IMRT for these rare malignancies. Finally, further improvements in the local control of sinonasal malignancies will require incorporating systemic agents as neoadjuvant or concurrent therapy. Again, the rarity of sinonasal cancer will most likely require international cooperative group trials to facilitate timely analyses of outcomes and design of future trials.
SEQUELAE OF TREATMENT
Soft Tissue and Bone
The formation of nasal cavity synechiae (fibrous mucosal bands causing airway stenosis) can be prevented by intermittent dilation of the nasal passages with a petroleum-coated cotton swab until mucositis has resolved. Dry mucous membranes can be managed symptomatically with saline nasal spray. Soft-tissue or cartilage necrosis is uncommon after therapy, at an estimated incidence of 5% to 10%.26,66,71,80
Eyes and Optic Pathway
Chronic keratitis and iritis (dry-eye syndrome) can develop after radiation therapy if tumor extension to the orbital cavity mandates irradiation of the lacrimal gland to doses of more than 30 to 40 Gy.26,80 Without lacrimal irradiation, fewer than 20% of patients treated with up to 55 Gy to the cornea develop chronic corneal injury.81 The risk of cataract formation at 5 years is approximately 5% after doses of up to 10 Gy to the lenses using conventional fractionation; this risk increases to 50% at 5 years after 18 Gy.82
Radiation retinopathy generally occurs within 18 months to 5 years after treatment.83 It is rare after doses of <45 Gy, but the incidence increases to about 50% after doses of 45 to 55 Gy.84 Optic neuropathy tends to develop between 2 and 4 years after radiation therapy, but it has been reported as late as 14 years after treatment.84 The reported incidence of optic neuropathy is <5% after 50 to 60 Gy but increases to around 30% for doses of 61 to 78 Gy. Factors that influence the risk of radiation-induced optic neuropathy were reported in 2006 for 273 patients treated between 1964 and 2000 in whom the radiation fields included the optic nerves or chiasm.85 The likelihood of developing optic neuropathy was primarily influenced by the total dose, but fraction size was marginally significant. The 5-year rates of freedom from optic neuropathy were 95% for doses ≤63 Gy treated once daily, 98% for doses ≤63 Gy treated twice daily, 78% for doses >63 Gy treated once daily, and 91% for doses >63 Gy treated twice daily. On multivariate analysis, the risk of optic neuropathy was found to correlate with increasing total dose (P = .0047) and possibly with increasing patient age (P = .091), once daily versus twice-daily fractionation (P = .068), and overall treatment time (P = .097). When the target volumes include the optic pathway, special attention must be paid to hot spots and dose per fraction to avoid optic neuropathies.
Optimizing the technique for paranasal sinus tumors is crucial so that the radiation dose to the optic apparatus is limited to the greatest extent possible to minimize the risk of complications. Investigators at the University of Florida, reviewing 464 patients treated from 1964 through 2001,44 reported a 20% incidence of ipsilateral radiation retinopathy at 5 and 10 years after conventional or 3D radiation therapy. In that study, patients were deemed functionally blind when visual acuity dropped to 20/100 on the Snellen chart, and neovascularization (rubeosis iridis or neovascular glaucoma) was coincident with radiation retinopathy. Use of IMRT has been shown to limit the doses to the optic apparatus without compromising local control. Indeed, Chen et al.49 reported findings for 127 patients treated between 1960 and 2005 with a variety of radiation therapy techniques that had evolved over that period, namely conventional, 3D conformal, and IMRT. They concluded that the incidence of severe (grade ≥3) complications depended on the radiation treatment technique used: 54% for conventional therapy, 22% for 3D-conformal therapy, and 13% for IMRT. Specifically, the incidence of grade 3 or 4 late ocular toxicity decreased from 20% with conventional techniques to 0% with IMRT, whereas grade 3 or 4 late auditory toxicity decreased from 15% with conventional to 4% with IMRT (P <.001). Moreover, to date no radiation-induced blindness has been reported among the collective experience, with 308 patients treated with IMRT as either definitive or postoperative therapy for nasal and paranasal malignancies.42,49,61,62,73,77,84
TABLE 42.9 OUTCOME OF PATIENTS WITH LOCALLY ADVANCED CANCER OF THE PARANASAL SINUSES TREATED WITH COMBINED SURGERY AND RADIATION THERAPY
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