General Principles and Management

Nancy Lee

Nadeem Riaz

Allen M. Chen

Carcinomas arising from the nasal cavity and the paranasal sinuses are rare tumors of the head and neck accounting for approximately 3% to 5% of all upper respiratory tract malignancies and <1% of all new cancers.¹ They are twice as common in males as in females and typically occur after 40 years of age.²^,³ Owing to their inconspicuous locations along the anterior skull base, these tumors generally present at advanced stages unless the cancer impinges on vital organs or extends from the maxillary sinus to the nasal cavity producing subsequent symptoms of epistaxis or obstruction. Because these tumors frequently involve multiple adjacent sites, determination of the exact site of origin may be difficult. Similarly, treatment decisions have historically been complicated by the close proximity of these cancers to critical normal tissue structures such as the optic pathways and the brainstem.

Owing to the rarity of paranasal sinus or nasal cavity tumors, published clinical outcomes are largely limited to retrospective reviews of single institutional experiences. Additionally, the heterogeneity of these study populations with respect to both clinical presentation and treatment strategy often makes drawing definitive conclusions challenging. For instance, primary sites and different histological subtypes are often grouped together, which lead to some confusion in comparing treatment results across series. Moreover, the proportion of patients treated by a nonsurgical approach in these studies can vary greatly. In general, early-stage cancer is often successfully managed with surgery alone, whereas more advanced disease requires the addition of postoperative radiotherapy.⁴^,⁵^,⁶^,⁷^,⁸^,⁹ In select situations, chemotherapy has been added to postoperative radiotherapy as adjuvant treatment. The use of primary radiotherapy has been reported in older series but with apparently higher treatment-related complications, perhaps due to the inability to give adequate dose to the gross disease without having to compromise the surrounding normal tissues. Because these tumors are often surrounded by multiple critical normal tissues, such as the optic structures and the brainstem, delivery of a high therapeutic dose to gross disease is often difficult and maximal tumor resection should be attempted whenever possible before radiation therapy. However, for patients who are medically or surgically inoperable, definitive radiotherapy with or without chemotherapy is a feasible alternative approach, although reported outcomes have been less favorable.¹⁰

Intensity-modulated radiation therapy (IMRT) offers the potential to reduce dose to critical structures while maintaining desired doses to the targeted tumor volume through inverse planning and the use of optimized nonuniform beams.¹¹ As a result, a higher tumoricidal dose of radiation can be administered while minimizing the dose delivered to the surrounding normal tissues.¹² Although numerous treatment-planning studies have demonstrated through dosimetric comparisons that IMRT can offer a superior dose distribution for the treatment of tumors of the nasal cavity and paranasal sinuses in comparison to threedimensional (3D) conformal and conventional methods,¹³^,¹⁴ several recently published articles suggest that the theoretic advantages associated with this technique do indeed translate into tangible benefits for patients treated in the clinical setting⁵^,¹⁵^,¹⁶^,¹⁷ directly compares 3DCRT to IMRT patients in paransal patients. Although most of these single-institutional series are limited by relatively short follow-up, the preliminary data with respect to both efficacy and toxicity are encouraging. In this chapter, the authors will discuss the management of cancer of the nasal cavity and paranasal sinuses using radiation therapy with or without chemotherapy.

CLINICAL PRESENTATION

The diagnosis of cancer of the nasal cavity and paranasal sinuses is often delayed for considerable periods of time due to the lack of specific symptoms.⁴^,¹⁸ Early symptoms are vague and can mimic sinusitis. Unilateral nasal obstruction, chronic unilateral nasal discharge, and intermittent epistaxis can result from nasal cavity tumors. Other less common symptoms include headache, epiphora, and localized pain. Diagnosis can often be delayed
further because these patients have a history of nasal polyps, which produce similar symptoms. Tumors of the maxillary antrum also tend to remain silent until they extend outside the sinus. As a result of tumor extension to the premaxillary region, patients can complain of facial pain, numbness, localized swelling, nasal obstruction, and epistaxis. Nasal obstruction from tumor extension to the nasal cavity and tumor extension into the orbit causing ocular problems such as epiphora, proptosis, diplopia, eye pain, and inner canthal mass are the most common symptoms of ethmoid sinus tumors. Sixth nerve palsy, severe morning headaches, and diplopia are common symptoms for primary sphenoidal tumors. Lastly, frontal sinus tumors can present with bilateral swelling of the glabella and the supraorbital ridge and with frontal pain.

Cervical lymph node metastases on initial clinical presentation are uncommon with an incidence of approximately 10% to 15%. Depending on the histological subtype and extent of the primary tumor, the incidence ranges from 20% to 44%.¹⁹^,²⁰^,²¹ Distant metastasis at the time of diagnosis is rare.

PATHOLOGY

Squamous cell carcinoma (SCC) or one of its variants is the most common histological subtype, making up 80% to 85% of all neoplasms of the nasal cavity and paranasal sinuses. Minor salivary gland tumors such as adenoid cystic carcinoma and adenocarcinoma comprise approximately 10% to 15% of all neoplasms in this region. Mucoepidermoid carcinomas are extremely rare. Adenocarcinoma can also represent a metastasis, most often from the kidney, the breast, or the lung. Although malignant melanoma accounts for approximately 10% to 15% of nasal cavity cancers, it is rare in the paranasal sinuses. Other less common histological subtypes include undifferentiated carcinoma, plasmacytoma, lymphoma, esthesioneuroblastoma, sarcoma, and inverted papilloma. Undifferentiated carcinomas have an extremely poor prognosis with up to 90% of patients dying within the first year from either extensive local or metastatic disease. Although histologically benign appearing, inverted papilloma often has a very aggressive clinical course even in the absence of malignancy. It is associated with SCC in 10% to 15% of cases.¹⁸^,²²

STAGING

Nasal cavity and paranasal sinus tumors are staged according to the current seventh edition of the American Joint Committee on Cancer (AJCC) TNM (tumor, node, metastasis) staging system. Within the paranasal sinuses, frontal and sphenoid sinuses are rare and not formally staged according to the AJCC TNM staging system. Magnetic resonance imaging (MRI) in addition to computed tomography (CT) is very useful as part of the staging workup as it can potentially differentiate between tumor and sinusitis. Table 21.1 contains the details of the staging system.

RADIATION TECHNIQUES

Over the last several decades, a remarkable evolution of radiotherapy techniques for the treatment of nasal cavity and paranasal sinus cancer has been witnessed. Reported techniques have included conventional radiotherapy using two-dimensional (2D) imaging to three-dimensional conformal radiotherapy (3D-CRT) using CT simulation, to more recently, IMRT with dose painting. Proton beam has also been utilized for the treatment of these tumors but its use is limited to few centers.

TABLE 21.1 Seventh Edition of AJCC Staging for Nasal Cavity and Paranasal Sinus Cancer

Primary Tumor (T)
Maxillary sinus
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor limited to the maxillary sinus mucosa with no erosion or destruction of bone
T2	Tumor causing bone erosion or destruction including extension into the hard palate and/or middle nasal meatus, except extension to posterior wall of maxillary sinus and pterygoid plates
T3	Tumor invades any of the following: bone of the posterior wall of maxillary sinus, subcutaneous tissues, floor or medial wall of orbit, pterygoid fossa, ethmoid sinuses
T4a	Tumor invades anterior orbital contents, skin of cheek, pterygoid plates, infratemporal fossa, cribriform plate, sphenoid or frontal sinuses
T4b	Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than maxillary division of trigeminal nerve V2, nasopharynx, or clivus
Nasal cavity and ethmoid sinus
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ
T1	Tumor restricted to any one subsite, with or without bony invasion
T2	Tumor invading two subsites in a single region or extending to involve an adjacent region within the nasoethmoidal complex, with or without bony invasion
T3	Tumor extends to invade the medial wall or floor of the orbit, maxillary sinus, palate, or cribriform plate
T4a	Tumor invades any of the following: anterior orbital contents, skin of nose or cheek, minimal extension to anterior cranial fossa, pterygoid plates, sphenoid, or frontal sinuses
T4b	Tumor invades any of the following: orbital apex, dura, brain, middle cranial fossa, cranial nerves other than V2, nasopharynx, or clivus
Regional nodes (N)
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastases
N1	Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2	Metastasis in a single ipsilateral lymph node, >3 cm but not >6 cm in greatest dimension, or in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension, or bilateral or contralateral lymph nodes, none >6 cm in greatest dimension
N2a	Metastasis in a single ipsilateral lymph node >3 cm but not >6 cm in greatest dimension
N2b	Metastasis in multiple ipsilateral lymph nodes, none >6 cm in greatest dimension
N2c	Metastasis in a lymph node >6 cm in greatest dimension
N3	Metastasis in a lymph node >6 cm in greatest dimension
Distant metastasis (M)
MX	Distant metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis
Stage grouping
0		Tis	N0	M0
I		T1	N0	M0
II		T2	N0	M0
III		T3	N0	M0
		T1	N1	M0
		T2	N1	M0
		T3	N1	M0
IVA		T4	N0	M0
		T4	N1	M0
IV B		Any T	N2	M0
		Any T	N3	M0
IVC		Any T	Any N	M1
Source: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer; 2010, with permission.

Conventional 2D radiotherapy techniques typically incorporate the use of a three-field technique with two lateral wedged fields and an anterior field. Because the dose required for treatment ranges from 66 to 70 Gy, significant toxicity can result from the excess radiation delivered to adjacent structures, especially optic structures, in which threshold doses for toxicity are below 60 Gy.⁸^,²³ Notably, with the introduction of 3D-CRT, the dose inadvertently given to the surrounding normal tissues can be significantly reduced without compromising delivery of high doses to the target volume. However, this technique relies significantly on the expertise of the radiation oncology and physics team, and careful manipulations with dose distributions are needed to optimize delivery of a high dose to the target while minimizing dose to critical structures.⁵^,²⁴^,²⁵ More recently, advances in radiation technology have resulted in additional refinement of 3D-CRT with the development of IMRT.¹⁶ IMRT utilizes a computer dose distribution optimization process to deliver the radiation dose to the tumor while minimizing the dose delivered to the surrounding normal structures. The delivery of IMRT is based on the use of multileaf collimators (MLCs) and allows for painting or sculpting of dose distribution with superb precision resulting in a rapid dose fall-off near normal tissue. Although several different treatment planning systems are available, the basic principles underlying this technology are similar.¹¹ The technical aspects of IMRT are discussed further in Chapter 5.

Tumors of the skull base, including those involving the nasal cavity and the paranasal sinuses, appear to be especially well suited to the use of IMRT, given the irregular contours of these cancers and the presence of vital structures in this region such as the brainstem, the optic nerves, the optic chiasm, and the spinal cord. Multiple dosimetric studies have eloquently shown that improved dose distributions with increased dose delivery to the tumor target while minimizing the dose delivered to the surrounding normal tissues can be achieved with IMRT when compared with conventional radiotherapy¹³^,²⁶ (Fig. 21-1). From a practical standpoint, the dose delivered to the optic pathways can be reduced selectively by IMRT, which has the potential to save binocular vision particularly for patients who have extensive and large-volume disease in the paranasal sinuses. Preliminary clinical data from several centers have demonstrated minimal toxicity from IMRT when compared with the historical series where the toxicity rates can be as high as 35%.¹⁵^,²⁷^,²⁸ In a longitudinal analysis of 127 patients treated with radiation therapy from 1960 to 2005 at the University of California, San Francisco (UCSF), the incidence of grade 3 and 4 late ocular toxicity among patients treated with CRT, 3D-CRT, and IMRT was 20%, 9%, and 0%, respectively.¹⁵ In another series from Memorial Sloan-Kettering Cancer Center, none of the 85 patients who underwent postoperative radiotherapy treated with CT simulation developed grade 3 to 4 late complication of the eye with a median follow-up of 60 months among surviving patients.⁵^,²⁹ Other series have shown similar results in terms of the reduction of late complications due to radiotherapy. As more centers publish their experience with IMRT in the treatment of paranasal sinus cancer, it is hopeful that the late complication rates continue to decrease. In addition to its ability to spare the organs at risk, IMRT can potentially increase disease control as a result of improvement in tumor coverage and by allowing the delivery of higher radiation doses than with conventional technique.¹³

ANATOMY AND PATTERNS OF SPREAD

The Nasal Cavity

The anterior, the superior, the inferior, and the posterior borders of the nasal cavity are located at the limen nasi, the base of skull (the frontal sinuses, the cribriform plate, and the ethmoid air cells), the hard palate, and the choanae, respectively (Fig. 21-2). The limen nasi is the line of transition from the skin to the mucous membrane. The septum divides the nasal cavity into right and left halves and attaches to the perpendicular plate of the ethmold bone posteriorly (Fig. 21-3). The medial walls of the maxillary sinuses define the lateral borders of the nasal cavity. The nasopharynx is located directly behind the nasal cavity. There are three turbinates or conchae (superior, middle, and inferior), which protrude downward and medially from the lateral wall into the nasal cavity, forming the superior, middle, and inferior meatus. Superiorly, the cribriform plate contains the branches of
the olfactory nerve, which innervates the superior nasal concha and upper third of the septum.

FIGURE 21-1. An example of an ethmoid sinus tumor being planned using (A) IMRT and (B) 3D-CRT. Notice that the 70-Gy isodose line (dark blue) coverage is superior in the IMRT versus the 3D-CRT plan. In addition, there is superior sparing of the optic chiasm when compared with the 3D-CRT plan. IMRT, intensity modulated radiation therapy; 3D-CRT, three-dimensional conformal radiotherapy. (See color insert.)

Nasal cavity tumors tend to spread by local extension into adjacent bones and sinuses because the bony partitions between the nasal cavity, the sinuses, the orbits, and the cranial vault are quite thin and offer little resistance to cancer infiltration. Nasal cavity tumors can also destroy the septum and invade through the nasal bone to the skin. Lateral wall tumors can spread to destroy the medial maxillary sinus wall and invade into the maxillary antrum, whereas tumors arising in the middle meatus invade first the ethmoid sinus and then the orbit. The sphenoid sinus and the nasopharynx are also sites of tumor extension particularly in more advanced cases. The cribriform plate serves as an avenue for cancer spread to the anterior cranial fossa. Minor salivary gland tumors, particularly adenoid cystic carcinoma, have a higher chance of perineural spread. Commonly involved nerves for perineural spread include olfactory nerves, infraorbital nerve, and the nerves within the superior orbital fissure.

FIGURE 21-2. Relationship of bones and cartilages of the nose.

Source: From Milton RR, Cassisi NJ, Wittes RE. Cancer in the head and neck. In: Devita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 2nd ed. Philadelphia, PA: JB Lippincott Co; 1985: 407-506, with permission.

Regional lymph node metastasis occurs in <5% at presentation and approximately 10% of patients have distant metastases. Lymphatic drainage is to the retropharyngeal lymph nodes and the cervical chain. One series from MD Anderson Cancer Center (MDACC) of 51 patients showed a 6% nodal relapse in the subdigastric region in patients who did not receive elective nodal irradiation.³⁰

FIGURE 21-3. A: Coronal whole-organ section through the vestibule. B: The upper lateral alar cartilages fuse with the cartilaginous septum. The nasal bones overlap the upper and lower cartilages. The limen vestibule is the junction of the upper and lower lateral cartilage.

Source: From Bridger MWM, van Nostrand AWP. The nose and paranasal sinuses—applied surgical anatomy: a histologic study of whole organ sections in three planes. J Otolaryngol. 1978;7(suppl 6):1-30, with permission.

Esthesioneuroblastoma

Esthesioneuroblastoma, also commonly known as olfactory neuroblastoma, was initially described in the early 1900s and remains a relatively rare disease accounting for approximately 1% to 6% of all nasal cancers.³¹^,³²^,³³ Arising from the olfactory mucosa, it frequently invades the paranasal sinuses, the orbits, and the skull base. Compared with other tumors located in this site, esthesioneuroblastoma is more likely to spread intracranially through the cribriform plate. Nasal obstruction, epistaxis, nasal discharge, pain, visual changes, facial numbness, or a neck mass are symptoms on presentation. Cervical nodal metastases have been reported to range from approximately 17% to 27% of the patients on presentation although distant metastases have been in the order of 10% to 40%.³¹ Although different staging systems have been proposed, the Kadish staging system is the most commonly used³⁴ (Table 21.2). Because esthesioneuroblastoma typically expresses a variety of neuroendocrine markers such as neuron-specific enolase, chromogranin, and synaptophysin, immunohistochemistry can facilitate its diagnosis.

The Ethmoid Sinus

The ethmoid sinus contains several small cavities, namely, the ethmoid air cells located between the medial wall of the orbit and the lateral wall of the nasal cavity (Figs. 21-4 and 21-5). The ethmoidal sinuses are divided into anterior, middle, and posterior groups of air cells, where the middle group opens directly into the middle meatus. These groups are distinguished from each other on the basis of their sites of communication with the nasal cavity. The lamina papyracea, a porous bone, separates the ethmoid sinus from the orbital cavity and is a source of tumor spread.

Tumors confined to the ethmoid sinus without any involvement of the surrounding structures and sinuses are extremely rare. Tumor extension to the ipsilateral nasal cavity, the maxillary sinus, the orbit, the sphenoid, the anterior cranial fossa, the frontal sinus, and the nasopharynx are common. Contralateral spread to the opposite ethmoid sinus is infrequent and reported to be approximately 10%.²² Tumors can extend to the orbit through the lamina papyracea and superiorly into the anterior cranial fossa through the cribriform plate, particularly esthesioneuroblastoma. If the dura is compressed but not involved with tumor, it does not portend the poor prognosis when compared with tumor extension with histologic involvement of the dura.

Lymphatic spread is reported to be 3% to 7%.²² Approximately 10% of the patients subsequently present with nodal failure when the lymph nodes are not electively radiated.

TABLE 21.2 Kadish Staging of Esthesioneuroblastoma

Kadish A	Disease confined to the nasal cavity
Kadish B	Disease confined to the nasal cavity and involving one or more of the paranasal sinuses
Kadish C	Disease extends beyond the nasal cavity and the paranasal sinuses to involve either the orbit, base of the skull, cervical lymph nodes, distant metastasis, or with intracranial extension

FIGURE 21-4. A: Horizontal section through the lacrimal sac, the orbit, and the ethmoid and the sphenoid sinuses. B: The posterior ethmoid cells extend farther laterally than the anterior cells. The sphenoid sinus is in close relationship to the optic nerve and the orbital apex. Note the short distance between the anterior ethmoid sinuses and the inner canthus.

FIGURE 21-5. Sagittal section through the nasopharynx and the sphenoid sinus, just left of midline. Note relationship of the sphenoid sinus ostium to the nasopharynx and the posterior nasal cavity. The anterior wall of the sphenoid sinus and the floor of the sella are thin bone.

FIGURE 21-6. A: Coronal section through the maxillary antrum. B: Note the thinness of all walls except the hard palate. Lateral to the antrum is the buccinators muscle and fat pad.

Source: Modified from Bridger MWM, van Nostrand AWP. The nose and paranasal sinuses—applied surgical anatomy: a histologic study of whole organ sections in three planes. J Otolaryngol. 1978;7(suppl 6):1-30, with permission.

The Maxillary Sinus

The maxillary sinus is shaped like a pyramid where the base separates the maxillary sinus from the nasal cavity (Figs. 21-6 and 21-7). The floor of the maxillary sinus is composed of the alveolar process, and it resides inferior to the floor of the nasal cavity, particularly for the edentulous patients. Superiorly, the floor of the orbit forms the roof of the maxillary antrum, which contains the infraorbital canal. The apex extends to the zygomatic bone. The facial wall is the anterior boundary of the maxillary sinus. Posteriorly, the infratemporal wall borders the infratemporal and the pterygopalatine fossae. Tumors gain access to the base of the skull when they spread posteriorly into these structures.

The Ohngren line, a theoretic plane joining the medial canthus of the eye with the angle of the mandible, divides maxillary sinuses into a suprastructure and an infrastructure.

Tumors can invade the nasal cavity through the medial wall, can involve the maxillary gingiva, may spread to the infratemporal fossa or the pterygopalatine fossa, or invade the orbit by direct superior extension through the ethmoids. In some sense, the pattern of spread of maxillary sinus cancer can vary depending on the site of origin within the antrum. Tumors in the suprastructure can extend to involve the nasal cavity, the ethmoid cells, the orbit, the pterygopalatine fossa, the infratemporal fossa, and the base of the skull. The routes of spread for infrastructure lesions include the hard palate, the alveolar process, the gingivobuccal sulcus, the soft tissue of the cheek, the nasal cavity, and the pterygoid fossa.

Lymphatic drainage ranges between 10% and 20%²⁰ The incidence can be as high as 30% for poorly differentiated histology. Approximately 10% to 15% will develop nodal relapse if elective lymph node irradiation is not done. When patients relapse in the lymph node region, they are rarely cured and also have high rates of distant metastases. The rate of distant metastasis is approximately 15% to 25%.¹⁹

The Sphenoid Sinus

The sphenoid sinus is a midline air cavity within the body of the sphenoid bone. It is located anterior to the clivus, posterior to the superior meatus of the nasal cavity, and medial to the cavernous sinuses (Figs. 21-2, 21-3, 21-4 and 21-5). The sphenoid sinus is divided by a septum into the right and left sphenoid sinuses. The septum is often incomplete or very thin and is rarely in the anatomic midline. The pituitary fossa and the optic chiasm lie above and the nasopharynx lies inferior to the sphenoid sinus. Tumors can spread to the cavernous sinus and intracranially to the anterior or the middle cranial fossae. There can be involvement of the adjacent ethmoid sinuses, the clivus, the sella turcica, the nasal cavity, the nasopharynx, and the orbit.

The Frontal Sinus

The frontal sinuses lie between the outer and inner tables of the frontal bone representing an extension of anterior ethmoidal cell (Figs. 21-2 and 21-8). The two frontal sinuses are irregularly shaped and asymmetric and are separated by a thin bony septum. The sinuses lie above the orbits and drains into the maxillary sinus through the frontal nasal duct.

TARGET DETERMINATION AND DELINEATION

Understanding the patterns of failure for nasal cavity and paranasal sinus cancers is essential for adequate target determination and delineation. Before delineation of the target, determination
of proper sites to be irradiated must be considered. For example, for patients with tumors at risk for perineural spread such as adenoid cystic carcinomas, the planned target volume should include the neural pathways up to the cranial nerve ganglion at the base of skull.

FIGURE 21-7. A: Sagittal section through the antrum and the apex of the orbit. B: The orbital apex communicates with the pterygopalatine fossa by way of the infraorbital fissure. Extension of antral tumor through the posterior wall provides access to the middle cranial fossa along the cranial nerves and the vascular foramina.

For definitive treatment, the gross tumor volume (GTV) is outlined by using all available imaging, that is, MRI and/or positron emission tomography (PET). MRI fusion with treatment planning CT scan can further aid in the delineation of the GTV. Unless contraindicated, every patient should undergo MRI due to the complex anatomy of this region as MRI is superior in differentiating between mucous versus tumor as well as visualizing more clearly the different nerve pathways. One study from Hokkaido University School of Medicine compared clinical outcomes among 82 patients who underwent CT-assisted planning to those of 88 patients who had no such treatment planning.³⁵ The investigators found that the combined use of CT and the shell for immobilizations in treatment planning allowed greater accuracy in tumor coverage. Multivariate analysis for predicting significant prognostic factors confirmed the critical role of CT in terms of overall survival and primary tumor control. Notably, the actuarial 5-year survival rate was improved by 10% in patients who underwent CT-assisted treatment planning with a particular improvement observed among patients whose tumors were located adjacent to critical organs at risk such as the brain and eye. The clinical tumor volume (CTV) is defined as the GTV plus microscopic spread of the tumor. Typically, this involves one or more adjacent sinuses. The planning target volume (PTV) typically includes a margin ranging from 3 to 5 mm surrounding the CTV. Each institution should have its own set of guidelines on the margin needed to account for patient motion and daily setup errors. For postoperative lesions, the CTV is defined as the postoperative bed which should include previous sites of gross disease as depicted from preoperative imaging, as well as the entire postoperative bed (Fig. 21-9). Areas with positive margins and/or gross residual disease should receive a higher dose, although every attempt to achieve gross total resection is needed to maximize local control.³⁶ Due to the possibility of surgical seeding, postoperative CTV should also include all tissue planes surgically violated.³⁷^,³⁸

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