General Principles and Management
Kenneth S. Hu
Adam S. Jacobson
Mark S. Persky
Louis B. Harrison
INTRODUCTION
Successful management of the neck is a prerequisite for the cure of most head and neck squamous cell carcinomas (HNSCC). Tumor spread to the regional nodes signals the transformation of the primary tumor to a more malignant phenotype with the ability to not only invade lymphatics but also spread hematogenously. Indeed, the clinical involvement of the regional node decreases the chance for cure by at least one-half.1 Even in a clinically negative neck, surgical data have demonstrated high rates of occult nodal involvement for the majority of head and neck primary sites. Usually, such regional spread occurs in a predictable, progressive pattern depending on the mucosal site of origin, local richness of lymphatics, proximity to midline, and tumor stage. Thus, in a clinically negative neck, the first echelon nodes and levels of potentially involved nodal stations are evaluated and risk of involvement assessed before a decision is rendered regarding selective management. For clinically node-positive patients, more comprehensive, intensive treatment is required that addresses the greater tumor burden and larger areas of potential spread. How the neck is managed usually follows the manner in which the primary site is addressed. Single modality therapy, either surgery or radiation, is used to manage early stage primary tumors and regional lymphatics at risk for harboring occult disease, whereas multidisciplinary approaches are required for advanced primary tumors. Although surgery was traditionally considered the mainstay of treatment of the primary site and neck, decades of randomized trials have established radiation therapy as an effective alternative. In that regard, advances in organ preservation therapies have resulted from the integration of concurrent chemotherapy with radiation2,3,4,5,6 altered fractionated radiation therapy,7,8,9,10 introduction of new chemotherapeutic/biologic agents,11 use of induction chemotherapy,12,13 better understanding of the role of functional imaging improved treatment techniques such as intensity-modulated radiation therapy (IMRT)14,15 as well as advances in molecular profiling, especially with regard to the human papilloma virus and epidermal growth factor receptor. Recent improvements in transoral robotic techniques have renewed primary surgical approaches for multiple sites (oropharynx and hypopharynx). In this regard, a neck dissection is usually performed in a staged manner, which has emphasized risk-adapted adjuvant treatment based on pathologic factors.
The purpose of this chapter will be to discuss the role of surgery and radiation therapy in the elective, adjuvant, and definitive management of the neck. Additionally, this chapter will discuss the use of imaging to assess oncologic response and to discuss evolving concepts which may better tailor treatment of regional disease. The management of regional metastatic disease from nasopharyngeal cancer will be discussed in a separate chapter.
CERVICAL LYMPH NODE LEVELS
The Committee for Head and Neck Surgery and Oncology of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) first published the guidelines for anatomic boundaries of the various cervical levels in 1991,16 which were modified and updated in 2002.17 These guidelines were all based on the original level designations that were created at Memorial Sloan Kettering Cancer Center to refer to the particular topographical location on the neck under which a consistent pattern of lymph nodes existed (Fig. 14-1).
NECK STAGING
It is clear that metastases to cervical lymph nodes has a profound impact on the prognosis of a patient. The current staging system is based on a consensus between the European UICC and American Joint Cancer Committees. This system utilizes the
clinical features of nodal size, number, and laterality. It does not integrate imaging features suggestive of extranodal extension, which is well known to adversely affect prognosis. Table 14.1 describes the N staging.
clinical features of nodal size, number, and laterality. It does not integrate imaging features suggestive of extranodal extension, which is well known to adversely affect prognosis. Table 14.1 describes the N staging.
 FIGURE 14-1. Nodal delineation for the electively treated node-negative and node-positive neck. On the left, are nodal stations delineated in a node-negative neck. On the right, are target delineation of level II nodal level up to the skull base in a node-positive neck. On the left, is shown the target delineation of level II in an electively treated neck. Note the differences in the superior margin allows substantial sparing of the parotid gland. RP, retropharygeal node; ICA, internal carotid artery; JV, jugular vein; PG, parotid gland; PB of JGD, posterior belly of the jugulodigastric muscle; BP, brachial plexus. See Table 14.10 for boundaries of nodal stations. (See color insert.) |
Patients staged as Nx have regional lymph nodes that cannot be assessed. NO patients have no identifiable regional nodal metastasis. N1 patients have a single nodal metastasis, ipsilateral to the primary tumor site, and <3 cm in greatest dimension.
Patients staged as N2a have a metastasis to a single ipsilateral node, which is >3 cm but <6 cm in greatest dimension. Patients staged as N2b have metastasis to multiple ipsilateral lymph nodes and none are >6 cm in greatest dimension. Patients staged as N2c have metastatic disease in bilateral or contralateral lymph nodes; none are >6 cm in greatest dimension. Patients staged as N3 disease have a lymph node or conglomerate of lymph nodes >6 cm in dimension.
TABLE 14.1 Cervical Lymph Node Staging System | ||||||||||||||||||||
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NECK DISSECTION TERMINOLOGY
Radical neck dissection: Radical neck dissection involves removal of lymph node levels I to V, including the submandibular gland, tail of the parotid gland, sternocleidomastoid muscle, internal jugular vein, and spinal accessory nerve (Fig. 14-2).
Modified radical neck dissection (MRND): MRND involves removal of lymph nodes from levels I to V (as in the radical neck dissection) but with preservation of at least one of the nonlymphatic structures (i.e., sternocleidomastoid muscle, spinal accessory nerve, and/or internal jugular vein).Modifications to the radical neck dissection include the following: (a) Type I: The spinal accessory nerve is preserved; (b) Type II: The spinal accessory nerve and the internal jugular vein are preserved; (c) Type III: The spinal accessory nerve, the internal jugular vein, and the sernocleidomastoid muscle are preserved.
 FIGURE 14-2. Removal of lymph node levels I to V. |
Extended radical neck dissection: Extended radical neck dissection refers to removal of additional lymph node levels or groups and/or nonlymphatic structures (i.e., muscle, blood vessels, nerves) not normally removed with a radical neck dissection. Examples of additional lymph node groups include superior mediastinal, parapharyngeal, retropharyngeal, periparotid, postauricular, suboccipital, and buccinator. Examples of other nonlympahtic structures are the external carotid artery, hypoglossal and vagus nerves, and other neural, osseous, cutaneous, muscular, or vascular structures that are potentially involved with tumor.
Selective neck dissection (SND): SND refers to preservation of one or more lymph node levels and sparing all vital structures (sernocleidomastoid muscle, internal jugular vein, spinal accessory nerve). There are several variations of the SND, which have been given specific names (i.e., lateral, supraomohyoid, extended supraomohyoid, posterior, and central) (Fig. 14-3A-C).
Super selective neck dissection: Super selective neck dissection involves complete removal of all fibrofatty tissue contents, including lymph nodes, along the defined boundaries of one or two contiguous neck levels.18
The super selective neck dissection has been pioneered by Robbins et al. who have utilized the super selective neck dissection in patients with advanced head and neck cancer that have been treated with primary chemoradiation and have residual pathologic lymphadenopathy limited to a single lymph node level.18,19 It is believed that by minimizing the surgical field, soft tissue fibrosis is reduced and its impact on swallowing, mastication, and range of motion of the neck are minimized.
THE EVOLUTION OF THE NECK DISSECTION
Surgeons of the early 19th century were aware that cancers of the head and neck metastasized to cervical lymph nodes; they often regarded this as a sign of incurability.20 It was believed that the cervical metastases needed to be removed with the primary tumor, in order for the patient to have any chance of survival. In 1888, Jawdynski published the first description of an en bloc neck dissection, which was later popularized by George W. Crile, who published a systematic approach to the neck dissection in 1906.21 In this procedure, all lymphatic tissue between the superficial and deep cervical fascial layers of the lateral neck were removed en bloc, including the sternocleidomastoid muscle, internal jugular vein, tail of the parotid gland, submandibular gland, and spinal accessory nerve.
In 1951, Hayes Martin and colleagues published their experience with 1,450 cases of neck dissections.22 This paper helped to define the technique, as well as gain acceptance within the surgical community. In 1952, Suarez published his modifications of the classical radical neck dissection, which he called the “functional neck dissection.” The goal of the functional neck dissection was to reduce morbidity while preserving the oncologic efficacy of the classic radical neck dissection. The modifications made by Suarez were preservation of the sternocleidomastoid muscle, internal jugular vein, omohyoid muscle, and, whenever possible, the spinal accessory nerve. Bocca and colleagues went on to popularize the selective removal of cervical lymphatics with preservation of vital structures (i.e., sternocleidomastoid
muscle, spinal accessory nerve, internal jugular vein).23 Preserving these structures allows for maximization of control of the regional disease with minimization of the morbidity associated with a radical neck dissection (chronic neck and shoulder pain, cosmetic deformity, facial edema, etc.).
muscle, spinal accessory nerve, internal jugular vein).23 Preserving these structures allows for maximization of control of the regional disease with minimization of the morbidity associated with a radical neck dissection (chronic neck and shoulder pain, cosmetic deformity, facial edema, etc.).
 FIGURE 14-3. Selective neck dissection. A: Selective removal of lymph node levels II, II, and IV. B: Illustration of selective remova of lymph node levels II, II, and IV. C: Neck after selective removal of lymph node levels II, II, and IV. (See color insert for Part B). |
At this point, surgeons had become adept at systematically removing cervical lymphatics, but it was not until 1972 when Robert Lindberg first recognized patterns of cervical metastases in correlation with the primary tumor location.24 This publication revealed that there were clear and predictable patterns of spread in the cervical lymphatics from each subsite within the upper aerodigestive tract. This observation that the patterns of cervical nodal disease are dictated by the location of the primary tumor has enabled surgeons to selectively remove nodal basins at risk for metastases based on the primary site of disease. This newfound knowledge opened the doors for preservation of low-risk nodal basins, thus decreasing patient morbidity. In the 1980s, Ballantyne from M. D. Anderson Cancer Center became one of the initial proponents of the SND. In 1988, Byers et al. described the patterns of nodal metastasis among 428 patients with HNSCC.25 In 1990, Shah reported the progression of metastatic disease in the neck in a consecutive series of 1,081 patients with primary tumors of the oral cavity, the oropharynx, the hypopharynx, and the larynx.26 The SND is now routinely used as a staging procedure to determine the presence or lack of occult metastases (which can help in the decision to apply adjuvant radiation therapy). More recently, the SND has been utilized in N+ necks as well as in postchemoradiation planned neck dissections. The use of the SND in clinically positive necks has been gaining widespread acceptance in recent years.
CURRENT PHILOSOPHY FOR LATERAL COMPARTMENT NECK DISSECTIONS
The contemporary approach to removing cervical lymphatics has evolved from the highly morbid radical neck dissection to the much less morbid yet effective SND. Although the pendulum has shifted to a much less aggressive extirpation of lymphatic and nonlymphatic tissues, the radical neck dissection still remains the gold standard by which all modifications to the neck dissection must be compared. The current philosophy of ablative surgeons can be distilled down to a few simple goals. The first is the removal of all clinically positive lymph nodes and all involved nonlymphatic structures. The second goal is to preserve all nonlymphatic structures, which are not diseased, to optimize functional outcomes. The third goal is removal of all lymph node levels, which are at high risk for harboring metastatic disease. With these simple but clear goals, ablative surgeons are now more thoughtful in their extirpation.
CENTRAL COMPARTMENT NECK DISSECTION
The central compartment (level VI) is important to address when managing patients with thyroid cancer and those tumors with subglottic extension. The boundaries for the central compartment of the neck (level VI) are the carotid arteries laterally, the hyoid bone superiorly, and suprasternal notch inferiorly. The inferior border of a central compartment neck dissection is located below the sternal notch at the level of the innominate artery and brachiocephalic vein (level VII). A comprehensive central compartment neck dissection incorporates level VI and level VII lymph nodes. These lymph node echelons are most commonly associated with metastases from thyroid cancer. In papillary thyroid
cancer, the incidence of central compartment metastases has been reported between 21 % and 60%.27,28 Lymph node metastases in patients with papillary thyroid cancer are associated with a higher recurrence rate.29 There is evidence that patients 45 years of age or older with regional nodal metastases have a higher mortality rate.30 There is also evidence that patients with clinically evident nodal disease who undergo lymphadenectomy may have a reduced rate of recurrence and mortality.29,31,32 Therefore, there is general agreement that clinically involved lymph nodes should be removed and comprehensive central compartment neck dissection should be performed in this situation.
cancer, the incidence of central compartment metastases has been reported between 21 % and 60%.27,28 Lymph node metastases in patients with papillary thyroid cancer are associated with a higher recurrence rate.29 There is evidence that patients 45 years of age or older with regional nodal metastases have a higher mortality rate.30 There is also evidence that patients with clinically evident nodal disease who undergo lymphadenectomy may have a reduced rate of recurrence and mortality.29,31,32 Therefore, there is general agreement that clinically involved lymph nodes should be removed and comprehensive central compartment neck dissection should be performed in this situation.
A prophylactic central compartment neck dissection is defined as a level VI lymph node dissection in patients with no evidence of lymph node metastases on preoperative physical examination or imaging. A prophylactic central compartment dissection remains controversial because occult metastatic disease within the central compartment of patients with papillary thyroid cancer have been reported to range between 31% and 62% and rarely become clinically relevant.28,33,34 In most series, the rate of recurrence in the central neck for patients with a papillary thyroid cancer >1 cm that were clinically node negative and were treated with total thyroidectomy without a central compartment neck dissection is 2 % to 3 %.33,34,35,36 Currently, there has been no proven benefit for a prophylactic central compartment neck dissection.
ROLE OF CAROTID ARTERY RESECTION IN NECK DISSECTION
Direct invasion or encasement of the carotid artery may occur in cases of advanced HNSCC. Resection of the carotid artery remains controversial because of the significant morbidity and mortality which may be associated with it. The prognosis for these patients is poor with the 1-year disease-free survival (DFS) ranging from 0% to 44%.37,38 The surgical alternatives consist of peeling the tumor off the carotid artery which may be palliative or curative, carotid resection without revascularization, and carotid resection with vascular bypass grafting. Since complete tumor removal is the most important prognostic factor in head and neck surgery, peeling the tumor of the carotid artery is not considered an oncologically sound resection.39
The indication for carotid resection is based on preoperative imaging such as magnetic resonance imaging (MRI) and computed tomography (CT). When studies suggest carotid involvement with no evidence of distant metastases (DM) consideration for carotid artery resection is given and a preoperative assessment is made to determine the patient’s risk for cerebrovascular accident when perfusion is interrupted during this procedure. A balloon occlusion study is often performed preoperatively in order to determine the patient’s ability to temporarily tolerate complete obstruction of blood flow through the carotid artery. If the patient is able to tolerate a balloon occlusion study, then they are considered a candidate for a carotid artery resection. If the patient is not able to tolerate the balloon occlusion study, then the consideration of a carotid artery resection is no longer a viable surgical alternative.
There are only a limited number of publications discussing the outcomes of a carotid artery resection during treatment for head and neck cancer. Brennan et al. reported their 10-year experience of carotid artery resection without revascularization in advanced squamous cell carcinoma of the neck.40 Seven patients underwent elective carotid artery resection, and all seven specimens showed invasion of the carotid artery fascia on pathological exam. Cerebrovascular accident occurred in two patients and the perioperative mortality was 29%.40 The 5 remaining patients all died of locoregional recurrence or metastatic disease within 1 year after surgery.40 The largest series reported in the literature is by Sessa et al. with 30 procedures reported.41 In this series, a 35% DFS rate at 2 years was reported.41 In 2001, Katsuno et al. performed a retrospective review via a computer search of all articles published in the English literature dealing with carotid artery reconstruction for head and neck cancer from 1987 to 1998.42 Studies of patients who underwent a carotid artery resection without a reconstruction were excluded and case reports were excluded. Only 11 articles met criteria for inclusion allowing for a total of 148 patients to be compiled in this series.42 Major neuromorbidity was 4.7% and mortality was 6.8% and the combined major neuromorbidity and mortality were 10.1%.42 The oncologic outcomes were surprisingly interesting. Four of 10 patients from one of the series were reported as disease free for >2 years.43 The Sessa series reported a 35% DFS rate at 2 years.41 Other articles also reported justifiable oncologic results.37,44,45,46
ELECTIVE MANAGEMENT OF THE CLINICALLY NO NECK
The basis and need for elective nodal treatment in head and neck cancer have been based largely on surgical series evaluating pathologic nodal involvement found on elective neck dissection in patients with clinically negative necks. In a consecutive series of 1,081 head and neck cancer patients undergoing radical neck dissection, the incidence of pathologic node involvement was 33 % among those undergoing elective neck surgery.47 The pathologic findings identified the nodal stations at risk by tumor site to establish the rationale for SND as the elective surgical procedure.
Several reports have summarized the risk for metastases and nodal stations at risk.24,48,49,50,51 Some general observations from such data can be made. Regarding larynx cancers, Candela reported the Memorial Sloan Kettering Cancer Center experience in determining the patterns of cervical nodal metastases in 247 larynx cancer patients undergoing 262 radical neck dissections.52 Seventy-eight underwent elective radical neck dissection whereas 118 underwent immediate radical dissection for clinically node-positive disease. The majority of patients (n = 189) were supraglottic larynx and 58 were glottic. Pathologic nodal involvement was found in 37% undergoing elective neck dissection. It is noted that cervical nodes spread in a similar fashion whether the patients are clinically node negative or positive with predominant involvement of level II and III jugular nodes. In clinically node-negative patients, the incidence of involvement of level I and V is <5% with <10% involvement of level IV. In node-positive patients, the incidence of level IV node increases from 15 % to 31% with greater involvement of levels II and III. In clinically node-positive patients, very rarely did patients present with isolated level I nodal metastases without involvement of the jugular nodes.
Similarly, Shah and Candela reported that among oropharynx or hypopharynx cancers treated with elective radical neck dissection occult metastases are found in 26% and that level I and V were involved in only 1.4%, always in association with nodal disease at level II to IV.47,52 No skip metastases were reported. Among oropharynx patients, levels II to IV were predominantly involved, and in the hypopharynx lesions, the primary levels involved were levels II and III. In patients clinically node positive undergoing therapeutic neck dissection, the incidence of level I and V involvement increased to about 10% to 15%; however, levels II to IV were predominantly involved (Table 14.2). Level V involvement only occurred in association with nodal involvement at levels II to IV whereas the incidence isolated level I involvement without levels II to IV involvement (“skip metastasis”) occurred in 0.4%. Thus, based on these studies, elective treatment of the neck in oropharynx or hypopharynx can be directed at levels II to IV.
TABLE 14.2 Percentage Incidence and Distribution of Pathologically Involved Nodes in a Clinical Node-Positive after Therapeutic Radical Neck Dissection | ||||||||||||||||||||||||||||||||||||
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Among oral cavity patients, the incidence of nodal disease was 34% on elective evaluation. The majority of metastatic nodes involved levels I to III with only 1.5% incidence of skip metastasis to level IV. Level V involvement is found in only 0.5% with occult disease simultaneously involving other levels. Among those undergoing therapeutic neck dissections, the incidence of level IV involvement increased to 20% while that at level V was 4% always restricted to lower gum or floor of mouth primary sites.
The need for elective treatment not only relates to the estimated probability of nodal involvement and usually is implemented when the risk is 20% or greater but also relates to the morbidity of such treatment as well as the adequacy of coverage. Table 14.3 demonstrates the incidence of nodal involvement of the most common head and neck cancer sites. It should be noted that such data are invaluable but do not address areas that are not addressed surgically, such as the retropharyngeal or pretracheal nodal basins.
Elective nodal treatment by radiation or surgery both offer distinct advantages as radiation may add more comprehensive nodal coverage including the contralateral neck and in regions difficult to surgically address such as the retropharyngeal nodes, inner mandibular nodal areas, and high subdigastric near the exit of the facial nerve at the mastoid process. However, surgery offers important pathologic data, which is useful prognostically, and tailors further therapy according to risk stratification. It should be noted that no randomized or comparative studies of observation versus neck dissection versus ENI have been reported, nor will likely be completed.
TABLE 14.3 Percentage Incidence and Distribution of Pathologically Involved Nodes in a Clinical Node-Negative Neck after Elective Radical Neck Dissection | ||||||||||||||||||||||||||||||||||||
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Elective Surgical Treatment
Byers reported a series of patients undergoing elective treatment with SND demonstrating excellent outcomes and thus establishing this procedure as a standard of care for elective treatment.53
Retrospective studies point to an improvement in disease-specific survival with the addition of elective neck dissection. Piedbois et al. reported a retrospective comparative study of 233 patients with early stage oral cavity carcinoma with the primary site treated with an interstitial iridium-192 (192Ir) implant who underwent either elective neck dissection or neck observation resulting in two cohorts of patients for analysis.54 This resulted from a change in departmental policies minimizing the impact of potential selection biases. Neck dissection revealed metastases in 25% who then received postoperative radiotherapy. Among those observed, 17% developed a neck relapse with salvage surgery successful in 62 %. Some patients were unable to undergo surgery because of unresectability of disease or poor patient performance status. The 10-year survival was 37% and 31%, respectively, with regression analysis demonstrating that neck observation was associated with an adverse risk for disease-related mortality (p < 0.04). Haddadin et al. reported on a retrospective analysis of 137 patients with T1 to T2 NO oral tongue carcinomas with at least 2 years of follow-up who either received an elective neck dissection, neck observation with salvage therapeutic neck dissection, or no neck surgery at all.55 The cohort receiving elective neck dissection had a superior 5-year cause-specific survival compared with the two other groups despite a negative bias due to a greater proportion of pathologic upstaging of the primary tumor and clinical T2 lesions.
Two randomized studies of patients with early stage oral cavity lesions failed to show a survival benefit in patients randomized to receive elective neck dissection compared to observation with salvage neck dissection if nodal disease developed. In one study, the primary site was managed with primary brachytherapy whereas in the other study the primary site was managed with radical resection.56,57 In the Vandenbrouck study, a 49% incidence of nodal involvement was reported in electively treated patients whereas nodal disease subsequently developed in 47% in the observation group. In the observation arm, the nodal disease appeared to become more aggressive with a higher incidence of extracapsular extension (25% vs. 13%) compared to the electively treated patients and 10% of patients could not undergo therapeutic dissection. However, no survival difference could be detected between the two groups. The authors recommended observation in patients with early stage lesions who could be followed regularly. In the second study of early stage oral tongue cancers, patients undergoing hemiglossectomy and elective neck dissection showed no difference in DFS or overall survival (OS) compared to patients undergoing hemiglossectomy alone.57 The number of patients enrolled on these trials was small and not powered to show equivalence of survival.
Elective Nodal Irradiation
The efficacy of elective nodal irradiation (ENI) is largely based on single institutional studies demonstrating reduced neck relapse.48,58 Fletcher established the dosimetric basis for elective nodal treatment and the need for comprehensive treatment. Delivering elective doses of 50 Gy to a clinically negative neck results in neck control in 95%.58 At a dose of 50 Gy in 5 weeks, the incidence of neck failure was 0% whereas doses of 30 to 40 Gy were associated with regional failure in 9% to 10.5%.58 Further support for ENI is reported by Mendenhall who reported a retrospective review of 125 patients with squamous cell carcinoma of the oral cavity, the oropharynx, the nasopharynx, the hypopharynx, and the supraglottic larynx with a clinically negative neck
and control at the primary site.48 The neck failure rate was 1.9% with ENI and 18% without ENI. Among a group of patients expected to have a <20 % risk for occult nodal metastases, the neck relapse rate was 13% in patients who did not receive ENI versus 6% in patients who received ENI. Similarly, among a group of patients with an expected risk for occult nodal metastases >20%, the neck relapse rate was 31% and 5 %, respectively. In a separate report, Mendenhall et al. demonstrated 100% disease control after ENI with 50 Gy in 25 fractions and 99% at a dose of 40.5 Gy in 15 fractions both given as daily fractions.59
and control at the primary site.48 The neck failure rate was 1.9% with ENI and 18% without ENI. Among a group of patients expected to have a <20 % risk for occult nodal metastases, the neck relapse rate was 13% in patients who did not receive ENI versus 6% in patients who received ENI. Similarly, among a group of patients with an expected risk for occult nodal metastases >20%, the neck relapse rate was 31% and 5 %, respectively. In a separate report, Mendenhall et al. demonstrated 100% disease control after ENI with 50 Gy in 25 fractions and 99% at a dose of 40.5 Gy in 15 fractions both given as daily fractions.59
Vergeer reported on a large Dutch experience evaluating the benefit of elective radiation therapy treatment of a NO neck. Nodal irradiation was delivered to 785 NO hemi-necks in 619 head and neck patients. Necks were clinical NO (cNO) in 558 and pathologically NO (pNO) in 227. About 47% of patients were oral cavity and well balanced between the two subgroups, with more larynx (22 vs. 13.6) and fewer oropharynx (25 vs. 31%) and hypopharynx (5.7% vs. 7.5%) in the pNO subgroup. Positive margins were noted in 17.0% versus 21.5% along with greater proportion of T3/4 (77% vs. 59%) in the pNO group. Patients were treated with a radiotherapy dose of 46 to 50 Gy. At 3 years, the regional failure for the entire cohort was 5% with a trend toward greater failure in the cNO of 6% versus 3% in the pNO (p = 0.08) and 10% in the ipsilateral neck compared to 4% in the contralateral neck (p = 0.006). Positive margins at the primary site increased the risk of regional failure in the ipsilateral cNO neck to 22% but not in the contralateral cNO neck, where it was 4%, and was significantly higher than those with close or negative margin with regional failure <1%. On multivariate analysis, the laterality (ipsilateral), positive margin status and clinically staged necks had worse regional failure.
Based on older radiation-delivery techniques, traditional ENI involves treatment of bilateral necks with generous coverage of the jugular nodes and major salivary glands with various degrees of coverage of the retropharyngeal, level I and level V nodes depending on the primary site. With the advent of IMRT, such comprehensive coverage can be duplicated or tailored much more extensively. The ability to treat lymphatic areas more discriminately has challenged radiation oncologists to integrate clinical judgment, experience, and understanding of the surgical data to adequately plan regional coverage that it is tailored appropriately for each case. There have been several excellent reviews regarding the delineation of lymph node target volumes indicated for head and neck radiation therapy.14,15,51,60 These summaries have served as a basis for axial-based image treatment planning guidelines that is used for conformal irradiation and IMRT.51 In general, surgical levels defined by Robbins et al. (America Academy of Otolaryngology-Head and Neck Society) are used as the basis for regional target delineation.61 However, there are a wide variety of radiographic landmarks that have been proposed.51,60,62,63 A transatlantic consensus has been reported for the electively treated neck as well as the clinically involved and postoperative neck. Gregoire et al. provide a summary recommendation of the nodal groups that should receive ENI in the neck without altered lymphatic flow (see Fig. 14-1; Table 14.4A).51 These recommendations do not address specific presentations that may modulate the risk for occult metastases. It has been accepted in practice that a risk for <20% warrants at least a deliberation for ENI considering the competing issues of potential benefit and toxicities and risk for secondary HNSCC requiring further therapy.
Elective Surgical versus Radiation Therapy Treatment
The efficacy of ENI versus elective neck dissection showed no obvious differences as reported by Barkley in a major retrospective experience of neck management in 596 patients with oropharynx, larynx, or hypopharynx carcinoma treated at MD Anderson Cancer Center.64 Two hundred thirteen were oropharynx, 202 larynx, and 181 hypopharynx. Of these, 226 were NO whereas 370 were node positive. Patients underwent radiation therapy (n = 292), surgical management (n = 199), or combined modality therapy (n = 105) of the neck. All patients had a minimum follow-up of 2 years and a median follow-up of 4 years. Among the electively treated patients, regional control was >90% regardless of the treatment approach as long as comprehensive neck treatment was implemented. However, partial treatment of the neck resulted in 15%, 35%, and 20% regional failure after radiation, surgery, or combined therapy, respectively.
RECOMMENDATIONS REGARDING ELECTIVE TREATMENT OF COMMON HEAD AND NECK CANCER SITES
Given the significant risk for occult nodal involvement, the standard of care has evolved to electively treat such patients despite the lack of confirmatory randomized trials. Nodal coverage of levels I to III for oral cavity tumors and levels II to IV for oropharyngeal, hypopharyngeal, and laryngeal tumors are mandatory as elective treatment24,47,52,65,66 (Table 14.4B). Elective nodal irradiation including the retropharyngeal lymph nodes is added for primary tumors involving the nasopharynx, tonsil, pharyngeal wall, and the soft palate. Bilateral ENI should be considered for tumors arising from or extending to midline structures such as the soft palate, the base of tongue, and the pharyngeal wall. Tumor sites such as the hypopharynx and the supraglottic larynx require bilateral ENI regardless of the specific tumor stage given high risk for contralateral nodal involvement. In contrast, tumor involvement of ipsilateral structures such as the parotid, the buccal mucosa, and selected tonsil cancers warrants consideration of ipsilateral ENI.67,68 Elective nodal irradiation including level IV lymph nodes should be considered in those with tumors involving the tip of the oral tongue due direct drainage to this area that bypass the orderly contiguous progression in the anterior jugular nodes.47,69 Involvement of the ipsilateral level V lymph nodes in node-negative oral cavity tumors is rare, occurring in <1%, and does not warrant ENI. However, with increasing involvement of levels I to III or the involvement of level IV, the risk for level V involvement increases warranting ENI. In contrast, involvement of only the true vocal cords does not warrant ENI due to the paucity of lymphatic drainage.
IPSILATERAL NECK RADIATION IN LATERALIZED OROPHARYNX CANCER
O’Sullivan et al. reported the results of a large retrospective review which identified oropharyngeal tumors that could be spared by contralateral ENI.67 Two hundred twenty-eight patients with tonsillar carcinomas were treated with ipsilateral radiotherapy at Princess Margaret Hospital. Eligible patients typically had T1 or T2 tumors (191 T1-2, 30 T3, 7 T4) with NO (133 NO, 35 N1, 27 N2-3) disease. Radiation was typically delivered with wedged pair Cobalt beams and ipsilateral low anterior neck field delivering 50 Gy in 4 weeks to the primary volume. At a median follow-up of 5.7 years, the 3-year local control rate was 77%, regional control 80%, and cause-specific survival 76%. Contralateral neck failure occurred in 3% (8/228). All patients with T1 lesions or NO neck status had 100% contralateral neck control.
Patients with a 10% or greater risk of contralateral neck failure included those with T3 lesions, lesions involving the medial one-third of the hemi-soft palate, tumors invading the middle third of the ipsilateral base of tongue, and patients with N1 disease. In the presence of ipsilateral node metastases, the risk for contralateral neck failure was 9.5%, 14%, and 21% (all crude rates) for involvement of the soft palate, the base of tongue, and both structures, respectively. However, the authors appropriately note the limitations of these observations as they included patients with uncontrolled primaries and involved a total of only eight patients with contralateral neck failures. Despite this, the report provides confidence in the selection of patients with T1 NO tonsil carcinomas (as well as selected patients with more advanced disease) for only ipsilateral ENI. Similar observations were also reported by Jackson et al. further supporting these observations.70
Patients with a 10% or greater risk of contralateral neck failure included those with T3 lesions, lesions involving the medial one-third of the hemi-soft palate, tumors invading the middle third of the ipsilateral base of tongue, and patients with N1 disease. In the presence of ipsilateral node metastases, the risk for contralateral neck failure was 9.5%, 14%, and 21% (all crude rates) for involvement of the soft palate, the base of tongue, and both structures, respectively. However, the authors appropriately note the limitations of these observations as they included patients with uncontrolled primaries and involved a total of only eight patients with contralateral neck failures. Despite this, the report provides confidence in the selection of patients with T1 NO tonsil carcinomas (as well as selected patients with more advanced disease) for only ipsilateral ENI. Similar observations were also reported by Jackson et al. further supporting these observations.70
TABLE 14.4A Consensus Guidelines for Target Delineation of Nodal Levels in the Elective Treated Neck | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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TABLE 14.4B Guidelines for Neck Treatment in Patients with Head and Neck Squamous Cell Carcinomas: Echelons of Lymph Nodes to Be Treated | ||||||||||||||||||
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ELECTIVE NODAL IRRADIATION FOR MAXILLARY SINUS CANCER
Traditionally, ENI has not been routinely considered for maxillary sinus carcinomas due to the low incidence of nodal disease at presentation. However, several investigators have suggested a benefit of ENI for locally advanced NO squamous cell carcinoma of the maxilla.71,72,73,74 Le et al. reported a retrospective review of 97 patients with maxillary sinus carcinoma treated with primary radiotherapy or postoperative radiation at UCSF and Stanford.73 Squamous cell histology was the most common with 60% (58/97), followed by adenoid cystic carcinoma in 20% (19/97) and undifferentiated carcinoma in 16% (16/97). Eighty-nine patients had T3-4 lesions with T2 in eight patients whereas 11% (11/97) presented clinically with nodal disease. Of these 11, one was treated with combined neck dissection and post-op radiation whereas 10 were treated with primary radiation to a median dose of 63 Gy. Of the 86 clinically node-negative patients, 25 patients received ENI (median dose 50 Gy) to the bilateral upper neck nodes. The 5-year actuarial risk for nodal relapse was 0% in patients receiving ENI and 20% for those not receiving ENI. The most common site of nodal relapse was in the ipsilateral level I and II nodal groups with a small number of regional failures in the ipsilateral parotid and upper level V nodes and no instance of failure at level III/IV or supraclavicular nodes. There was no association between primary recurrence and risk for neck failure. However, on multivariate analysis, there was significant association between neck failure and incidence of distant metastasis with higher risk after neck recurrence compared to those regional controlled (82% vs. 19%, p = 0.02). The influence of selection bias with regard to these results is unclear. However, it is likely to have biased against the efficacy of ENI because those patients receiving ENI were likely to have had more advanced disease. Only 1 of 10 patients with neck relapse was salvaged. Of greater significance was the observation that the 5-year actuarial risk for DM was 29% for patients with neck control and 81% for patients with neck failure. Multivariate analysis demonstrated that T stage, N stage, and regional nodal control (HR = 4.5, p = 0.006) independently influenced this risk. The 5-year survival was 37% and 0% for patients with neck control and neck relapse, respectively (p = 0.3). Late complications arising from neck irradiation occurred in 1 of 36 patients who developed ipsilateral brachial plexopathy and severe neck fibrosis. In light of the relapse pattern, the investigators concluded that ipsilateral ENI to only the upper neck (levels I and II) be considered for patients with T3 and T4 NO squamous cell carcinoma of the maxillary sinus. Similar conclusions were reached by other investigators.23,25
MANAGEMENT OF THE CLINICALLY NODE-POSITIVE NECK (N+)
Management of the clinical positive neck is controversial with a wide variety of approaches that mirrors the complexity and competing regimens established to treat the primary site. These include neck dissection followed by postoperative radiation; definitive concurrent chemoradiation, radiation, or concurrent chemoradiation followed by planned or salvage neck dissection; and induction chemotherapy followed by neck dissection before or after radiation. Refinements in the radicality of neck dissection (radical vs. modified vs. selective vs. super selective neck dissection) and the identification of patients at high risk for recurrence, development of consensus guidelines in nodal target delineation for intensity-modulated treated patients, radiation dosing, and fractionation as well as integration of chemotherapy have been issues that have been explored to maximize regional control and preserve quality of life and function. The manner in which the primary site is managed guides treatment of the neck. Thus, relevant considerations in the decision include the resectability of the primary and neck disease, the functional morbidity incurred by surgery or radiation at the primary site, and the appropriateness of the primary lesion for potential organpreserving therapy with either radiation alone or in combination with chemotherapy. When unresectable disease exists, the use of chemoradiation strategies has largely been favored. Although the optimal chemoradiotherapy regimen for both organ preservation and unresectable disease remains to be defined, the bulk of the data favor concurrent chemoradiation whereas more recent data point to possible additional benefit of induction chemotherapy or to integration of biologic therapies. Following these therapeutic considerations for the primary lesion, the principal issue with regard to neck management has been the necessity of adjuvant postoperative radiotherapy/chemoradiation or postradiotherapy/chemoradiation neck dissection.
Surgery and Postoperative Radiation
Surgery and postoperative radiation remains a common strategy for regional management especially for the majority of resectable oral cavity tumors and many locally advanced but resectable HNSCC such as bulky or cartilage invasive hypopharynx or larynx cancers. More recently with early and intermediate stage oropharynx cancer, transoral robotic surgery is used increasingly followed by neck dissection. Historically, radical neck dissection alone had been the mainstay of regional treatment with radical extirpation of the neck nodes and adjacent nonlymphatic structures with significant functional and cosmetic morbidity as described by Crile in 190375,76 and reintroduced in the 1950s by Martin.77 However, it was well recognized that recurrence in the neck after radical neck dissection carried an ominous prognosis.78 Large series evaluating risk factors for recurrence after neck dissection have been reported. Of these, the most consistently reported risk factor for recurrence is extracapsular extension (ECE). Snow et al. reported one of the first important large institutional experience using pathologic factors to predict risk of recurrence. In a series of 405 patients, he reported that the presence of extracapsular extension of nodal disease was the single most important predictive factor on multivariate analysis for neck recurrence and poor survival.79 Furthermore, he noted that although there was a relationship between node diameter and fixation with ECE as >75% of nodes >3 cm and 70% with fixation had ECE, these parameters themselves were not sufficient as 20% of nodes <1 cm had ECE and 30% with nodal fixation had no ECE.79 Carter et al. reported an extensive analysis of 250 radical neck specimens and their clinical significance.80 Both the presence and the extent of
ECE was found to be the most important factor predicting for neck relapse with a distinction between macroscopic and microscopic ECE emphasized with the former having a worse prognosis.80 Others have verified such findings.80,81,82 and reported other poor prognostic pathologic factors including lymphvascular invasion,1 perineural invasion,83 number of nodes involved,79,84 as well as nodal level involved.64,84,85,86,87,88 Risk factors for recurrence based on findings from primary site include most importantly the status of the resection margins89,90,91,92 as well as the primary tumor site origin.93,94
ECE was found to be the most important factor predicting for neck relapse with a distinction between macroscopic and microscopic ECE emphasized with the former having a worse prognosis.80 Others have verified such findings.80,81,82 and reported other poor prognostic pathologic factors including lymphvascular invasion,1 perineural invasion,83 number of nodes involved,79,84 as well as nodal level involved.64,84,85,86,87,88 Risk factors for recurrence based on findings from primary site include most importantly the status of the resection margins89,90,91,92 as well as the primary tumor site origin.93,94
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