Level II is the most frequent nodal metastatic site for tumors in all mucosal sites. This level can be subdivided into the internal jugular (IIA) and spinal accessory (IIB) subdivisions. In the surgical classification system, the spinal accessory nerve serves as the division between these levels, with level IIA lying anteriorly and IIB posteriorly (Fig. 4.1) (Robbins 1998). Due to the difficulty in discerning the division between these levels on axial imaging, however, the adapted radiographic classification instead defined these nodes relative to the posterior border of the internal jugular vein, which can be readily visualized on a simulation CT scan (Som et al. 1999). By this widely adopted system, level IIA includes those nodes located anteriorly, laterally, or medially to the internal jugular vein as well as those located posteriorly without a fat plane separating them from the jugular vein; level IIB nodes lie posterior to jugular vein with an intervening fat plane, thus approximating a location posterior to the spinal accessory nerve. The important specific nodal stations within level II include the subdigastric (jugulodigastric) node, which is located within level IIA immediately inferior to the crossing of the posterior belly of the digastric muscle past the internal jugular vein, and the more cranially located “junctional” node, aptly named for its location within level IIB at the superior junction of the jugular nodal chain (level II) and spinal accessory nodal chain (level V) (Rouvière 1938). The subdigastric node is the most commonly involved node for both ipsilateral and contralateral nodal metastases from primary tumors of the oropharynx, supraglottic larynx, and hypopharynx, while the more cephalad junctional node is the first echelon node for the nasopharynx and parotid gland, which is commonly involved in cases of nasopharyngeal cancer and is at risk in the case of coexistent metastases to levels II, III, or VA (Million 1994). Therefore, the ipsilateral subdigastric node and level IIA below the transverse process of C1 should be included in the CTV for all N0 patients with cancers arising in most head and neck mucosal sites receiving definitive radiotherapy (with or without chemotherapy), with the notable exception of early stage, node-negative squamous cell carcinomas of the glottic larynx (i.e., T1–2N0). Ipsilateral level IIA superior to the C1 transverse process and level IIB, meanwhile, are included in the CTV in all patients with nasopharynx primary cancers, irrespective of nodal involvement, and in those patients with other primary sites with nodal metastases in the ipsilateral level II. Contralateral level IIA below the C1 transverse process should be included in the elective CTV in all cases of mucosal squamous cell carcinomas originating in sites with bilateral lymphatic drainage (i.e., base of the tongue, soft palate, nasopharynx, supraglottic larynx, hypopharynx) or in any case of N2a or greater nodal involvement with any primary mucosal tumor site (Fig. 4.2). In contrast, contralateral level IIA superior to the C1 transverse process and level IIB can be safely excluded from the CTV in non-nasopharyngeal cancer patients without involvement of the adjacent level II, thus allowing for sparing of the majority of the contralateral parotid gland and a significant preservation of salivary function (Eisbruch et al. 2001; Beetz et al. 2012) (Fig. 4.3).

Level III is included in the CTV when there is a risk of subclinical disease or if level II on the same side of the neck is grossly involved. Designation of level III as a high-risk or low-risk CTV is dependent on whether lymph nodes in this level are grossly involved (as described below).

Level IB is treated in all cases with a significant clinical involvement of ipsilateral level II (e.g., oropharyngeal cancer with nodal involvement of level II of >N1) and in primary tumors that drain directly to level IB (i.e., oral tongue, floor of the mouth, anterior tonsillar pillar, retromolar trigone, buccal mucosa), irrespective of clinical nodal involvement (Figs. 4.3 and 4.4). Level IB should additionally be included for oropharyngeal cancers of the tonsil or base of the tongue with a significant anterior extension to the anterior tonsillar pillar or oral tongue, respectively. For well-lateralized primary tumors (i.e., buccal mucosa, retromolar trigone), only the ipsilateral side can be treated, whereas more midline tumors (i.e., floor of the mouth) or those with bilateral lymphatic drainage (i.e., oral tongue for both level IB) require bilateral coverage. Exclusion of level IB from the CTV in cases lacking the above risk factors facilitates partial sparing of the submandibular gland, preserving non-stimulated, mucin-rich submandibular salivary flow and thereby reducing xerostomia (Eisbruch et al. 2001; Little et al. 2012; Murdoch-Kinch et al. 2008).

Level IV is treated in all cases of either ipsilateral level II or III involvement and in primary sites that drain directly to level IV, regardless of additional nodal involvement (i.e., tip of the oral tongue, supraglottic larynx, hypopharynx). As is the case for level IB above, midline tumors and those with bilateral lymphatic drainage (i.e., oral tongue, posterior pharyngeal wall) require bilateral level IV coverage.

Inclusion of level V in the CTV is advised in all cases of a significant (>N1) involvement of levels II–IV on the same side of the neck (Fig. 4.4) as well as in primary tumors of the nasopharynx, which drains directly to level V.

The risk of RP involvement relates strongly to the primary tumor site and to the extent of jugular chain nodal involvement (McLaughlin et al. 1995). As such, the lateral retropharyngeal (RP) nodes are treated bilaterally in all cases of nasopharyngeal cancer, tumors that involve the posterior pharyngeal wall, and oropharyngeal and hypopharyngeal cancers with clinical involvement of levels II–IV (Figs. 4.2 and 4.3). At present, our policy is to limit the coverage of the lateral RP nodes to the ipsilateral side only in cases of early lateralized oropharyngeal tumors with N0 or small-volume N1 disease. Recent preliminary evidence, however, suggests that the contralateral RP nodes may be safely excluded from the CTV in oropharyngeal cancers without contralateral jugular chain involvement, which if supported by more mature and conclusive evidence will provide a strong rationale for limiting treatment to only the ipsilateral RP nodes in this circumstance as well (Spencer et al. 2012). The medial RP nodes are included only in tumors that involve the posterior pharyngeal wall.

Level VI nodes are treated in all cases with clinical involvement of level IV nodes, in cases of hypopharynx cancer where the apex of the pyriform sinus is involved, laryngeal cancers extending to the subglottic larynx, and in all cases of thyroid cancer for which RT is indicated.

Level VII nodes are treated in all cases of gross level VI nodal involvement.

Two of the four marginal recurrences in our institutional series occurred near the base of the skull at the site of the lateral RP nodes (Eisbruch et al. 2004a). Both occurred in patients with oropharyngeal cancer (one tonsillar and one base of the tongue) who presented with N0 necks, in whom the RP nodes had been included within the CTV with a cranial most extent to the top of C1. However, the epicenter of the recurrence volume of the two marginal RP recurrences lays cranial to the top of C1, one ipsilateral to the primary tumor and the other contralateral and extensive. Given this unexpected pattern of failure, and the scant details in the literature regarding the pattern of metastases to the RP nodes in non-nasopharyngeal cancers, our institutional policy was modified to include the lateral RP nodes bilaterally with a cranial extent to the skull base in all cases of locally advanced oropharyngeal cancer, irrespective of extent of neck node involvement (Figs. 4.2 and 4.3) (King et al. 2000; McLaughlin et al. 1995). This practice is consistent with the recent cooperative group consensus guidelines for CTV delineation and is supported by surgical series of RP node involvement, other institutional case reports of marginal RP failures near the skull base, and RT series demonstrating an absence of RP nodal failures following IMRT using elective CTVs extending to the skull base (Chen et al. 2011; Chung et al. 2011; Coskun et al. 2011; Eisbruch et al. 2004a; Gregoire and Levendag; Hasegawa and Matsuura 1994). One recent preliminary report, however, suggested that in selected cases of ipsilateral-only nodal involvement, treatment of the contralateral RP nodes can be avoided without an increased risk of marginal or out-of-field failure (Spencer et al. 2012). If supported by more mature and conclusive evidence, exclusion of the contralateral RP nodes in cases of locally advanced oropharynx cancer without contralateral nodal involvement will be incorporated into our future treatment policies and recommendations.

The third marginal recurrence in our institutional series was in a patient with oral tongue cancer who had bulky low neck nodal involvement (Eisbruch et al. 2004a). Despite achieving a complete response after RT, the patient subsequently recurred in level VI, highlighting the potential for involvement retrograde lymphatic flow and unpredictable patterns of nodal metastasis in patients with bulky nodes (Fisch 1968). Rouvière described lymphatic drainage channels to the pretracheal/prelaryngeal nodes (level VI) from the jugular nodes (levels III–IV) which provide a conduit for distal lymphatic drainage in cases of extensive nodal involvement (Rouvière 1938). These connections, in tandem with flow obstruction at level IV, explain this marginal recurrence at level VI. As such, level VI nodes should be treated in all cases with clinical involvement of level IV nodes.

A recent review of our institutional experience between 2003 and 2011 revealed six cases of patients with primary cancers of the oropharynx and nasopharynx who presented with pathologically confirmed parotidean metastases (unpublished data). All of these patients had locally advanced stage N2c or N3 disease, with diffuse multilevel and bulky involvement of ipsilateral level II. Based on these findings, we have changed out institutional practice to include elective coverage of the ipsilateral parotidean nodes in all cases of extensive involvement of the level II lymph nodes.

The fourth marginal recurrence in our institutional patterns of failure series was observed in a patient who had a history of prior neck dissection more than 1 year prior to recurrence of an oral cavity cancer (Eisbruch et al. 2004a). He was treated with local excision of the primary site recurrence followed by postoperative IMRT and experienced subsequent recurrence in the subcutaneous tissues of contralateral level I – an unpredictable location given the site of his primary tumor. As in patients with extensive nodal involvement, those patients with a history of neck surgery more than 1 year prior to tumor recurrence may experience unpredictable lymphatic drainage, in this case due to collateral lymphatics which fully develop 1 or more years after surgery (Fisch 1968; Rouvière 1938). These collaterals commonly develop in the submental and submandibular areas, including within the subdermal tissues, thus leading to unpredictable patterns of recurrence. As such, the use of IMRT in patients who have had major neck surgery more than 1 year prior to tumor diagnosis should be approached with caution due to the uncertainty regarding their targets.

Chao et al. reported the outcomes of 126 HNC patients treated at Washington University in St. Louis using IMRT for the upper neck only to spare the parotid glands with a matched anterior low neck field (Chao et al. 2003). Twenty-eight percent of recurrences in this series (five patients) occurred in the supraclavicular area, underscoring the importance of avoiding underdosing of low neck nodal levels in patients in whom these regions are at high risk, such as those with clinical nodal involvement in levels III or IV or with bulky nodal involvement of level II. In cases where the lower neck is at low risk, a split-neck technique with a larynx block does confer certain potential benefits over a comprehensive IMRT plan, such as reduced dose to the glottic larynx, reduced labor-intensiveness of target delineation, short treatment time, less monitor unit delivery, and less daily setup deviation in the low neck (Eisbruch and Gregoire 2009). These benefits, however, may come at the cost of reduced dose certainty to targets in the low neck targets and particularly at the IMRT field and low neck field junction, potentially resulting in over- or underdosing in these regions. Additionally, we have found that in cases where the low neck is at low risk, a comprehensive IMRT plan which prioritizes avoidance of the glottic larynx, inferior pharyngeal constrictor, and upper esophagus can consistently reduce the mean dose to these structures to 20–30 Gy over 35 fractions, which is comparable to the dose received when using a split-neck technique. In cases where the low neck is a high risk, a comprehensive IMRT plan may result in higher doses to these avoidance structures, but with the benefit of more accurate coverage of at-risk targets in the low neck, reduced risk of underdosing at the split-neck field junction, and the ability to partially spare OARs such as the larynx, cricopharyngeus, esophagus, and brachial plexus while delivering high doses to gross disease in the low neck (i.e., level IV). Therefore, at our institution, we employ the use of a single comprehensive IMRT plan rather than a matched anterior low neck field for treatment of the low neck and strongly recommend this approach in cases where the low neck targets are grossly involved or at high risk of subclinical metastases.

Dysfunction of the swallowing structures is a common cause of severe acute and late toxicity after head and neck radiotherapy and is perhaps the strongest determinant of long-term quality of life in HNC survivors (Hunter et al. 2013; Langendijk et al. 2008; Machtay et al. 2008; Terrell et al. 2004). Radiotherapy dose to the swallowing structures, specifically the pharyngeal constrictor (PC) muscles, has been implicated as a primary treatment-related predictor of swallowing dysfunction after chemoradiotherapy (Eisbruch et al. 2011; Feng et al. 2007; Popovtzer et al. 2009). Therefore, avoidance of dose to the PCs should be attempted where possible, although this goal must be balanced against the need for adequate coverage of the RP nodes, due to their frequent involvement in cancers of the nasopharynx, oropharynx, and hypopharynx (Chung et al. 2011; Coskun et al. 2011; Eisbruch et al. 2004a; Hasegawa and Matsuura 1994; King et al. 2000). The RP nodes consist of lateral and medial groups, with the medial RPs located near midline close to the center of the PCs. As metastatic involvement of the medial RP nodes is rare in HNC (with the exception of tumors that invade the posterior pharyngeal wall), it has been postulated that these nodes may be excluded from the CTV such that high dose to adjacent PCs can be avoided. This hypothesis was tested at the University of Michigan in a prospective study of 73 patients with locally advanced (stages III–IV) oropharynx cancer designed to assess the clinical and functional results of chemoradiotherapy using IMRT to spare the important swallowing structures (Feng et al. 2010). IMRT planning was performed with the intent of sparing non-involved parts of the swallowing structures, namely, the pharyngeal constrictors, glottic larynx, supraglottic larynx, and esophagus as well as the oral cavity and major salivary glands (Fig. 4.5). At a median follow-up of 36 months, 3-year disease-free and locoregional recurrence-free survival was 88 and 96 %, respectively. At 1 year after completion of therapy, observer-rated dysphagia was absent or minimal (scores 0–1) in all except four patients: one who was feeding-tube dependent and three who required soft diet. These outcomes clearly indicate that IMRT aimed at reducing dose to the swallowing structures in oropharynx cancer can safely minimize dysphagia while maintaining high rates of locoregional tumor control.

In summary, these analyses suggest the additional recommendations shown in Table 4.3 for target volume delineation in IMRT and augment those already understood.

At our institution, our current treatment policy is to deliver 70 Gy to the GTV in 35 fractions (2.0 Gy per fraction). The high-risk CTV, which is around the GTV and the first echelon nodes, receives 59–63 Gy (at 1.7–1.8 Gy per fraction, biologically equivalent to 54–60 Gy at 2.0 Gy per fraction). The lower-risk areas receive 56–59 Gy (1.6–1.7 Gy per fraction, biologically equivalent to approximately 49–54 Gy at 2.0 Gy per fraction). These specifications are very similar to the policies at UCSF, Washington University in St. Louis, University of Iowa, and MSKCC (Chao et al. 2003; Lee et al. 2003; Setton et al. 2012; Yao et al. 2005). Concurrent chemotherapy for patients with locally advanced (stages III–IV) disease is strongly recommended for fit patients based upon level I evidence (Denis et al. 2004; Forastiere et al. 2003; Pignon et al. 2009). For patients receiving concurrent RT, we favor the use of the standard fractionation scheme above rather than accelerated radiotherapy, which has failed to show a benefit in terms of locoregional control or survival in phase III studies (Ang et al. 2010; Bourhis et al. 2012). In patients with locally advanced disease who do not receive concurrent chemotherapy, due typically to comorbid illness or other contraindication, accelerated or hyperfractionated radiotherapy is recommended, on the basis of multiple randomized trials demonstrating improvement in locoregional control and a meta-analysis demonstrating an improvement in overall survival compared with conventional radiotherapy (Bourhis et al. 2006; Fu et al. 2000; Horiot et al. 1992; Overgaard et al. 2003). Our institutional preference in this situation has been to use the DAHANCA regimen of 6 fractions per week (with the sixth fraction given either on Saturday or as a second fraction 1 day per week given at least 6 h apart) to deliver our standard fractionation scheme above while accelerating the course of therapy by 1 week (Overgaard et al. 2003).