Radiation Therapy for Neck Metastases

This article addresses the role of radiation therapy in the management of patients with squamous cell carcinoma metastases of the head and neck. ^[1] Postradiotherapy neck dissection is discussed as well.

The risk of lymph node metastases is influenced by the primary site of the lesion, the degree of histologic differentiation, the degree of the lesion's depth of invasion, and the density of capillary lymphatics. Table 1 shows the estimated risk of subclinical disease in patients with clinically negative neck findings as a function of primary site and T stage. Locally recurrent lesions have a higher risk of lymphatic involvement than do untreated lesions.

Table 1. Definition of Risk Groups (Open Table in a new window)

The most commonly involved lymph nodes in the head and neck are the subdigastric (level II) lymph nodes, followed by the midjugular (level III) lymph nodes. Tumors arising from some sites (eg, oral tongue) may occasionally skip level II lymph nodes and metastasize to level III or IV lymph nodes. Lesions that are well lateralized usually spread first to the ipsilateral neck nodes, while nasopharyngeal lesions and lesions on or near the midline and lateralized base of the tongue may spread to both sides of the neck. (See the image below.)

If the metastatic nodes significantly obstruct the lymphatic trunks, patients who have clinically positive lymph nodes on the ipsilateral side of the neck may be at risk for contralateral lymph node spread. Additionally, patients who have undergone previous surgery on one side of the neck shunt lymph across the submentum to the opposite side of the neck. When contralateral lymph node metastases occur, the level II lymph nodes are involved most frequently, followed by the level III and level IV nodes.

As a tumor grows within a lymph node, the node becomes indurated, rounded, and enlarged. The tumor eventually extends through the capsule of the lymph node and invades surrounding structures; extension to the neurovascular bundle is relatively common and results in fixation. The prevalence of tumor involvement and the probability of capsular penetration increase with lymph node size.

Richard et al reported the prevalence of tumor involvement and extranodal extension (ENE) versus lymph node size in a series of patients with a total of 519 nodes as follows: 1 cm, 33% and 14%; 2 cm, 62% and 26%; 3 cm, 81% and 49%; 4 cm, 88% and 71%, and 5 cm, 100% and 76%, respectively. ^[4]

The risk of lateral retropharyngeal lymph node involvement is related to the primary site of the lesion and the neck stage; the medial retropharyngeal nodes are almost never the sites of metastatic disease.

Workup for neck metastases

Imaging and tissue diagnosis are imperative following initial clinical assessment. In most cases, an image-guided fine-needle aspiration (FNA) of involved nodes can yield diagnostic cytologic information.

Based on the anatomic site, immunohistochemical staining of tissue specimens for p16 (a surrogate of human papillomavirus [HPV] infection) or Epstein-Barr virus (EBV) may be warranted.

Cross-sectional imaging may include a computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) of the neck as the preferred options.

Although positron emission tomography (PET)–CT scanning has unique advantages in generating information related to staging, identification of occult primary sites and regional or distant metastases, treatment planning, and assessment of response to therapy, it should not be used as a modality to diagnose head and neck malignancies in the absence of supporting information from clinical assessment and tissue evaluation.

Management of neck metastases

Elective treatment

Radiation therapy may be used in the management of cervical lymph node metastases as elective treatment when no palpable lymph nodes are present, as the only treatment for clinically positive lymph nodes, or as preoperative or postoperative treatment in combination with neck dissection for clinically positive lymph nodes. ^[5] Intensity-modulated radiation therapy (IMRT) is considered the standard of care when radiation therapy is employed for head and neck malignancies.

The factors that influence the decision to irradiate the neck electively are the site and size of the primary lesion, histologic grade, difficulty in neck examination, relative morbidity for adding lymph node coverage, likelihood of the patient's return for follow-up examinations, and the suitability of the patient for a neck dissection if the tumor appears in the neck at a later date.

Treatment of clinically positive cervical lymph nodes

The dose required to control a clinically positive lymph node that is included within the radiation portals depends on the size of the lymph node and, to some degree, its histology.

Currently, planned neck dissection after radiation therapy for nodal disease is not considered the standard of care. The decision to add a neck dissection after radiation therapy is individualized and most commonly employed upon observing persistent PET avidity after radiotherapy, or in cases where posttreatment surveillance of persistent neck abnormalities cannot be reliably ensured. ^[6]

The role of brachytherapy in neck management has been limited mostly to previously irradiated patients with incompletely resectable positive neck nodes. Hence, brachytherapy is not routinely performed for neck metastases related to head and neck squamous cell carcinomas.

The following staging system is from the 2010 American Joint Committee on Cancer (AJCC) seventh edition cancer staging for neck lymph nodes (N):

• NX - Regional lymph nodes cannot be assessed

• N0 - No regional lymph node metastasis

• N1 - Metastasis in a single ipsilateral lymph node; 3cm or smaller in greatest dimension

• N2 - Metastasis in a single ipsilateral lymph node, larger than 3cm but not larger than 6cm in greatest dimension; in multiple ipsilateral lymph nodes, none larger than 6cm in greatest dimension; or in bilateral or contralateral lymph nodes, none larger than 6cm in greatest dimension

• N2a - Metastasis in a single ipsilateral lymph node, larger than 3cm but not larger than 6cm in greatest dimension

• N2b - Metastasis in multiple ipsilateral lymph nodes, none larger than 6cm in greatest dimension

• N2c - Metastasis in bilateral or contralateral lymph nodes, none larger than 6cm in greatest dimension

• N3 - Metastasis in a lymph node, larger than 6cm in greatest dimension

Isolated positive contralateral nodes are very rare and should alert the clinician to search for another primary lesion.

Evaluation of a suspected squamous cell carcinoma in the head and neck should begin with a complete history and physical examination. The history should assist in making the case for malignant versus benign causes (eg, recent infections, tobacco history, painful neck nodes, etc). Physical examination should include a complete otorhinolaryngologic assessment, including the area of suspected primary tumor. A clinic-based flexible fiberoptic laryngoscopy and bedside ultrasonography can serve as important extensions of the physical examination. Laboratory tests should include blood counts, chemistries, and liver function tests.

Imaging and tissue diagnosis are imperative following initial clinical assessment. In most cases, an image-guided fine-needle aspiration (FNA) of involved nodes can yield diagnostic cytologic information. FNA is safe, often achievable in the clinic, and less invasive than open incisional or excisional biopsy of neck nodes. Open biopsy of a clinically positive neck node before definitive treatment carries the potential to spill tumor cells along tissue planes that may not be removed with a radical neck dissection. McGuirt and McCabe reported that incisional or excisional biopsy of positive neck nodes before definitive surgery increased the risk of neck failure and worsened the prognosis for patients with squamous cell carcinoma of the head and neck. ^[7] Hence, FNA should be considered the preferred primary method with which to biopsy a neck node.

Based on the anatomic site, immunohistochemical staining of tissue specimens for p16 (a surrogate of human papillomavirus [HPV] infection) or Epstein-Barr virus (EBV) may be warranted.

Cross-sectional imaging may include a computed tomography (CT) scan with contrast or magnetic resonance imaging (MRI) of the neck as the preferred options.

Although positron emission tomography (PET)–CT scanning has unique advantages in generating information related to staging, identification of occult primary sites and regional or distant metastases, treatment planning, and assessment of response to therapy, it should not be used as a modality to diagnose head and neck malignancies in the absence of supporting information from clinical assessment and tissue evaluation.

PET scanning offers functional assessment of any potential disease sites, including sites for primary disease, neck metastases, occult primary disease, potential distant metastases, and second primary malignancies (estimated in 5-10% of head and neck cancer patients). Estimates of PET-CT–scan sensitivity and specificity are 86-100% and 69-87%, respectively, which are higher than those of CT imaging (67-82% and 25-56%, respectively). ^[8] PET scanning also offers unique benefits in radiotherapy treatment planning, as fusion of preradiotherapy PET images onto planning CT scans can greatly assist in target-volume definition.

Another major advantage of PET scans are their high (>95%) negative predictive value; this can be useful in assessment of treatment response, which in turn can influence management of continued surveillance or consideration of salvage neck dissection. A randomized study with a preponderance of oropharyngeal squamous cell carcinoma patients demonstrated similar survival outcomes and decreased costs with PET-scan surveillance versus planned neck dissection in N2-N3 patients after treatment with definitive chemoradiation. ^[9] It should also be mentioned that limitations of PET imaging include the presence of normal physiologic uptake (in areas such as the base of tongue), as well as diminished specificity in inflammatory circumstances, such as after surgery and/or chemoradiotherapy.

Other elements of workup in selected patients may include CT scanning of the chest if metastatic disease is suspected.

Preradiotherapeutic dental assessment and speech and swallow function evaluation at baseline and after treatment are critical to reduce risks related to treatment-related complications associated with osteoradionecrosis and speech/swallowing dysfunction.

Patients receiving radiation therapy for head and neck malignancies may be at risk for developing depression. Psychological/psychiatric assessment and support is recommended. There is increasing evidence to support the prophylactic use of anti-depressants to mitigate the effects of treatment-related depression. ^[10]

Radiation therapy may be used in the treatment of cervical lymph node metastases as elective treatment when no palpable lymph nodes are present, as the only treatment for clinically positive lymph nodes, or as preoperative or postoperative treatment in combination with neck dissection for clinically positive lymph nodes. ^[5]  Although substantial data in support of and assessing the effects of radiation for neck metastases originate from studies utilizing two- and three-dimensional techniques, intensity-modulated radiation therapy (IMRT) is considered the standard of care when radiation therapy is employed for head and neck malignancies.

The regional lymph nodes are considered when planning treatment of the primary lesion. With clinically negative neck nodes, treatment planning depends on the estimated risk of subclinical disease in the nodes. With clinically positive lymph nodes, the plan is influenced by the location, number, size, and mobility of the lymph nodes and the mode of treatment for the primary lesion.

Owing to the relatively high proliferative rate of head and neck neoplasms, there have been many randomized trials of altered fractionated radiotherapy. Compared with standard fractionation (eg, for definitive radiotherapy, 70 Gy in 35 daily fractions [7 weeks] of 2 Gy), hyperfractionation is defined in the strictest sense as decreasing the dose per fraction while administering radiation over roughly the same period of time as conventional radiotherapy, often resulting in irradiation being performed more than once a day. Because of radiobiologic considerations, administration of 70 Gy in 35 daily fractions of 2 Gy is not the same as administering 70 Gy in twice-daily fractions of 1 Gy each. Hence, “biologic equivalence” of various hyperfractionated regimens results in differing absolute doses.

The term “accelerated fractionation” refers to decreasing the overall treatment time as compared with the baseline (eg, 7 weeks in the above example), which intuitively could be delivered in either hyperfractionated or hypofractionated (increasing the dose per fraction) regimens.

Because many radiation regimens are quite toxic to patients, trials have used “split-course” regimens in order to give patients a brief treatment break, allowing tissues to heal prior to recommencing radiotherapy.

A “boost” of radiation (extra radiation) is often given to areas with high disease burden; this can be administered sequentially (eg, primary radiation followed by a boost to a smaller volume) or concurrently/simultaneously (extra radiation delivered at the same time as primary radiation).

The Radiation Therapy Oncology Group (RTOG) 9003 trial randomized 1073 patients with locally advanced head and neck cancer into four arms: standard fractionation (70 Gy in 2-Gy, daily fractions), hyperfractionation (81.6 Gy in 1.2-Gy, twice-daily fractions), split-course accelerated fractionation (38.4 Gy in 1.6-Gy, twice-daily fractions, followed by two-week break, followed by 28.8 Gy in 1.6-Gy, twice-daily fractions; cumulative dose 67.2 Gy), and accelerated fractionation with concomitant boost (54 Gy in 1.8-Gy, daily fractions with concurrent boost of 18 Gy in 1.5-Gy, twice-daily fractions; cumulative dose of 72 Gy). ^[11]

Although no differences in overall survival were observed in this study, 2-year locoregional control was increased with the hyperfractionated and concomitant-boost regimens (54% in each, versus 47% in the other two arms), along with a trend toward improved disease-free survival. Of note, acute toxicity (but not late toxicity) increased in all three experimental regimens as compared with standard fractionation. Utilization of the results of this trial were mixed; although some centers adopted altered fractionation, others did not, owing to logistical difficulty with twice-daily treatments. Some have argued that small absolute improvements in locoregional control (with borderline disease-free survival and no overall survival improvements) may be, in a sense, offset by increased acute toxicities (which can lead, for instance, to withdrawal from radiotherapy). ^[11]

Since this study, other trials have explored various fractionation schemes with chemotherapy administration and confirmed that, in eligible patients, chemoradiotherapy is most efficacious, likely owing to chemotherapy acting as a true radiation sensitizer to enhance locoregional tumor control. ^[12] Accelerating radiotherapy alone, although providing locoregional control benefits, cannot compensate for a lack of radiosensitizing chemotherapy and may remain inferior to chemoradiation given in a nonaccelerated (standard fractionation) manner, where clinical indications exist. ^[13]

Irradiation of cervical lymph nodes when the primary tumor receives radiation therapy

The factors that influence the decision to irradiate the neck electively are the site and size of the primary lesion, histologic grade, difficulty in neck examination, relative morbidity for adding lymph node coverage, likelihood of the patient's return for follow-up examinations, and the suitability of the patient for a neck dissection if the tumor appears in the neck at a later date. Patients in whom the primary lesion is to be managed with radiation therapy who have clinically negative nodes and in whom the risk of subclinical disease is 20% or greater receive elective neck irradiation to a minimum dose equivalent of 45-50Gy over 4.5-5 weeks or its radiobiologic equivalent.

Patients with lesions arising in the lip, nasal vestibule, nasal cavity, or paranasal sinuses have a low risk of subclinical neck disease, and the neck is not treated electively unless the lesion is recurrent, advanced, or poorly differentiated. Similarly, the risk of occult neck disease is essentially 0% for T1 and 1.7% for T2 glottic carcinomas, and elective neck nodal irradiation is not indicated. It has also been relatively well accepted that well-lateralized primary sites such as the tonsil (although the retromolar trigone and buccal mucosa may fit this description as well) have overall rates of contralateral neck failure of less than 5% and hence may not warrant contralateral radiotherapy. ^[14]

In industrialized countries, the recent advent of IMRT for various head and neck cancers has made three-dimensional conformal radiotherapy (3DCRT) less frequent in many—but not all—cases, and two-dimensional radiotherapy (2DRT) all but obsolete. Marginal misses are important to note for modalities with higher conformality; marginal misses in this setting may have a relatively low likelihood of successful retreatment.

In 2DRT and 3DCRT, the lateral treatment portals used to encompass cancers in the oropharynx, supraglottic larynx, and hypopharynx incidentally include the upper internal jugular and often the midjugular chain lymph nodes. Radiation portals used for primary lesions of the oral cavity, nasopharynx, glottis, nasal cavity, and paranasal sinuses must be enlarged if one intends to irradiate the lymph nodes. The treatment portals for irradiation of the cervical lymph nodes must be designed in such a way as to minimize additional mucosal radiation therapy.

A common error in irradiating oropharyngeal and nasopharyngeal cancers is enlarging the lateral (primary) portals inferiorly to unnecessarily include the entire larynx in these portals. Because the midneck is smaller in circumference than the upper neck, the total dose and dose per fraction are higher in the larynx than along the central axis of the beam, leading to "double trouble." Using a customized tissue compensator may help to account for the change in contour, if necessary. Treating an unnecessarily large field increases the acute and late effects of radiation therapy and, by increasing the risk of an unplanned split, reduces the probability of disease control.

Elective neck irradiation for early oral cavity lesions includes the submaxillary and subdigastric lymph nodes. In addition, the midjugular and low jugular lymph nodes are treated by using a narrow anterior field. The lower neck nodes are also routinely irradiated in patients with primary lesions located in the oropharynx, nasopharynx, supraglottic larynx, and hypopharynx. The low neck is treated with a single anterior field. A tapered midline larynx/trachea shield is added to protect the spinal cord, larynx, and pharynx.

For primary lesions below the thyroid notch, a small midline tracheal block is placed in the low-neck field, primarily to avoid field overlap at the spinal cord. A 5-mm–wide midline block made of Lipowitz metal may be used to shield the trachea, esophagus, and spinal cord below the level of the cricoid. When the block is placed 15-18 cm above the patient (source-to-skin distance = 80 cm), an 18-mm midline gap between the 90% isodose lines for cobalt-60 (⁶⁰Co) beams results. Great care must be used to ensure that this block does not shield the midjugular and low jugular lymph nodes. Improper design of the midline larynx/trachea block is a common error.

When employing IMRT, target delineation is performed to cover the same aforementioned structures, but precise delineation of several organs at risk (eg, the parotid glands, spinal cord, larynx) can result in corresponding dose calculations and reoptimization of treatment plans in order to keep doses below tolerance levels. In many centers, an anteroposterior low-neck field is used in order to shield the larynx with a midline block; other centers perform whole-neck IMRT alone.

The schema for treatment of the clinically negative neck is summarized in Table 2, below.

Table 2. Elective Treatment of Clinically Negative Neck Nodes (Open Table in a new window)

Nodal treatment when the primary tumor is treated with radiation therapy

The dose required to control a clinically positive lymph node that is included within the radiation portals depends on the size of the lymph node and, to some degree, its histology. The dose for lymph nodes involved by lymphoepithelioma may be 5 Gy less than that for squamous cell carcinoma if the nodes show rapid, early regression. For squamous cell carcinoma, the recommended minimum doses (at 2 Gy/fraction, 5 fractions/wk) for lymph nodes of various sizes are 1 cm, 60 Gy; 1.5-2 cm, 66 Gy; 2.5-3 cm, 70 Gy; and 3.5-6 cm, 74 Gy.

If the treatment is delivered at 1.8 Gy per fraction, 5 fractions per week, the total dose is increased approximately 5 Gy. The dose is not reduced when early complete regression occurs during fractionated therapy. The control rates after treatment with 1.8 Gy per fraction are probably not as good as rates obtained with 2 Gy per fraction.

Currently, planned neck dissection after radiation therapy for nodal disease is not considered the standard of care. The decision to add a neck dissection after radiation therapy is individualized and most commonly employed upon observing persistent PET avidity after radiotherapy, or in cases where posttreatment surveillance of persistent neck abnormalities cannot be reliably ensured. If clinically positive lymph nodes have received full-dose irradiation and disappear completely during radiation therapy, then the likelihood of control by radiation therapy alone is improved. ^[6]

However, when a neck dissection is considered necessary, performing the procedure immediately after radiation therapy may be safer from a complications standpoint.

Results from the aforementioned RTOG 9003 trial showed improved locoregional control for two aggressive altered-fractionation schedules compared with conventional radiation therapy.

Data suggest that a CT scan obtained approximately 1 month after completing radiotherapy may be used to help define a subset of patients for whom the likelihood of residual cancer in the neck nodes is less than 5%. ^[15] If posttreatment PET-CT scanning is planned, it is advisable to defer this until approximately 12 weeks after completion of radiation-based treatment, to avoid false positives related to inflammation. A negative PET-CT scan has a high negative predictive value, and most patients can be observed without a planned neck dissection in this setting. ^[16]

The schema for treatment of a clinically positive neck is shown in Table 3, below.

Table 3. Schema for Treatment of Clinically Positive Neck Nodes (Open Table in a new window)

Some patients who undergo surgery as the initial treatment and who have zero or one positive node and no ENE may require postoperative irradiation because of indications relating to the primary tumor site (eg, close or positive margins, perineural invasion).

Because IMRT automatically accounts for spinal cord tolerance limits, modification of fields is largely unnecessary in these cases.

When using non-IMRT modalities, if the lymph node is behind the plane of the spinal cord, electrons may be used to boost the dose after the primary fields have been reduced off the spinal cord. Another technique commonly used for boosting the dose to the neck mass, after spinal cord tolerance has been reached and the treatment to the primary lesion has been completed, is opposed anterior and posterior fields with wedges. The final dose to the neck node (not to the entire neck) may be 70-80Gy without exceeding the spinal cord tolerance.

The anterior and posterior wedge-pair technique is preferable to an appositional electron boost field because high-energy electron beams increase the dose to the skin and underlying structures, such as the mucosa and spinal cord. The technique is well suited for patients with a small or unknown primary tumor in whom the mucosal dose may be in the range of 60-64Gy, after which the dose to the node may be boosted as necessary. ^[18]

When the cervical lymph nodes are located superficially, sometimes within 1cm of the skin or fixed to it, treatment with high-energy photon beams (≥6MV) may underdose these nodes, particularly if an ipsilateral field arrangement is used. Treatment should be initiated with ⁶⁰ Co or 4MV radiographs for the initial 45-50Gy (if such beam energies are available). To follow, a higher-energy photon beam can be used to continue radiation therapy of the primary tumor if the neck nodes are clinically negative or if a neck dissection is planned to follow radiation therapy. Parallel-opposed 6MV radiograph beams may adequately treat the upper neck nodes included in the primary treatment fields; however, the supraclavicular nodes in the en face low-neck field may be underdosed with a 6MV beam in very thin patients unless bolus material or a beam spoiler is used to alter the depth of the dose.

Although electrons alone may be used to treat cervical nodes, combining them with photons is preferable because of the high surface dose and resultant fibrosis that may occur if electrons are the sole modality. The addition of the radiograph beam decreases the surface dose and also produces a dose distribution that is less affected by bone than is that from the electron beam alone. Another attractive alternative is a wedge-pair technique using 3-dimensional treatment planning and 6MV radiographs alone.

Brachytherapy

The role of brachytherapy in neck management has been limited mostly to previously irradiated patients with incompletely resectable positive neck nodes. Hence, brachytherapy is not routinely performed for neck metastases related to head and neck squamous cell carcinomas.

In carefully selected scenarios, insertion of an interstitial implant may be performed in conjunction with surgery to remove as much gross disease as possible or may be performed alone, without surgery.

For the most part, 2 techniques have been used: (1) placement of hollow catheters afterloaded with iridium-192 (¹⁹² Ir) wire or seeds or (2) placement of permanent iodine-125 (¹²⁵ I) seeds. If technically feasible to do so, the former technique probably results in a better dose distribution, although implanting ¹²⁵ I seeds via absorbable sutures is possible. ^[19]

Control rates for neck disease in this unfavorable subset of patients range from approximately 30-70%, depending on the extent of the tumor and whether brachytherapy has been combined with subtotal resection. Most reports have relatively limited follow-up, but long-term survival rates appear to be no better than 10-20%.

The risk of late complications ranges from approximately 10-40% and is increased in patients who have received prior high-dose radiotherapy and in those who have tumors extending into the skin. Resection of previously irradiated skin in the area of the interstitial implant followed by reconstruction with previously unirradiated flaps may reduce the risk of late complications, although a surgical approach may be challenging due to adverse anatomy, poor tissue characteristics, a paucity of donor vessels, and the overall operative suitability of the host patient.

Adjuvant chemotherapy

Induction chemotherapy may be used to select treatment based on the response to chemotherapy, but it likely does not improve survival rates. For patients with advanced disease, concomitant radiation therapy and chemotherapy appear to offer improved local-regional control and survival rates compared with radiation therapy alone. The acute toxicity associated with concomitant chemoradiation may be significantly more pronounced than that observed with irradiation alone, particularly if chemotherapy is combined with altered fractionation.

The drugs used are usually cisplatin, carboplatin, and/or fluorouracil. Given the promising results of some of the altered-fractionation trials, the challenge is how to optimally combine such dose-fractionation schedules with concomitant chemotherapy without having excessive toxicity. ^[20]

A literature review by Rivelli et al found that in cisplatin-based chemoradiation therapy for head and neck squamous cell carcinomas, prevalences of the most commonly reported late toxicities were as follows ^[21] :

• Xerostomia (40-80%, depending on technique)
• Hypothyroidism (42%)
• Ototoxicity (27%)
• Dysphagia (25%)
• Osteoradionecrosis (4%)

Elective neck dissection and elective neck irradiation are equally effective in controlling subclinical disease. The decision whether to use surgery or radiation therapy for the purpose of electively treating the neck nodes depends on the method used to treat the primary lesion. Patients with a relatively early primary lesion and clinically negative nodes should be treated with one modality, administered to the primary tumor and the neck (if the risk of subclinical disease in the neck is ≥20%).

The results of elective neck irradiation for patients with squamous cell carcinoma of the head and neck in whom the primary lesion was controlled are shown in Table 4. Six neck failures (21%) occurred in 28 patients who did not receive elective neck irradiation, and 8 neck failures (5%) occurred in 162 patients who received elective neck irradiation. Of the 8 failures in patients receiving elective neck irradiation, 2 occurred within the irradiation fields, 1 at the field margin, and 5 outside the irradiation fields.

Table 4. Control of Disease in the Clinically Negative Neck with Elective Neck Irradiation (Number Controlled/Number Treated) (Open Table in a new window)

No correlation was found between the control rate in the first-echelon lymph nodes and the radiation dose for doses ranging from 40-55 Gy or greater. Only 1 failure occurred in the first-echelon lymph nodes, and this was after 48Gy in 25 fractions using continuous-course irradiation. The low neck, defined as that part of the neck below the treatment portals used to treat the primary lesion, received either 50 Gy in 25 fractions or 40.5 Gy in 15 fractions, specified at the maximum dose. Both of these dose-fractionation protocols were equally effective for sterilizing subclinical disease in the low neck. Elective neck irradiation is equally efficacious for squamous cell carcinoma arising from various head and neck primary sites.

If the primary lesion recurs, the risk of lymphatic spread to the neck is renewed, even after elective neck irradiation has been administered, because of the possibility of reseeding of the neck lymphatics. In patients in whom primary failure occurs in addition to failure in the clinically negative nodes, the chances of surgical salvage are poor. In patients in whom the primary lesion is controlled but failure develops in the initially negative neck, the chances of salvage with neck dissection are approximately 50-60%.

A caveat is that patients who experience an isolated failure in the initially N0 neck have not usually received elective neck treatment and are probably at lower risk of harboring cancer in the neck than are patients who have received elective therapy. The salvage rates are likely not as high for patients with cancers arising in sites associated with very high rates of cervical metastases (ie, base of tongue, nasopharynx), who would likely harbor a higher burden of subclinical disease.

Although elective neck irradiation significantly reduces the risk of recurrence in the neck, no definite evidence indicates that it improves survival rates. A large, randomized trial would need to be performed to detect a survival difference, if one exists. Another problem is that the first-echelon lymph nodes are often included in the irradiation portals used to treat the primary lesion; consequently, avoiding at least partial elective neck irradiation is often impossible. Therefore, such a trial would have to be restricted to primary sites where the portals would have to be enlarged to electively irradiate the neck or to patients treated with elective neck dissection rather than elective neck irradiation.

Vandenbrouck et al and Fakih et al, in randomized trials comparing elective neck dissection with no elective neck treatment for patients with oral cavity carcinoma and oral tongue cancer, respectively, found no survival advantage for patients undergoing elective neck dissection. However, because of the small number of patients in both trials, the possibility exists that even if a survival difference occurred, it could have been missed. ^{[22, 23]}

Dearnaley et al, conducting a multivariate analysis using a series of 148 patients treated for cancer of the tongue or floor of the mouth, found that elective neck irradiation significantly improved survival and reduced the risk of death from cancer. The patients were treated with an interstitial implant, alone or in combination with external-beam irradiation. ^[24] Of 131 patients with negative neck nodes at diagnosis, 59 patients (45%) received elective neck irradiation to a dose of 40Gy.

Piedbois et al, reporting a series of 233 patients with T1-T2 N0 carcinoma of the oral cavity treated with interstitial iridium brachytherapy, found a benefit to additional treatment with elective neck dissection. ^[25] No elective neck treatment was given to 123 patients, and an elective neck dissection was performed in 110 patients. Patients who received an elective neck dissection tended to have more advanced primary lesions. Although the ultimate rates of neck control were similar, a multivariate analysis revealed that elective neck dissection was significantly associated with improved survival rates.

A randomized trial from India compared outcomes in 500 patients with T1-2 N0 oral cavity (mostly oral tongue) carcinoma based on receipt of elective (at time of primary surgery) versus therapeutic (at time of relapse) neck dissection. ^[26] Radiotherapy was administered adjuvantly on a case-by-case basis. There were increases in disease-free and overall survival with elective dissection. On subgroup analysis, the greatest benefits were seen in the setting of T2 disease, lymphovascular or perineural invasion, and tumor depth of greater than 3 mm. Whereas nearly three quarters of recurrences in the therapeutic neck dissection group were nodal (neck) recurrences, the same was true for only 31% in the elective neck dissection group.

The incidence of treatment failure in the neck based on N stage and treatment category has been reported by Barkley et al from the MD Anderson Cancer Center (see Table 5) and the University of Florida (see Table 6). ^[27]

Table 5. Failure of Initial Ipsilateral Neck Treatment: 596 Patients with Carcinoma of the Tonsillar Fossa, Base of Tongue, Supraglottic Larynx, or Hypopharynx (Open Table in a new window)

 

Table 6. Five-Year Rate of Neck Control by 1983 American Joint Committee on Cancer Stage and Treatment (459 Patients; 593 Heminecks)* (Open Table in a new window)

The incidence of recurrence in the contralateral side of the neck versus neck stage is depicted in Table 7. The risk of recurrence increases with the extent of disease in the ipsilateral side of the neck.

Table 7. Cervical Metastasis Appearing in the Contralateral N0 Neck: 596 Patients with Carcinoma of the Tonsillar Fossa, Base of Tongue, Supraglottic Larynx, or Hypopharynx (Open Table in a new window)

When the initial treatment is surgery, a neck dissection is sufficient treatment for patients with a single positive lymph node, unless extracapsular spread of disease is present. The presence of multiple positive nodes in the surgical specimen is an indication for postoperative radiation therapy of the neck, especially when positive nodes are found at more than 1 level.

The postoperative dose prescribed usually ranges from 60Gy in 30 fractions to 65Gy in 35 fractions over 6-7 weeks for patients with negative margins; higher doses may be prescribed when residual disease is present in the neck. If radiation therapy is to be added after surgery, it is usually initiated within 4-6 weeks after the operation.

The likelihood of neck node control with irradiation alone is related to the size of the node and to time, dose, and fractionation parameters. Dubray et al reported a series of 1251 patients treated at the Curie Institute (Paris, France) with external-beam radiotherapy alone for node-positive oropharyngeal and pharyngolaryngeal squamous cell carcinomas. ^[29] The nodal control rates as a function of node diameter were 0.5cm, 77%; 2cm, 67%; 4cm, 60%; 6cm, 52%; 8cm, 37%; and 10cm, 7%.

In a small percentage of patients with enlarged cervical lymph nodes, the primary lesion cannot be found, even after extensive evaluation. Patients with enlarged lymph nodes in the upper neck have a good prognosis when treated aggressively compared with patients with enlarged lymph nodes in the low internal jugular chain or supraclavicular fossa.

The latter group is more likely to have a primary lesion located below the clavicles, which is associated with a bleak prognosis. The majority of patients have either squamous cell carcinoma or poorly differentiated carcinoma. Patients with adenocarcinoma almost always have a primary lesion below the clavicles, although if the nodes are located in the upper neck, one must exclude a salivary gland, thyroid, or parathyroid primary tumor. This section addresses patients who have squamous cell or poorly differentiated carcinoma in the upper or middle neck.

A study by Harper et al of 69 patients with metastatic squamous cell carcinoma in their neck nodes and an unknown primary lesion suggested that either mucosal irradiation significantly reduces the risk of primary site failure or that patients with unknown primary sites have a much lower risk of developing a second primary head and neck cancer. ^[30]

The main complication of radiation therapy for patients treated for an unknown head and neck primary tumor is xerostomia. The complications of treatment of the neck depend on whether a neck dissection is performed.

Irradiation area

Some patients may be cured with treatment directed only at the involved area of the neck; however, the nasopharynx, oropharynx, hypopharynx, larynx, and both sides of the neck are usually irradiated. Irradiating the oral cavity is not usually necessary unless the patient has submandibular adenopathy, in which case a neck dissection can be performed, followed by observation or irradiation of the oral cavity and oropharynx (but not the nasopharynx, larynx, or hypopharynx).

Surrogate information from p16 or Epstein Barr virus (EBV) status of tissue obtained from cervical nodal FNA may help to provide clues to the likely location of the primary site and may thus help in tailoring radiation fields.

In the non-IMRT setting, patients are treated with parallel-opposed fields at 1.8 Gy per fraction to a midline dose of 55.8 Gy, with reduction off the spinal cord at 45 Gy tumor dose. The lower neck is treated through a separate en face anterior field. Dosimetry is obtained at the level of the central axis (which usually corresponds to the oropharynx), the nasopharynx, and the larynx.

The mucosal sites included in the lateral portals to the oropharynx and nasopharynx have become limited because the most common primary sites are the tonsillar fossa and tongue base. The mucosal dose has also been increased to 64.8Gy. Although the nasopharynx is a relatively low-risk site, treating the skull base is necessary to include the retropharyngeal nodes. In other words, some of the nasopharynx is already within the irradiation fields. The hypopharynx is included if the bulk of the patient's neck disease is located in level III or IV lymph nodes.

Human papilloma virus (HPV) may be associated with a significant number of oropharyngeal squamous cell carcinomas in the Western world. Biologically, the HPV-related E6 and E7 proteins inhibit the tumor suppressor proteins p53, p21, and Rb, which promote cell cycle progression, survival, and evasion from apoptosis. As part of this mechanism, the protein p16 is upregulated, which serves as a surrogate marker for HPV infection. Retrospective data was able to be used to prognostically stratify oropharyngeal cancers solely on the basis of HPV status, ^[31]  with initial prospective data in 2008 supporting these results and showing that HPV-positive tumors not only responded better to chemoradiation (84% HPV+ vs 57% HPV-) but were also associated with a large increase in 2-year overall survival (95% HPV+ vs 62% HPV-). ^[32]

A large piece of corroboratory evidence was published in 2010. ^[33] Three hundred and twenty three patients in the RTOG 0129 trial were stratified based on HPV status. Compared with HPV-negative patients, those who were HPV positive enjoyed improved 3-year overall survival (82% vs 57%), progression-free survival (74% vs 43%), and locoregional control (relapse rates of 14% vs 35%). Notably, there were no significant differences in distant metastatic rate at 3 years between HPV-positive and HPV-negative patients (9% vs. 15%, respectively). However, the 3-year rate of second primary malignancies was 6% in the HPV-positive cohort and 15% in the HPV-negative cohort; this was most likely due to HPV-negative tumors being associated with tobacco use and its resulting so-called “field cancerization." Based on these data, the authors separated the cohort into risk groups: patients with HPV-negative tumors were all high-risk, except those with a smoking history of 10 or less pack years and T2-3 disease (intermediate risk); patients with HPV-positive tumors were low risk, except for those with a smoking history of over 10 pack years and N2b-N3 disease.

Clinical implications

Although p16 status (as a surrogate for HPV status) lends valuable prognostic information in oropharyngeal squamous cell carcinoma, in the absence of robust clinical data, this information should not be used to modify management strategies outside of the setting of a clinical trial. Several ongoing trials are testing the role of deescalated therapy for these patients, such as omission of chemotherapy, de-intensified radiotherapy, and utilization of transoral surgical resection–based approaches.

A study by Bauwens et al found that in patients with oropharyngeal squamous cell carcinoma, the prevalence of clinically and pathologically positive nodes was greater in the p16-positive individuals than in those who were p16 negative. In the p16-positive and -negative groups, the rates of clinically positive nodes were 88.3% and 54%, respectively, while the rates of pathologically positive nodes were 91.2% and 61.9%, respectively. Nonetheless, the investigators stated that a lack of meaningful difference in lymph node drainage distribution between the p16-positive individuals and the p16-negative ones indicates that the extent of neck treatment should not differ based on positive or negative status. ^[34]

O’Sullivan and colleagues investigated the interactions of stage and HPV association on oncologic outcomes. ^[35] They performed recursive partitioning analysis of 382 HPV-positive oropharyngeal malignancies while considering differences in and patterns of recurrences in low-risk (T1-3, N0-2c) and high-risk (T4 or N3) patients. Although the risk groups were slightly different than in previous studies, the authors noted a decrease in locoregional and distant control rates for HPV-associated oropharyngeal malignancy when comparing high-risk to low-risk groups. The 3-year rates for locoregional control (82%) and distant control (78%) for the high-risk group were inferior to the outcomes for the low-risk group (95% and 93%, respectively). This suggested that advanced stage at presentation may significantly and adversely impact outcomes despite the prognostic advantages related to HPV association.

Additionally, O'Sullivan et al's data suggested that among low-risk HPV-positive patients presenting with N2b disease and a more than 10–pack-year history of smoking and among those with advanced nodal stage (N2c), there was a higher risk for distant failures when they were treated with radiation therapy alone. These findings indicate that some subsets of patients with HPV-associated oropharyngeal malignancies may be at risk for poor outcomes. Deescalation strategies that aim to limit treatment-related morbidity by eliminating chemotherapy or altering radiation protocols must take into consideration the impact of stage and patient factors such as tobacco use on oncologic outcomes. ^[35]

Though no phase III trials have been published to date, a phase II trial examined 44 patients with p16-positive oropharyngeal cancer (T0-3N0-2c) treated with definitive chemoradiation to 60 Gy, with weekly cisplatin (30 mg/m²) administered. ^[36] In this cohort, there was a 98% pathologic complete response rate for the primary tumor and 84% for cervical neck lymphatics. The six patients with residual neck disease had exceedingly low volumes (4/6 patients with 1 mm or less). Toxicities were quite low, without any patient requiring a feeding tube. No more than 2% experienced grade 3+ hematologic toxicity and grade 3+ rates of xerostomia, dysphagia, and mucositis were 2%, 39%, and 34% respectively.

Future important ramifications also include changes in staging based on HPV status. Research data was used to group HPV-positive malignancies using two methods (by T/N staging and by adding smoking history/age), both of which correlated well with survival outcomes. ^{[37, 38]} In accordance with aforementioned data, stage III is denoted by T4 and/or N3 disease, stage II by T-3N2cM0, and stage I by T1-3N0-N2bM0. Group I includes stage I-II patients with a smoking  history of 20 pack years or less, group II encompasses stage I-II patients with a smoking history of over 20 pack years, group III is composed of stage III patients aged 70 years or less, and group IVA consists of stage III patients over age 70 years.

Though the importance of HPV infection in head and neck carcinomas is just beginning to be understood, its far-reaching and practice-changing implications will be more definitively addressed in the future as clinical trials mature. The Eastern Cooperative Oncology Group (ECOG) 3311 trial is currently underway and aims to examine the possibility of de-intensification of adjuvant radiation therapy in intermediate-risk, p16-positive oropharyngeal squamous cell carcinoma patients who receive initial transoral surgery and neck dissection. ^[39]

Clearly, the role and rationale related to radiation therapy in HPV-associated oropharyngeal squamous cell carcinoma is still evolving, and information from ongoing trials may identify opportunities for de-intensification of therapy, with consequent reduction in treatment-related side effects and complications.

The complications of neck irradiation include subcutaneous fibrosis and lymphedema of the larynx and submentum. In a non-IMRT setting, lymphedema may be minimized by sparing an anterior strip of skin when designing the parallel-opposed lateral portals used to encompass the primary lesion. Clothespins may be used to retract additional skin and subcutaneous tissues out of the radiation field and thereby further decrease the risk of laryngeal edema by providing an escape route for the fluids, a situation analogous to “sparing a strip” in patients with soft tissue sarcoma.

The probability of complications is directly related to radiation dose and volume, with little, if any, morbidity observed with the doses used for elective radiation therapy of the neck. Data suggest that late radiation fibrosis may be ameliorated with the combination of vitamin E (1000 IU/day) and pentoxifylline (400mg BID).

Findings from one study suggested that patients suffered cognitive dysfunction following curative-intent radiotherapy or chemoradiotherapy for squamous cell carcinoma of the head and neck. The sample size in this study was small (n = 10), and further study is needed. ^[40]

Hypothyroidism commonly occurs following radiation therapy for head and neck cancer. A study by Mulholland et al found that the highest rate of hypothyroidism in patients treated with radiation therapy for early stage laryngeal squamous cell carcinoma was at 12 months, with the investigators suggesting therefore that routine screening for hypothyroidism in such patients, using thyroid stimulating hormone levels, begin at 1 year. ^[41]

Complications of radiation therapy with neck dissection

Complications of neck dissection include hematoma; seroma; lymphedema; wound infection; wound dehiscence; chyle fistula; damage to cranial nerves VII, X, XI, and XII; carotid exposure; and carotid rupture. The frequency of complications is higher when neck dissection follows a course of radiation therapy, particularly if treatment is combined with resection of the primary lesion.

The frequency of postoperative complications in a series of patients treated with radiation therapy to the primary lesion and neck followed by unilateral neck dissection is shown in Table 8. The frequency of complications was higher for maximum subcutaneous doses greater than 60Gy.

Table 8. Postoperative Complications of Unilateral Neck Dissection After Irradiation to the Primary Lesion and Neck (143 Patients) (Open Table in a new window)

In a study by Taylor et al of a series of 205 patients who underwent a planned unilateral neck dissection after radiation therapy, the frequency of wound complications tended to increase with the total dose and dose per fraction. ^[42]

The frequency of postoperative complications in 18 patients undergoing bilateral neck dissection after radiotherapy to the primary lesion and neck were as follows: acute laryngeal edema in 2 patients, wound breakdown in 6 patients, and chyle fistula in 1 patient. Overall, 9 patients (50%) experienced a complication, and 6 patients (33%) required a second operation. No postoperative deaths were reported.