eMedicine Specialties > Otolaryngology and Facial Plastic Surgery > Head & Neck Surgery

Radiation Therapy, Management of Neck Metastases

Author: William M Mendenhall, MD, Professor, Department of Radiation Oncology, Shands Hospital, University of Florida
Coauthor(s): Robert J Amdur, MD, Associate Chairman of Clinical Affairs, Associate Professor, Department of Radiation Oncology, Shands Hospital, University of Florida; John Werning, MD, DMD, FACS, Assistant Professor, Department of Otolaryngology-Head and Neck Surgery, University of Florida; Russell W Hinerman, MD, Assistant Professor, Department of Radiation Oncology, Shands Hospital, University of Florida; Douglas B Villaret, MD, Residency Director, Assistant Professor, Department of Otolaryngology, Shands Hospital, University of Florida
Contributor Information and Disclosures

Updated: May 22, 2007

Introduction

This article addresses the role of radiotherapy in the management of the neck in patients with squamous cell carcinoma of the head and neck. Included is the use of postradiotherapy neck dissection in patients treated with radiation therapy alone or with radiation therapy combined with adjuvant chemotherapy to the primary lesion.

Natural History

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 untreated lesions.

Table 1. Definition of Risk Groups

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Adapted from Mendenhall and Million, 1986

The N-stage distribution at diagnosis based on the primary site and T stage is shown in Table 2. 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.

Table 2. Clinically Detected Nodal Metastases Upon Admission Based on T Stage*

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Adapted from Lindberg, 1972

*Of 2044 patients at MD Anderson Cancer Center from 1948-1965

†T stage defined by Lindberg (Lindberg, 1972)

‡T stage defined by Fletcher et al (Fletcher, 1967)

§T stage defined by Fletcher et al (Fletcher, 1970)

||T stage defined by MacComb et al (MacComb, 1967)

¶T stage defined by Chen and Fletcher (Chen, 1971)

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 extracapsular extension (ECE) 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.

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. The incidence of positive retropharyngeal nodes based on pretreatment computed tomography (CT) scanning and/or magnetic resonance imaging (MRI) is shown in Table 3.

Table 3. Incidence of Positive Retropharyngeal Nodes for Various Primary Sites and Clinical Neck Stages (794 Tumors)*

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Adapted from McLaughlin, 1995

*Detected during pretreatment CT scan and MRI

†N+: Neck nodes clinically involved (stages N1-N3b)

Staging

The following staging system is from the 2002 American Joint Committee on Cancer (AJCC) and is 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; 3 cm or smaller in greatest dimension
• N2: Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in greatest dimension; in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension; or in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension
  • N2a - Metastasis in a single ipsilateral lymph node, larger than 3 cm but not larger than 6 cm in greatest dimension
  • N2b - Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension
  • N2c - Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension
• N3 - Metastasis in a lymph node, larger than 6 cm in greatest dimension

Until recently, most of the published data from the University of Florida were analyzed using the 1983 AJCC staging system. The 1983 system defined bilateral nodes 6 cm or smaller as N3b and clinically positive ipsilateral nodes larger than 6 cm in diameter as N3a. Additionally, positive contralateral nodes only, ie, smaller than or equal to 6 cm, were classified as N3c.

Positive contralateral nodes only are very rare and should alert the clinician to search for another primary lesion. A significant improvement in the 2000 staging system compared with the 1983 system is not evident. The University of Florida data presented in this article were analyzed using the 1983 system and cannot be presented according to the 2000 system because 1983 N3b would include some patients with both 2000 N2c and N3 disease.

The AJCC staging system is based on both clinical and pathologic information. Keeping this in mind when comparing end results is important; avoid comparing data analyzed using different staging systems because this could result in a biased comparison.

Elective Treatment Of The Neck

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.

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.

Elective radiation therapy of cervical lymph nodes when the primary tumor is treated with 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 45-50 Gy over 4.5-5 weeks or its radiobiological 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 irradiation is not indicated.

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.

The availability of 3-dimenisional conformal radiation therapy and intensity-modulated radiation therapy has enhanced the ability to adequately irradiate the tumor and potentially involved lymph nodes while minimizing the volume of normal tissues included in the radiotherapy portals. However, as the target volume is reduced using these newer radiotherapeutic tools, avoiding marginal misses, which have a relatively low likelihood of successful retreatment, is important.

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 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 Co 60 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.

The schema for treatment of the clinically negative neck at the University of Florida is summarized in Diagram 1.

Diagram 1. Elective Treatment of Clinically Negative Neck Nodes

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Adapted from Mendenhall, 2000

Treatment Of Clinically Positive Cervical Lymph Nodes

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, on 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.

The decision to add a neck dissection after radiation therapy for multiple unilateral positive nodes or bilateral lymph node disease is individualized and is based on the diameter of the largest node, node fixation, number of clinically positive nodes in the neck, and the dose received by the nodes. Because no randomized data are available that address the efficacy of planned postradiotherapy neck dissection, treatment of the disease is based on nonrandomized data.

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; furthermore, a neck dissection may be withheld because of the relatively low risk of an isolated nodal failure. However, performing the neck dissection immediately after radiation therapy may be safer because detecting lymph node recurrence may be difficult. Factors contributing to this difficulty include fibrosis of subcutaneous tissues of the neck, the likelihood of successful salvage after recurrence in the neck is 5% or less, and data indicating that the probability of both control of neck disease and survival is enhanced by the addition of a planned dissection.

Results from the MD Anderson Cancer Center, which suggest that neck dissection may be safely withheld, are based on patients who received very aggressive radiation therapy (ie, 72 Gy over 6 wk) to the neck. The conclusion may not apply to patients who receive less aggressive schemes.

Results of a large, randomized trial (ie, Radiation Therapy Oncology Group 9003) have shown improved local-regional control for 2 aggressive altered-fractionation schedules compared with conventional radiation therapy.

Data similar to those reported by the MD Anderson Hospital investigation have been reported by Johnson et al from the Medical College of Virginia, where an aggressive altered-fractionation schedule was also used.

Recent data suggest that a CT scan image 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%.

Limited data also suggest that neck dissection may be safely withheld in patients who experience a complete response to induction chemotherapy followed by high-dose radiation therapy.

The schema for treatment of a clinically positive neck at the University of Florida is shown in Diagram 2.

Diagram 2. Schema for Treatment of Clinically Positive Neck Nodes

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

If a neck dissection is to follow radiation therapy in patients with clinically positive lymph nodes, the preoperative dose varies with the size and location of the lymph node, fixation, and response to radiation therapy. Preoperative doses of 50 Gy are sufficient for mobile lymph nodes of 3-4 cm, but a dose of 60 Gy or more is recommended for nodes of 5-6 cm and for fixed nodes. Lymph nodes of 7-8 cm are almost always fixed to adjacent structures and often require doses of 70-75 Gy to achieve a complete resection.

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 70-80 Gy 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 60-64 Gy, after which the dose to the node may be boosted as necessary.

When the cervical lymph nodes are located superficially, sometimes within 1 cm of the skin or fixed to it, treatment with high-energy photon beams (>6 MV) may underdose these nodes, particularly if an ipsilateral field arrangement is used. Treatment should be initiated with⁶⁰ Co or 4-MV radiographs for the initial 45-50 Gy (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 6-MV 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 6-MV 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 that from the electron beam alone. Another attractive alternative is a wedge-pair technique using 3-dimensional treatment planning and 6-MV radiographs alone.

Patients with bilateral neck disease require individualized treatment planning designed as a joint effort between the radiation oncologist and the surgeon. If disease is minimal on one side, radiation therapy alone may be used to control the disease on that side of the neck. A neck dissection may be used on the side with more disease. If major bilateral disease is present, bilateral neck dissection should follow radiation therapy.

Treatment of the neck after incisional or excisional biopsy

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.

The University of Florida experience with incisional or excisional biopsy of positive neck nodes followed by radiation therapy as the initial step in the treatment of the patient was reported by Parsons et al, Ellis et al, and Mack et al. After excisional biopsy of a single lymph node, radiation therapy alone to the primary lesion and to the neck resulted in a 95% rate of neck control. If residual disease remained in the neck after biopsy, radiation therapy followed by neck dissection was more successful for controlling neck disease than radiation therapy alone.

If the primary lesion is to be treated surgically, the patient's neck is also treated with preoperative radiation therapy to the primary lesion and neck, followed by resection. If the primary lesion is to be treated with radiation therapy, the patient's neck is treated with radiation therapy.

If no gross disease remains in the neck after excisional biopsy of a positive node, the neck may be treated with radiation therapy alone. Virtually all such patients have palpable induration secondary to hematoma. CT scans may be very useful in determining whether the residual induration is due to hemorrhage and edema or a tumor.

If an incisional biopsy of the node has been performed (leaving gross disease) or if other positive nodes remain after an excisional neck node biopsy, radiation therapy is followed by a neck dissection (see Diagram 3).

Diagram 3. Schema for Treatment of the Neck After Incisional or Excisional Biopsy

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Adapted from Mendenhall, 2000

The dose of radiation preceding a neck dissection depends on the amount of gross disease in the neck and the degree of node fixation.

Brachytherapy

The role of brachytherapy in neck management has been mostly limited to previously irradiated patients with incompletely resectable positive neck nodes. The 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 Ir 192 wire or seeds or (2) placement of permanent iodine I 125 seeds. If technically feasible to do so, the former technique probably results in a better dose distribution, although implanting¹²⁵ I seeds via absorbable sutures is possible.

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.

Adjuvant chemotherapy

Induction chemotherapy may be used to select treatment based on the response to chemotherapy, but it probably 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.

Complications Of Neck Treatment

Complications of neck irradiation

The complications of neck irradiation include subcutaneous fibrosis and lymphedema of the larynx and submentum. The latter complication 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. Recent data suggest that late radiation fibrosis may be ameliorated with the combination of vitamin E (1000 IU/d) and pentoxifylline (400 mg bid).

Complications of neck treatment in patients who receive radiation therapy in conjunction with resection of the primary lesion and a neck dissection are essentially the same as those occurring after neck dissection alone, but complications may occur with an increased frequency, depending on the radiation dose and extent of surgery.

Complications of 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 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 4. The frequency of complications was higher for maximum subcutaneous doses greater than 60 Gy.

Table 4. Postoperative Complications of Unilateral Neck Dissection After Irradiation to the Primary Lesion and Neck (143 Patients)

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Adapted from Mendenhall et al, 1986

*Thirty-five complications were noted in 33 patients.

†Deaths occurred 6, 7, 8, and 35 days after surgery.

Taylor et al updated the University of Florida experience with an analysis of the frequency of moderate (2+) and severe (3+) wound complications in a series of 205 patients who underwent a planned unilateral neck dissection after radiation therapy. Radiation therapy was given once daily to 123 patients, twice daily to 80 patients, and with both techniques to 2 patients. The frequency of wound complications tended to increase with the total dose and dose per fraction.

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.

Results Of Treatment: Clinically Negative Nodes

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 to both the primary tumor and the neck (if the risk of subclinical disease in the neck is >20%).

The results of elective neck irradiation at the University of Florida for patients with squamous cell carcinoma of the head and neck in whom the primary lesion was controlled are shown in Table 5. 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 5. Control of Disease in the Clinically Negative Neck with Elective Neck Irradiation (Number Controlled/Number Treated)

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Adapted from Mendenhall and Million, 1986

*Estimated risk of subclinical disease in the neck nodes

†ENI - Elective neck irradiation

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 48 Gy 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 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 to harbor cancer in the neck than those who 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 conducted randomized trials comparing elective neck dissection with no elective neck treatment for patients with oral cavity carcinoma and oral tongue cancer, respectively. No survival advantage was noted for patients undergoing elective neck dissection in either study. However, because of the small number of patients in both trials, the possibility exists that even if a survival difference occurred, it would have been missed.

Dearnaley et al reported a series of 148 patients treated for cancer of the tongue or floor of the mouth at the Royal Marsden Hospital (London, United Kingdom) with an interstitial implant, alone or combined with external-beam irradiation. Of 131 patients with negative neck nodes at diagnosis, 59 patients (45%) received elective neck irradiation to a dose of 40 Gy. A multivariate analysis revealed that elective neck irradiation significantly improved survival and reduced the risk of death from cancer.

Piedbois et al reported a series of 233 patients with T1-T2N0 carcinoma of the oral cavity treated with interstitial iridium brachytherapy. 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 is significantly associated with improved survival rates.

Results Of Treatment: Clinically Positive Nodes

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 6) and the University of Florida (see Table 7).

Table 6. Failure of Initial Ipsilateral Neck Treatment: 596 Patients with Carcinoma of the Tonsillar Fossa, Base of Tongue, Supraglottic Larynx, or Hypopharynx

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Adapted from Barkley, 1972; MD Anderson Hospital data, patients treated from 1948-1967

Table 7. Five-Year Rate of Neck Control by 1983 AJCC Stage and Treatment (459 Patients; 593 Heminecks)*

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Adapted from Mendenhall, Principles and Practice of Radiation Oncology, 1998

Note that for University of Florida data, patients were treated from October 1964 to October 1985. The analysis was performed Eric R. Ellis, MD, in December 1988.

*Excludes 67 heminecks on which incisional or excisional biopsy was performed before treatment

The incidence of recurrence in the contralateral side of the neck versus neck stage is depicted in Table 8. The risk of recurrence increases with the extent of disease in the ipsilateral side of the neck.

Table 8. Cervical Metastasis Appearing in the Contralateral N0 Neck: 596 Patients with Carcinoma of the Tonsillar Fossa, Base of Tongue, Supraglottic Larynx, or Hypopharynx

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Adapted from Barkley, 1972; MD Anderson Hospital data, patients treated from 1948-1967

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 one level.

Olsen et al reported a series of 284 patients who underwent neck dissection at the Mayo Clinic (Rochester, Minn) for pathologic stage N1 and N2 squamous cell carcinoma of the head and neck; no patient received adjuvant therapy. Recurrence-free survival rates in the neck at 5 years were as follows: N1, 76%; N2, 60%; and overall, 69%. A multivariate analysis revealed that 4 or more positive nodes (P = .005), invasion of lymphatic and/or vascular spaces (P = .003), invasion of soft tissue (P = .0008), and a desmoplastic stromal pattern (P = .0001) were significantly associated with an increased risk of recurrence in the neck.

The postoperative dose prescribed usually ranges from 60 Gy in 30 fractions to 65 Gy 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. The nodal control rates as a function of node diameter were 0.5 cm, 77%; 2 cm, 67%; 4 cm, 60%; 6 cm, 52%; 8 cm, 37%; and 10 cm, 7%.

Radiation therapy alone is sufficient for patients with N1 disease smaller than or equal to 2 cm as long as the fraction size (2 Gy) and the total dose are sufficient. Radiation therapy followed by neck dissection has provided better rates of disease control than radiation therapy alone for patients with more advanced neck disease. As shown in a multivariate analysis by Ellis et al, the addition of neck dissection after radiation therapy is independently related to a significantly decreased risk of dying from cancer. The likelihood of disease control in each side of the neck treated with irradiation and neck dissection is decreased when the node is fixed before treatment or when residual tumor is found in the pathologic specimen. No difference is observed in the rate of control as a function of the interval between radiation therapy and neck dissection when comparing patients who have surgery within 6 weeks with those who have neck dissection more than 6 weeks after radiation therapy.

In the event of a subsequent local recurrence, prior combined treatment of the neck does not diminish the chance of successful surgical salvage of the patient. Some authors have reported that the likelihood of local control after radiotherapy is inversely related to neck stage; others have not observed this finding. If such a relationship exists, it is likely weak.

Clinically positive nodes with incisional or excisional biopsy

Ellis et al reported 508 patients with 660 positive heminecks treated at the University of Florida with radiation therapy alone or followed by a planned neck dissection. Pretreatment node biopsy did not influence outcome when irradiation was the next step in treatment. The results of the forward stepwise log rank tests of prognostic factors for predicting time to recurrence are shown in Table 9.

Table 9. Prognostic Factors, in Order of Importance, for Predicting the Time to Occurrence of Various Events

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Adapted from Ellis, 1991

*RT - Radiation therapy

†This factor is thought to be correlated with the censoring pattern.

Neck Node Metastases With An Unknown Primary Site

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 those 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. Those 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.

The patient evaluation should include the following:

• A thorough physical examination, including a careful evaluation of the head and neck
• Needle biopsy of the lymph node: Fine-needle aspiration is preferred to biopsy because it is less traumatic, and the likelihood of seeding tumor cells along the needle track is lower. Limited data suggest that evaluation of neck node biopsy specimens for Epstein-Barr virus DNA, via polymerase chain reaction, may be useful for detecting a nasopharyngeal primary tumor. Tumors that test positive for Epstein-Barr virus DNA are likely to be nasopharyngeal in origin.
• After chest roentgenography, CT scanning or MRI of the head and neck to detect an unknown primary lesion arising from the mucosa of the head and neck
• Direct endoscopy and examination under anesthesia, with directed biopsies of the nasopharynx; tonsils (including an ipsilateral or bilateral tonsillectomy); base of tongue; pyriform sinuses; and any abnormalities noted on CT scan images, MRI, or endoscopy (eg, suggestive mucosal lesions): If the primary lesion is not found after repeated physical examinations by multiple examiners or on the CT scan image or MRI result of the head and neck, a subset of patients have their primary sites detected based on results from directed biopsies. Recent data suggest that microsatellite analysis of histologically negative directed mucosal biopsy results may reveal foci of preneoplastic cells that are genetically related to those in the metastatic node(s). This suggests that such a mucosal site may be the occult primary cancer and that this technique may become an additional tool for identifying such sites.
• Nuclear medicine studies: These have also been used in a limited number of patients to help detect unknown head and neck primary sites. The rationale for these tests is that a tumor, which has a higher metabolic rate than surrounding normal tissues, preferentially takes up a radioactive tracer (eg, fluorodeoxy-glucose), and the lesion appears as an area of increased uptake on the scan. Because only limited data are available pertaining to these studies, evaluating their usefulness if difficult. The authors' limited experience with fluorodeoxy-glucose single-photon emission computed tomography scans indicate that few patients benefit from the test.

The diagnostic evaluation for a patient with cervical metastasis from an unknown head and neck primary lesion is summarized as follows (Mendenhall, Principles and Practice of Radiation Oncology, 1998):

• General
  • History
  • Physical examination
  • Careful examination of the neck and supraclavicular regions
  • Examination of oral cavity, pharynx, and larynx (indirect laryngoscopy)
• Radiographic studies
  • Chest roentgenogram
  • CT scanning and/or MRI of head and neck (special attention to nasopharynx, pharynx, and larynx)
• Direct endoscopy and directed biopsies
  • Nasopharynx, both tonsils, base of tongue, both pyriform sinuses, and any suggestive or abnormal mucosal areas
  • Tonsillectomy if sufficient lymphoid tissue is present in the tonsillar fossa to warrant such a procedure
  • Fine-needle aspiration or core-needle biopsy of the cervical node

The results of the radiographic workup followed by panendoscopy and directed mucosal biopsies for a series of 130 patients evaluated at the University of Florida are in Table 10. More than 80% of the primary sites detected were in the tonsillar fossa or base of the tongue.

Table 10. Biopsy-Proven Primary Site Versus Physical and Radiographic Findings

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Adapted from Mendenhall, Head Neck, 1998

*Significance levels - 7/42 versus 34/65, P = .00023; 7/42 versus 15/23, P = .00012; 34/65 versus 15/23, P = .20413

†PE neg - No suggestive findings on physical examination

‡RAD neg - No suggestive findings on radiographic studies

§RAD pos - Radiographic studies suggestive of primary site

||One of 29 patients had positive results from a 2-[flourine-18]-2-deoxy-D-glucose single-photon emission CT scan and negative results from a CT scan of the head and neck; the remaining 28 patients had positive CT scan and/or MRI findings.

¶PE pos - Suggestive of a primary site, but not definitely positive

#Two of the 15 remaining patients had positive results from a 2-[flourine-18]-2-deoxy-D-glucose single-photon emission CT scan and negative results from a CT scan of the head and neck; the remaining 13 patients had positive CT scan and/or MRI findings.

Some patients may be cured with treatment directed only to 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 perform a neck dissection and observe the patient or irradiate the oral cavity and oropharynx and not the nasopharynx, larynx, or hypopharynx.

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.

Within the past 7 years, the mucosal sites included in the lateral portals to the oropharynx and nasopharynx have been limited because the most common primary sites are the tonsillar fossa and tongue base. The mucosal dose has also been increased to 64.8 Gy. 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.

Treatment of the neck depends on the extent and location of the adenopathy, as previously outlined.

One hundred eighty-four patients with squamous cell carcinoma from an unknown head and neck primary site were treated at the MD Anderson Cancer Center. The relationship of primary site appearance versus treatment was as follows: surgery alone, 21 of 104 (20%); radiation therapy, 3 of 52 (6%); and irradiation plus surgery, 4 of 28 (14%). The absolute survival rate at 3 years, as a function of treatment group and disease stage, is shown in Table 11.

Table 11. Metastatic Cervical Lymph Nodes, Unknown Primary Site 3-Year Disease-Free Absolute Survival Rates

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Adapted from Jesse, 1973; MD Anderson Hospital, 184 patients treated from July 1948 to June 1968

*Salvage in 8 patients by radiation therapy and in 6 patients by surgery

†Salvage in 1 patient by surgery

The incidence of subsequent mucosal primary lesions was compared by Harper et al for patients with a known primary site of lesion and a series of 69 patients treated for an unknown primary site at the University of Florida. The incidence rate for both groups was approximately 25% at 10 years, suggesting that either mucosal irradiation significantly reduces the risk of primary site failure or patients with unknown primary sites have a much lower risk of a second primary head and neck cancer subsequently developing.

Reddy and Marks reported 52 patients treated to the neck alone (16 patients) or the neck and potential head and neck primary sites (36 patients). Failure in the head and neck mucosa occurred in 44% of those who underwent treatment to the neck alone, compared with 8% in those who underwent irradiation of the head and neck mucosa (P = .0005). The 5-year survival rates were similar for the 2 treatment groups.

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.

Keywords

radiotherapy, RT, neck RT, radiation therapy, neck radiation, cervical metastasis, lymphatic metastasis, squamous cell carcinoma, SCC, neck cancer, cervical cancer, head and neck carcinoma, head and neck cancer, lymph node cancer, oropharyngeal cancer, nasopharyngeal cancer, oropharyngeal carcinoma, nasopharyngeal carcinoma, lymphatic cancer, radiotherapeutic management, radiotherapeutic treatment, postradiotherapy neck dissection, post-radiotherapy neck dissection, post radiotherapy neck dissection, lymph node metastasis, elective neck dissection, END, elective neck irradiation, ENI, oral cavity carcinoma, oral cavity cancer, oral tongue cancer, oral tongue carcinoma

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