Management of the N3 Neck Treatment & Management

Local control with chemoradiation therapy has been reported to be as high as 90%. Clinical response, however, does not correlate with pathologic response (see Futures and Controversies). Although studies have shown that no clinical or pathologic parameters are able to predict a response to chemoradiation therapy, studies suggest that a tumor volume of less than 20 mL, tumor grade, lower epidermal growth factor receptor (EGFR) overexpression, and response to induction chemotherapy predict response to chemoradiation.

Concurrent chemoradiation therapy has survival rates similar to those of surgical therapy and preserves the function of important structures. Surgical therapy, however, carries better locoregional control rates.

Complete response to chemoradiation therapy requires a complete disappearance of all clinical, radiologic, and pathologic (if applicable) evidence of disease; however, not all clinically complete responses show histologic complete response after planned neck dissection. Anything less than a complete response requires surgery of the primary site and the neck nodes, if possible.

Treatment of the neck following chemoradiation is controversial. In the presence of a partial or incomplete response in the neck to chemoradiation, a completion neck dissection is mandatory (assuming the primary site is controlled or is resectable). In the presence of a complete response in the neck to chemoradiation, reports vary regarding the need for planned neck dissection (see Future and Controversies).

The following complications are associated with chemoradiation therapy:

• Feeding tube (required in 32% of patients)

• Mucositis

• Neutropenia

• Carotid stenosis (range, 30-50% of patients) ^[19]

• Renal insufficiency

• Ototoxicity

• Esophageal stricture

Surgery alone for the N3 neck carries a local failure rate of 21% and 5-year survival rate of 15%. Surgery for a stage N3 neck should always be in conjunction with chemoradiation or radiation (performed either preoperatively or postoperatively). The complication rates for a neck dissection after concurrent chemoradiation range from 8-35%.

Table 2. Type of Neck Dissection Chosen as Dictated by What Structures are Involved (Open Table in a new window)

 

Classically, the N3 neck, if treated surgically, requires a radical neck dissection. Although a modified neck dissection may be possible in some cases, the classic radical neck dissection is necessary in most cases of the N3 neck.

Carotid artery resection is controversial. A 13-year retrospective study by Freeman et al (2004) reported on 41 patients whose carotid arteries were resected and reconstructed and 11 patients who underwent preoperative embolization or intraoperative ligation of the carotid artery. ^[20] The median disease-specific survival and the median disease-free interval were both 12 months. Distant metastasis developed in 24% of patients, and 20% of patients had recurrence within 6 months of the resection. Eight (20%) of 41 patients who underwent resection and reconstruction of the carotid artery developed stroke postoperatively. Three (27.7%) of the 11 patients who underwent embolization or ligation of the carotid artery developed stroke postoperatively.

Cancer seldom invades the lumen of the carotid artery; based on a study by Huvos et al, only 42% of patients had invasion of the adventitia and external elastic membrane. ^[21]

The treatment options in the management of cervical metastasis that involves the carotid artery are as follows:

• Permanent occlusion can be performed if collateral circulation is adequate.

• Resection with carotid shunt and reconstruction can be performed if collateral circulation is inadequate.

• Nonsurgical palliation is an option if collaterals are inadequate and reconstruction is not possible.

• Nussbaum et al (2000) developed a unique technique in the management of carotid involvement in head and neck cancer. ^[22] Endovascular stenting of the carotid artery is initially placed and followed by a staged neck dissection after 1 month of placement. Because the neoendothelial barrier has formed in the stent and prevents bleeding, dissection of the arterial wall with neck dissection can be performed. This is a technical case report that is currently under investigation.

Lore and Boulos reported that one third of their patients who underwent carotid artery resection lived longer than 2 years after the procedure, and a meta-analysis on carotid resection by Snyderman showed improved local control. ^{[23, 24]} The decision to resect the carotid artery depends on the risk-benefit ratio in relation to local control, survival, stroke risk, quality of life, mortality, and available expertise.

The external carotid artery should be resected as needed; however, the authors' view is that resection of the carotid bulb or internal carotid artery is rarely, if ever, indicated. This is because the chance for cure is exceedingly low. The hypoglossal and or vagus nerve can also be invaded aside from the carotid artery. Resection of both the hypoglossal and vagus nerves increases the morbidity and mortality. Stroke is a risk, even when results of balloon occlusion studies are favorable. Even with resection of the carotid, the median survival is only 12 months.

Consider the primary site during treatment planning. Generally, primary site management dictates the plan for the neck. Patients who will undergo surgery for the primary site must also have resectable neck disease. As discussed previously, incomplete resection of the neck disease is of no benefit to the patient (see Contraindications). Careful inspection of preoperative imaging is critical to making this assessment.

Certain patients may not have an operable primary tumor and would not normally undergo a neck dissection. However, they may have morbidity associated with advanced neck disease and could benefit from a palliative neck dissection. This situation includes patients with the following:

• Nonhealing ulcer

• Bleeding neck mass not attached to vascular structure

• Unresponsive to conservative wound care

• Unresponsive tumor embolization

• Neck mass is operable, resectable, and adequate margins can be achieve

This highly selected subset of patient may be a candidate for palliative neck dissection. However, one must carefully weigh the risks of creating a worse wound and having the patient hospitalized for his or her remaining life against potential quality-of-life improvements.

Intraoperatively, the surgeon must assess whether the N3 neck is completely resectable. Involvement of structures not normally included in the standard neck dissection must be assessed and resected as needed to achieve a complete resection. However, unless the tumor is completely resectable, resecting important neurovascular structures, causing unnecessary morbidity, is not advisable. (See Relevant Anatomy and Surgical Therapy.)

When possible, patients benefit from adjuvant therapy following neck dissection for advanced neck disease. Chan et al (2003) showed that patients with N3 disease treated with surgery and postoperative radiotherapy had improved survival when compared with surgery and preoperative radiotherapy or surgery alone. ^[25] Patients with advanced neck disease derive additional benefit from postoperative concurrent chemoradiation. ^[18]

Following treatment for the N3 neck, patients require close follow-up, as they are at high risk for both regional recurrence and distant metastases. The risk of relapse is highest in the first 2 years following treatment. Many surgeons advocate monthly physical examinations, and imaging every 3 months in the first year following treatment.

The following are complications associated with surgical resection of the N3 neck:

• Perioperative stroke (range, 0.2-4.8%)

• Wound complications (range, 8-35%)

• Fistula

• Bleeding

• Infection

• Carotid artery rupture

• Chyle leak

Carotid artery rupture is a dreaded complication of advance neck disease. Rupture may be preceded by a sentinel bleed, wherein a patient has a short-lived episode of bleeding from the mouth, neck, or stoma. After bleeding subsides, all may appear to be well, but hospitalized patients may need to be placed on carotid artery precautions unless the patient refuses resuscitation. Precautions include a prepositioned stretcher to quickly take the patient to the operating room (OR) and rolled gauze bandages to obtain adequate pressure to the artery. Make no attempt to clamp the vessel. The following are the appropriate sequence of events in the management of carotid blowout:

1. Apply pressure and volume support.

2. Transfer the patient to the OR immediately.

3. Manage the condition either by endovascular stent graft or by surgically obtaining proximal and distal control followed by surgical repair or ligation, depending on hemodynamic status and condition of the tissue.

Outcomes are best when combined modality therapy is used. However, patients with the N3 neck have overall poor outcomes as a result of developing regional recurrence and distant metastases. ^{[22, 24]} Assessing the outcomes of the N3 neck is sometimes difficult because these patients frequently are grouped with patients with N2 neck disease.

Several recent studies have specifically addressed the outcomes of patients with N3 neck disease. Carvalho et al (2005) achieved the best regional control of 73% using surgery and postoperative radiotherapy, although overall 3-year survival was still poor at 17.9% in this group of patients. ^[26] Chan et al (2003) also found the best results in the N3 patient by treating with surgery followed by radiation. ^[25] Their 1-year, 3-year, and 5-year neck control rates in this group were 92.3%, 46.1%, and 46.1%, respectively. The overall disease free survival rates in their patients at 1, 3, and 5 years was 44.4%, 25%, and 22.2%, respectively.

Ballonoff et al (2008) reported their results in patients with N3 neck disease treated with primary chemoradiation, with or without planned neck dissection. ^[27] Their rates of locoregional control and distant control were 88% and 56%, respectively. Actuarial overall survival and disease-free survival at 2 years were 51% and 29%, respectively.

A study by Sellami et al indicated that although the overall survival (OS) rate is low in patients with locally advanced head and neck SCCA with an N3 neck, long-term locoregional control is more achievable in those with a body mass index (BMI) of 25 or greater at diagnosis. The 5-year OS rate in the report was 20%, but the 5-year locoregional control rate in patients with overweight or obesity was 55.0%, versus 15.3% for individuals with a lower BMI. Patients in the study were treated either with radiotherapy (with or without chemotherapy) or with nodal surgery (with or without primary tumor resection and, in most cases, with adjuvant radiotherapy with or without chemotherapy). ^[28]

A study by Alvarado et al found that in patients with clinical N3 (cN3) esophageal cancer, those who underwent surgery following neoadjuvant chemoradiation therapy had a better 5-year OS rate than did those who were treated with chemoradiation therapy alone (18.0% vs 11.8%, respectively). ^[29]

The following methods for local control of recurrent tumor in the neck are currently under investigation:

• Radiofrequency ablation ^[30]

• Microwave interstitial hyperthermia (915 MHz) ^[31]

• Intratumoral administration of cisplatin and epinephrine ^[32]

• Interstitial photodynamic therapy ^{[33, 34]}

• Intratumoral administration of ONYX-015 adenovirus and chemotherapy ^[35]

• Reirradiation therapy and chemotherapy with amifostine ^[36]

• Electroporation with chemotherapy ^[37]

A controversial topic in managing advanced neck metastasis treated with definitive chemoradiation is whether to offer the patient a planned neck dissection after a complete response. Undoubtedly, a patient with resectable neck disease with no response or a partial response after chemoradiation should undergo salvage neck dissection; however, there may be a role for planned neck dissection even after clinical and radiological complete response. The debate stems from the fact that after a clinical and radiological complete response from chemoradiation, there is still 20% ^{[38, 39]} of patients with pathological nodes confirmed with histology after planned neck dissection.

Some authors advocate that patients with N2-N3 neck have improved regional control after planned neck dissection, which reduces the need for surgical salvage, which has a low likelihood to succeed. There is limited ability for physical examination and imaging to predict viable cancer cells in lymph nodes despite apparent complete response. A planned neck dissection performed 4-12 weeks after surgery has a 10% morbidity rate, with improved local control in specimens found to have viable tumor cells. ^[39] In addition, an observation approach to complete responders is complicated by the increased morbidity of surgery outside of the 4- to 12-week window following chemoradiation therapy, owing to increased fibrosis. ^[39]

Other authors routinely monitor patients after a complete response to chemoradiation therapy because of the lack of survival benefit from planned neck dissection and the low risk of neck recurrence. The strategy of planned neck dissection originated in the era of primary radiation therapy as a single-modality treatment, which showed poor response to advanced neck disease. ^[40]

With improved imaging and radiation therapy advancements, treatments have become more effective, with a better ability to detect residual disease. ^[41] In a series of 60 patients with N2-N3 disease with complete response to chemoradiation therapy, there was no isolated neck failure despite not undergoing planned neck dissection. ^[42] There is an 80% negative specimen rate for patients who undergo planned neck dissection, ^[38] and those patients who have viable tumor cells in the specimen have aggressive disease that may be more likely to develop distant metastasis or primary site failure. ^[40] In addition, there is a reported better response in HPV-positive tumors, so this could influence decision making about treatment of the neck. ^{[40, 43]}

There is new debate about the utility of positron emission tomography (PET) scanning to detect viable tumor cells in clinical complete responders. There have been disappointing data in the ability of PET to accurately predict histologic response to treatment when used prior to 12 weeks after completion of chemoradiation therapy. ^{[44, 45]} The optimal timing of PET scanning is 12 weeks following chemoradiation therapy, which is outside the window for ideal timing of planned neck dissection, but a negative PET scan may avoid an unnecessary surgery. ^[46]

In a study of 31 patients who underwent chemoradiation for N3 neck disease, 28 had a complete response at 12 weeks post therapy at the primary site and of these, 20 showed complete response in the neck as well on PET scan. ^[47] In this study, complete response was defined as having a fluorodeoxyglucose (FDG) PET complete nodal response, regardless of the size of any residual nodal abnormality. Of these 20 patients who were observed after a negative PET study, 1 had nodal recurrence that was inoperable, 3 had metastatic disease, and 16 were without nodal recurrence. Of these 20 patients, 12 had residual nodes seen on CT—median size 13 mm (range, 6–40 mm)—whereas another had diffuse thickening that was not able to be measured. ^[47] Using CT criteria for residual disease instead of PET criteria would have led to an increased number of neck dissections in patients who ultimately were without nodal relapse with observation alone.

Selection criteria for planned neck dissection versus observation among patients who have had a complete response to chemoradiation therapy need to be established. Yao et al (2004) correlated residual pathology in postradiation or postchemoradiation neck specimens to the standard uptake value (SUV) in post-treatment FDG PET-CT scans. ^[48] They found that an SUV of less than 3.0 had a negative predictive value of 100% and a positive predictive value of 80% for the residual tumor in the neck specimen.

Other authors have found that FDG PET-CT scanning adds little value over traditional CT scanning in determining who requires a postchemoradiation neck dissection for advanced neck disease. ^[49] The exact role of FDG PET-CT is still unclear and requires further investigation.