ABSTRACT: The presence of regional nodal metastases represents a significant adverse prognostic factor for patients with squamous cell carcinoma of the head and neck. Early-stage head and neck cancers, localized to the primary site without regional lymph node metastases have excellent cure rates with either surgery or radiation therapy. The presence of regional metastases results in cure rates that are approximately half of those obtainable in early-stage disease. Therefore, due to the significant adverse impact of neck metastases on prognosis, the treatment of the neck remains a vital part of the decision-making process in determining therapy for head and neck cancer.
Over the past decade, the role of chemoradiotherapy in the definitive management of head and neck squamous cell carcinoma has been extensively studied. Several different sequences of treatment modalities have been explored, including neoadjuvant chemotherapy followed by definitive radiotherapy, alternating chemotherapy with radiotherapy, and concurrent chemoradiation. Concurrent chemoradiation has emerged as a preferred treatment option and has been shown to yield tumor response rates that are higher than the other combinations, while simultaneously achieving the goal of organ preservation.
Several phase III randomized trials and meta-analyses have shown that platinum-based concomitant chemotherapy and radiotherapy are superior to conventional radiotherapy alone in improving clinical response rates at the primary site, local and regional control, relapse-free survival, and overall survival in locally advanced disease.[1-5] However, despite the improved benefit of concurrent chemoradiation, there is no consensus in the literature on the optimal management of neck metastases in a concurrentapproach. In addition, because of the paucity of data, a number of controversies persist regarding optimal treatment of the neck in concurrent chemoradiation, and this has reopened the debate on the role of a planned neck dissection in these patients to control regional node metastases. The main question that needs to be addressed is: Should a neck dissection be a planned component in the concurrent chemoradiotherapy strategy?
Management Considerations
The initial pretreatment stage of the neck is important in deciding the appropriate management of the neck after definitive chemoradiation. Studies from The University of Texas M. D. Anderson Cancer Center in the 1970s showed a relationship betweenthe size of nodal burden and response to radiation.[6] For example, occult neck metastases or a single node less than 3 cm in diameter can generally be sterilized with chemoradiation therapy. Therefore, patients with low-volume (N1) neck disease have very high rates of control in the neck[7] and do not require neck dissection unless there is clinical evidence of persistent palpable disease after chemoradiation. The risk of neck failure climbs steadily with increasing neck node stage and tumor burden. Due to this risk,patients with stage N2 or N3 neck initially treated nonsurgically, have historically undergone planned neck dissection after chemoradiotherapy.
The site of the primary tumor may be equally important in therapeutic decision-making: Metastatic nodal disease from tumors of certain sites such as the nasopharynx and the tonsil are known to be exquisitely sensitive to radiation therapy. A planned neck dissection following complete response to chemoradiation may not be particularly beneficial in these patients with tumors arising from the Waldeyer's ring.
The decision for neck dissection following chemoradiation is clear when patients have residual neck disease.[ 8] However, controversy surrounds neck dissection in patients with a complete clinical response to chemoradiation. Recently, some authors have questioned whether planned neck dissection after chemoradiotherapy is necessary for patients with a complete clinical response, because a large percentage of these patients have negative neck dissection specimens on histologic examination.[9,10]
This controversy has led to institutional differences in the management of the neck after chemoradiation. Proponents of neck dissection argue that the procedure reduces the regional failure rate and may improve the cause-specific survival rate. In addition, salvage surgery in the event of recurrence is unlikely to succeed. Proponents of observation argue that the probability of an isolated recurrence in the neck is low, and many patients needlessly undergo neck dissection to benefit a few. However, no randomized trials have addressed the question specifically.
Role of Neck Dissection
The Postirradiated Neck
The purpose of the planned neck dissection in patients with N2/3 neck disease undergoing radiation or chemoradiation is to maximize the probability of achieving regional control. Parson et al reported improved neck control rates in patients with N2 and N3 disease treated with radiotherapy followed by neck dissectionvs radiotherapy alone.[11] In a large series of patients with advanced neck disease treated with radical radiotherapy alone at the Institut Curie, Dubray et al reported overall 3-year actuarial neck failure rates of 33% for N2 (n = 103) and 45% for N3 (n = 699).[12] However, in the same series, the incidence of isolated neck failure was only 7%. One can conclude from these reports that planned neck dissection contributes to neck control in unselected N2 and N3 patients treated with radiation or chemoradiation, but its exact role remains undefined.[12]
The Postchemoradiated Neck
The main controversy in the literature is whether patients could be selected for neck dissection following chemoradiation based on their response to treatment. In other words, can neck dissection be omitted in the subset of patients with N2/3 neck disease who achieve a complete response in the neck after concurrent chemoradiation?
• Residual Disease—Several studies have shown that patients with a complete response to chemoradiation clinically and radiographically may have microscopic residual disease in the neck. McHamm et al recently reviewed 109 patients with N2/3 disease treated with concurrent chemoradiation followed by neck dissection and found that 25% of the patients achieving a complete response in the neck had residual pathologic evidence of disease in the neck dissection specimen.[ 13] In addition, no clinical parameters could reliably predict for a pathologically positive neck or for those patients destined to have a recurrence in the neck, suggesting a role for neck dissection in all N2/3 patients.[13]
Similarly, Stenson et al reviewed 69 patients with advanced-stage head and neck cancer who underwent a neck dissection within 5 to 17 weeks after concurrent chemoradiotherapy.[ 14] Of these 69 patients, 24 (35%) had microscopic residual disease, and this was not correlated with clinical or radiographic response. Only one patient had recurrent disease in the neck after neck dissection, emphasizingthe importance of neck dissection after chemoradiation to remove residual viable tumor.
Wanebo et al reported a series of 43 patients treated with concurrent chemoradiotherapy for advancedstage head and neck squamous cell carcinoma. A planned neck dissection was performed 3 to 4 weeks after the completion of chemoradiotherapy; among patients with clinically N1-3 nodes prior to therapy, 9 (31%) of 29 had residual node involvement at neck dissection, and none of these patients had failure in the neck. The authors concluded that planned neck dissection is an essential component of aggressive chemoradiotherapy protocols to ensure and optimize tumor control in the neck.[15]
• Recurrence and Survival—The presence of pathologically positive nodal disease in neck dissection specimens after radiotherapy or concurrent chemoradiotherapy has been found to correlate with neck recurrence and survival probability. Lavertu et al evaluated 53 patients with N2/3 necks who had planned neck dissections after radiotherapy or concurrent chemoradiotherapy.[15] Of 53 patients with N2/3 disease, 35 underwent neck dissections, 18 of whom had a clinical complete response in the neck, with 17 achieving less than a complete response. Of the 18 patients with a complete response, 4 (22%) had viable tumor in the neck compared with 8 of 17 (47%) with less than a complete response. Disease recurred in 1 of the 35 necks after neck dissection; no recurrences occurred among the 18 patients with a complete response who underwent neck dissection, compared with 3 recurrences among 12 patients with a complete response but no neck dissection.
Disease-specific survival was not significantly affected by clinical response in the neck. However, among the N2/3 patients, pathologically positive neck disease was associated with a worse survival (6 of 12) compared with pathologically negative patients (4 of 23; P = .03). These data also support the use of planned neck dissection for management of clinicalneck disease. Furthermore, they demonstrated a lower rate of nodal recurrence following neck dissection, and the inability to salvage patients who had not undergone neck dissection.
Those who advocate limiting neck dissection only to patients with residual disease after initial chemoradiation believe that planned neck dissection in patients with a complete response results in many unnecessary neck dissections. In addition, several studies have reported that patients who have a complete response to radiation or chemoradiation, but do not undergo neck dissection, show a low rate of recurrent neck disease (11% to 25%).[7,16]
Armstrong et al reported a series of 54 node-positive patients treated with various regimens of induction chemotherapy followed by radiation alone or combined with a neck dissection. They reported 24 of 54 patients (44%) had a complete responseto induction chemotherapy, and 17 subsequently received radiation therapy alone. The neck remained controlled after irradiation in 16 (94%) of the 17 patients who did not undergo a neck dissection. Due to the high neck control rate in these patients, the authors recommended that patients with a complete response after chemoradiation need not undergo planned neck dissection.[7]
Summary of Literature for Chemoradiation in Head and Neck Cancer PatientsKoch et al prospectively studied 22 patients with advanced head and neck cancer of the oropharynx, oral cavity, and hypopharynx entered into a concurrent chemotherapy/radiotherapy protocol.[17] All patients with > N2 disease were scheduled for planned neck dissections. Although 11 patients were entered with N2/3 disease, only six neck dissections were documented, and two of these were performed for salvage or palliation. The 2-year overall survival was estimated at 64%, and the disease-specific survival at 71%. Neck recurrence was shown in 5 (23%) of 22. Neck dissection was not documented in 7 of the 11 N2/3 patients, all of whom had no evidence of disease at 13- to 36-month follow-up. These authorsbelieve that neck dissection after organ preservation therapy is of uncertain value in this subgroup of patients.[17] A summary of the literature for chemoradiation is presented in Table 1.[16-20]
• Neck Failure/Pathologic Node Discrepancy—Interestingly, the rate of neck failure in these studies is lower than the incidence of pathologic nodes among the neck dissection specimens of patients who had a complete response to radiation therapy and underwent a neck dissection, suggesting to some that many of the pathologically positive necks did not contain viable cancer cells, or alternatively, that continued cell kill occurs for several weeks or months after chemoradiotherapy.
A recent study tried to distinguish the neck specimens with viable cancer cells from those without by studying Ki-67, a marker for dividing cancer cells. In a series of 17 neck dissection specimens, only 3 of 11 with histology positive for carcinoma demonstrated the presence of Ki-67, whereas many samples had extensive apoptosis, suggesting tumor demise.[21] These findings led to speculation that the difficulty in interpreting positive but nonviable tumor cells in lymph nodes in the neck may be responsible for the discrepancy in the rates of neck recurrence among various reports. It is also important to consider the timing of neck dissection and the interval at which the neck dissection is, therefore, examined for the presence of "residua" disease, because it appears that cell death continues to occur for many weeks following completion of treatment.
• Complications—Neck dissection after organ-preservation therapy is also not without complications and morbidity. Complication rates from neck dissections after concurrent chemoradiotherapy have been reported to range from 26% to 35% and have most often reflected impaired wound healing. However, Newman et al reported that postoperative complication rates after induction chemotherapy followed by concurrent chemoradiotherapy were similar to a control group for both major and minor complications.[22]
Similarly, Lavertu et al found that surgery following radiation or concurrent chemoradiation can be performed with an acceptable rate of major complications (7% after neck dissection for radiation only and 0% after neck dissection for chemoradiation).[ 18] Although the major complication rate is relatively low, the question remains as to whether this surgical morbidity is justified for all N2/3 patients, or is it reasonable to reserve surgery for those who recur despite an initial complete response in the neck?
