Progression-free survival (PFS) for patients with limited nodal disease (N0-N2a) (2-year PFS: 60.0% vs 68.2%; P = .98) (A) and those with advanced nodal disease (N2b-N3) (2-year PFS: 74.6% vs 39.1%; P < .001) (B). Local control (2-year local control: 85.5% vs 53.5%; P < .001) (C), regional control (2-year regional control: 96.9% vs 90.1%; P = .21) (D), freedom from distant metastases (2-year freedom from distant metastases: 79.5% vs 67.5%; P = .03) (E), and overall survival (2-year overall survival: 84.5% vs 61.7%; P = .004) (F) for those with N2b or greater nodal disease.
Local control (2-year local control: 87.4% vs 66.2%; P = .02) (A), regional control (2-year regional control: 100% vs 93.8%; P = .15) (B), progression-free survival (2-year progression-free survival: 80.7% vs 53.4%; P = .01) (C), and overall survival (2-year overall survival: 88.5% vs 70.8%; P = .18) (D).
Local control for patients with N2b or greater nodal disease stratified by the hypopharynx (2-year local control: 88.9% vs 50.4%; P = .10) (A), larynx (2-year local control: 76.2% vs 81.3%; P = .33) (B), oral cavity (2-year local control: 80.0% vs 35.6%; P = .01) (C), and oropharynx (2-year local control: 88.5% vs 35.6%; P = .01) (D) sites. Progression-free survival for patients with N2b or greater nodal involvement stratified by the hypopharynx (2-year PFS: 63.6% vs 18.5%; P = .02) (E), larynx (2-year PFS: 88.9% vs 51.3%; P = .03) (F), oral cavity (2-year PFS: 61.5% vs 39.3%; P = .07) (G), and oropharynx (2-year PFS: 85.2% vs 38.5%; P = .001) (H) sites.
Ranck MC, Abundo R, Jefferson G, Kolokythas A, Wenig BL, Weichselbaum RR, Spiotto MT. Effect of Postradiotherapy Neck Dissection on Nonregional Disease Sites . JAMA Otolaryngol Head Neck Surg. 2014;140(1):12-21. doi:10.1001/jamaoto.2013.5754
After chemoradiation for head and neck cancer, more than 90% of patients who achieve a complete clinical response on imaging have their disease regionally controlled without postradiotherapy neck dissections (PRNDs). Because several groups have reported that lymph node involvement also predicts failure at both the primary and distant sites, the extent to which PRND affects nonregional sites of disease remains unclear.
To evaluate how PRND affects local control (LC) and distant control in patients who achieve a complete clinical response.
Design, Setting, and Participants
We retrospectively reviewed 287 patients (74 of whom underwent PRND) from the University of Illinois at Chicago Medical Center who were treated for stage III/IV disease with definitive chemoradiation from January 1, 1990, through December 31, 2012.
Chemoradiation followed by lymph node dissection or observation.
Main Outcomes and Measures
End points evaluated included LC, regional control, freedom from distant metastasis, progression-free survival (PFS), and overall survival using first-failure analysis.
Patients with advanced nodal disease (stage N2b or greater; n = 176) had improved PFS (74.6% vs 39.1%; P < .001), whereas patients with lesser nodal disease had similar PFS. For patients with advanced nodal disease, PRND improved 2-year LC (85.5% vs 53.5%; P < .001), locoregional control with PRND (78.9% vs 45.7%; P < .001), freedom from distant metastasis (79.5% vs 67.5%; P = .03), and overall survival (84.5% vs 61.7%; P = .004) but not regional control (96.9% vs 90.1%; P = .21). The benefit in LC (87.4% vs 66.2%; P = .02) and PFS (80.7% vs 53.4%; P = .01) persisted for those with negative posttreatment imaging results who underwent PRND. On univariate analysis, PRND, alcohol use, nodal stage, and chemoradiation significantly affected 2-year LC and/or PFS. On multivariate analysis, PRND remained strongly prognostic for 2-year LC (hazard ratio, 0.22; 95% CI, 0.07-0.54; P < .001) and PFS (hazard ratio, 0.42; 95% CI, 0.23-0.74; P = .002).
Conclusions and Relevance
Postradiotherapy neck dissection improved control of nonregional sites of disease in patients with advanced nodal disease who achieved a complete response after chemoradiation. Thus, PRND may affect the control of nonnodal sites through possible mechanisms, such as clearance of incompetent lymphatics and prevention of reseeding of the primary and distant sites.
In squamous cell cancer of the head and neck (HNSCC), lymph node positivity correlates with worse progression-free survival (PFS) and overall survival (OS).1,2 Traditionally, patients with nodal disease at presentation or with residual palpable neck disease after definitive therapy have been considered for postradiotherapy neck dissection (PRND).3,4 As attempts are made to reduce treatment-related morbidity, the continued necessity of PRND has been questioned. Recently, several articles3,5- 15 have used computed tomography (CT) with or without positron emission tomography (PET) to select patients who can avoid PRND. However, these imaging studies assumed that PRND only affected persistent disease in the nodal basins as measured by pathologic findings or subsequent regional control (RC) rates. In detecting residual cancer cells in surgical specimens, CT and PET-CT had a negative predictive value (NPV) of 86% to 100% and 95% to 100%, respectively.3,6,12,13,15- 20 Other reports demonstrated that a complete clinical response (cCR) on PET-CT or CT predicted RC in 85% to 100% of patients.5,7,9,13,21 Thus, patients achieving a cCR on imaging may avoid PRND after definitive chemoradiation with little detriment to RC.
However, involved cervical lymph nodes have also predicted worse local control (LC) and distant control (DC). For example, in patients treated with definitive surgery, Leemans et al22 demonstrated that 3 or more involved nodes increased local recurrence by 10%. Furthermore, for patients undergoing definitive radiotherapy, involved lymph nodes predicted worse LC across multiple head and neck sites.23- 25 Regarding DC, 3 or more involved nodes correlated with a 4.5-fold increase in distant metastases.2 Therefore, it remains unclear whether clearance of lymph node metastasis may also affect LC or DC.
We examined the effect of lymph node dissection in patients with locally advanced HNSCC. For patients with N2b or greater nodal disease, we found that PRND improved LC and PFS in patients achieving a cCR with chemoradiation. Thus, these findings are hypothesis generating in that clearance of involved lymphatics may improve outcomes at nonregional disease sites.
From January 1, 1990, through December 31, 2012, 457 patients with head and neck cancer and without distant metastatic disease were treated with definitive radiotherapy at the University of Illinois at Chicago Medical Center, including 356 patients with locally advanced HNSCC. We excluded 11 patients who had persistent disease after radiotherapy; 13 patients with a very high Charlson Comorbidity Index,26 which may affect disease control; and 45 patients who had follow-up times shorter than 1 year and were without evidence of disease. A total of 287 patients were used for analysis. Data were collected in accord with the University of Illinois at Chicago Institutional Review Board guidelines (protocol 2011-1075). A single physician (M.T.S.) collected all patient data from available physical and electronic medical records. Patients were staged according to the American Joint Committee on Cancer staging system at the time of diagnosis. The University of Illinois at Chicago Institutional Review board waived informed consent given that this study used preexisting medical records, and obtaining informed consent on all patients would be impractical given the associated time and cost.
In general, patients underwent history and physical examination, endoscopic evaluation of primary tumor, dental evaluations, and CT of the head, neck, and chest. All patients received radiotherapy as a component of their care, and more than 93.0% of patients received chemoradiation. Follow-up data were acquired from visits within any University of Illinois at Chicago Medical Center department. Posttreatment imaging (PTI) consisted of CT of the head and neck performed at a median of 6 weeks after radiotherapy. Patients were then followed up every 2 to 4 months as per the clinic routine. PET-CT was not uniformly performed and was not analyzed in this article. Positive imaging findings on CT were defined as residual lymphadenopathy, extracapsular spread, or residual disease at the primary site. Residual local disease was determined by imaging, physical examination, and direct laryngoscopy. Workup of potentially recurrent disease was ordered at the discretion of the treating physician. The incidence of late treatment-related morbidity was recorded at subsequent follow-up visits.
We divided the decision to proceed with PRND into 4 categories: (1) per protocol, where the patient had a cCR but underwent PRND because of advanced nodal disease at presentation; (2) clinical suspicion despite cCR, where a cCR was documented in radiographic reports but a PRND was performed because of clinical suspicion; (3) residual disease, where the surgeon operated because of radiographic evidence of residual disease; and (4) not stated. We divided the decision not to proceed with PRND into 7 categories: (1) surveillance, where the patient achieved a cCR; (2) nonadherence, where the patient refused a recommended PRND; (3) N0 to N2a nodal disease; (4) comorbidity that precluded surgery; (5) myocardial infarction during or after radiotherapy that precluded surgery; (6) failure to thrive after radiotherapy that precluded surgery; and (7) not stated. Patient comorbidity burden was approximated using a modified Charlson Comorbidity Index.26 Time to events for LC, RC, locoregional control, freedom from distant metastasis (FFDM), PFS, and OS was determined from the last day of radiotherapy. Patterns of local, regional, or distant failure were documented as sites of first failure. The RC was calculated for regional-only failure. The LC and FFDM were determined as failure with any component of local or distant failure, respectively. Of the 176 patients with N2b or greater nodal disease, 9 received radiotherapy alone, 18 received induction chemotherapy followed by radiotherapy, and 149 received concurrent chemoradiation. For the patients receiving concurrent chemoradiation, 69 received paclitaxel, hydroxyurea, and fluorouracil with radiation alternating in a week-on/week-off schedule, 58 received platinum-based chemotherapy, and 22 received other systemic agents.
Statistical analysis was performed using JMP statistical software, version 9 (SAS Institute Inc). All tests of statistical significance were 2-sided, and significance was defined as P < .05. To compare differences between groups, the χ2 test was used for discrete variables and the t test for continuous variables. Survival estimates were obtained using the Kaplan-Meier method. All events were calculated using standard life table methods, and the differences were compared using Cox proportional hazards regression models. Positive predictive values (PPVs), NPVs, and accuracy of PTI were assessed in PRND patients regardless of length of follow-up (n = 83). Survival analysis was performed for both patients with stage III to IVB disease and those with advanced nodal disease at presentation (defined as N2b or greater). Cox proportional hazards regression multivariate analysis was performed to adjust for explanatory confounding prognostic factors, including all variables with significance on univariate analysis (P < .10) and those that are known to affect outcomes in HNSCC.
Median follow-up was 25.4 months for all patients. The median time to PTI was 5.0 weeks for those who underwent PRND and 6.9 weeks for those who did not (P < .001). Baseline characteristics for those with advanced-stage HNSCC are included in Table 1. In general, groups were balanced for sex, Karnofsky Performance Status, comorbidities, and alcohol or tobacco use. Patients who underwent PRND were younger (53.3 vs 56.9 years; P = .04), had more advanced disease (stage IVA/B: 91.9% vs 77.4%; P = .01), and had more oropharyngeal (46.0% vs 29.1%; P = .007) and fewer laryngeal primary tumors (16.2% vs 20.7%). Patients undergoing PRND also had more advanced nodal disease at presentation (P < .001) but less locally advanced primary tumor stage (P = .05). Chemoradiation, either induction or concurrently, was used more frequently in the PRND group (98.7% vs 93.0%; P = .04). Finally, radiotherapy delays were more frequent in non-PRND patients.
Of the 74 patients undergoing PRND, 89.2% underwent a modified radical neck dissection or a selective neck dissection. For patients undergoing a selective neck dissection, the most common nodal levels removed were levels II and III (n = 8) followed by levels I to III (n = 6) and II to IV (n = 4).The most common reason to proceed with PRND was per protocol (44.6%; n = 33), where patients had a cCR on imaging and physical examination. The most common reason for patients with N2b or greater nodal disease to avoid PRND was surveillance. A median of 16.5 (interquartile range, 9-24) nodes were resected. Twenty-three patients had residual disease, with a median of 1 involved node (interquartile range, 1-8). Nine patients had multiple involved nodes, and 4 had greater than 3 cm of residual disease. For all patients with radiographic evidence of disease on PTI, 21 and 11 patients had pathologic positive and negative lymph nodes on PRND, respectively. For all patients without radiographic evidence of disease on PTI, 4 and 47 patients had pathologic positive and negative lymph nodes on PRND, respectively. For all patients, the PTI PPV was 63.6%, the PTI NPV was 92.2%, and the accuracy was 81.9%. For patients with N2b or greater nodal disease with radiographic evidence of disease on PTI, 18 and 8 patients had pathologic positive and negative lymph nodes on PRND, respectively. For patients with N2b or greater nodal disease without radiographic evidence of disease on PTI, 4 and 41 patients had pathologic positive and negative lymph nodes on PRND, respectively. For patients with N2b or greater nodal disease, the PTI PPV was 69.2%, the PTI NPV was 91.1%, and the accuracy was 83.0%.
Patients with advanced nodal disease (N2b or higher; n = 176) experienced improved PFS with PRND (74.6% vs 39.1%; P < .001), whereas those with N2a or less nodal disease did not (60.0% vs 68.2%; P = .98; Figure 1). Patients with N2b or higher nodal disease undergoing PRND had superior LC (85.5% vs 53.5%; P < .001), FFDM (79.5% vs 67.5%; P = .03), locoregional control (78.9% vs 45.7%; P < .001), and OS (84.5% vs 61.7%; P = .004) but similar RC. The benefit for PRND persisted for those with negative posttreatment scans (n = 103) despite the high NPV in our data set (Figure 2). In patients with a cCR by PTI, PRND continued to be associated with improved LC (87.4% vs 66.2%; P = .02) and PFS (80.7% vs 53.4%; P = .01). As shown in Figure 3, the effect of PRND on LC and/or PFS persisted across multiple disease sites, including the hypopharynx (2-year PFS: 63.6% vs 18.5%; P = .02); larynx (2-year PFS: 88.9% vs 51.3%; P = .03), oral cavity (2-year LC: 80.0% vs 35.6%; P = .01), and oropharynx (2-year OS: 88.5% vs 35.6%; P = .01; and 2-year PFS: 85.2% vs 38.5%; P = .001).
On univariate analysis, PRND, nodal stage, chemoradiation, and alcohol history significantly affected 2-year LC and/or PFS (Table 2). These factors and those known to affect outcomes in HNSCC were included on multivariate analysis. Table 3 details pertinent findings on multivariate analysis for PRND in terms of LC, FFDM, PFS, and OS. Importantly, PRND remained strongly prognostic for 2-year LC (hazard ratio, 0.22; 95% CI, 0.07-0.54; P < .001) and PFS (hazard ratio, 0.42; 95% CI, 0.23-0.74; P < .002). No statistically significant differences were found in outcomes between the oropharyngeal and nonoropharyngeal sites.
The rates of late toxic effects did not reach statistical significance for any differences between the PRND and non-PRND groups, including the need for permanent feeding tube (47.3% for PRND vs 37.1% for no PRND; P = .13), tracheostomy tube (27.0% for PRND vs 19.3% for no PRND; P = .19), and osteoradionecrosis (10.8% for PRND vs 9.4% for no PRND; P = .20).
We found that PRND improved control at nonnodal disease sites in patients with advanced nodal disease who achieved a cCR after chemoradiation. Furthermore, advanced nodal stage correlated with decreased PFS in the absence of PRND. This increase in LC for the PRND group was not likely due to poor imaging technique because the NPV for CT-based cCR was 91.1% in this series and consistent with previous articles.4,6,15,19,20 Furthermore, improved LC occurred despite cCR at the primary site on initial posttherapy imaging and clinical examination. Therefore, it is unlikely that locally persistent disease would preferentially occur in the non-PRND group. By contrast, patients with less advanced nodal disease at presentation (N0-N2a) had similar rates of PFS whether or not they underwent PRND, indicating that patients with limited nodal disease did not benefit from PRND. Thus, even with a cCR on imaging, PRND improved control at nonregional disease sites in patients with HNSCC and advanced nodal disease.
Lymph nodes are often the first sites of metastatic spread, and several groups have found that increasing lymph node positivity correlates with distant spread.2 In addition, several reports22- 25 have correlated lymph node positivity with increased rates of local failure, suggesting that lymph node metastases were a surrogate for locally aggressive disease. Several investigators found worse LC with advanced nodal disease in multiple head and neck sites and for both early and advanced T-stage tumors.22,24,25,27,28 In the absence of PRND, we found that patients with early nodal disease had better LC than patients with advanced nodal disease. Thus, increasing lymph node involvement adversely affects LC and DC.
Fewer reports have addressed whether clearance of initially involved cervical lymphatics affect local or distant disease. Demonstrating that nodal control affects LC, Wall et al25 reported that when the neck was controlled, LC was 65% to 80%, but when cancer recurred in the neck, LC decreased to 20% to 40%. Furthermore, Bernier and Bataini23 demonstrated that even with a cCR, patients with N2 nodal disease or greater had worse disease-free survival if they were observed after definitive treatment (75% for PRND vs 53% for observation). Only 2 of the 16 patients in whom treatment failed had nodal recurrence only. Compared with those in the PRND group in whom treatment did not fail (n = 8), Soltys et al11 demonstrated that 27% of patients who did not undergo PRND (n = 48) had disease recurrence; 2 patients had regional-only failed treatment, whereas 11 patients had treatment failure that involved other sites. Similarly, we observed that PRND decreased local treatment failures and trended to lower distant failures. Thus, our data and others suggest that clearance of involved lymphatics may affect disease control at nonregional sites.
By contrast, some groups have observed that cCR on imaging provides both high rates of RC and LC in the absence of PRND. With both CT and PET-CT, patients who achieved a cCR had LC rates of 85% or greater regardless of whether patients underwent PRND.3,6,14,17 However, in these series, 70% or more of the patients had oropharyngeal primary tumors, which is associated with improved LC, PFS, and OS that are often attributed to human papillomavirus (HPV) positivity.28,29 To this end, Shonka et al30 found that chemoradiation cleared 82% of involved lymph nodes in p16-positive (and likely HPV-positive) cancers compared with only 50% of p16-negative cancers. We rely on other studies to address the role of PRND for HPV-positive patients because, in our series, only 2 of the 60 cancers tested were positive for HPV. Therefore, because of our limited numbers of HPV-positive patients, our results suggesting a benefit of PRND on nonregional control likely apply to HPV-negative HNSCCs.
Studies31- 33 in other disease sites also suggest that increasing lymph node positivity adversely affected LC. For example, Stock et al33 demonstrated that early-stage cervical cancer had increased rates of local failure when regional nodes were involved. Similarly, in non–small cell lung cancer, increasing numbers of involved lymph nodes portended worse LC, with 50% of the failures occurring at the bronchial stump.32 In rectal cancer, addressing regional lymph nodes with pelvic radiotherapy and total mesorectal excision resulted in improved LC (3%) compared with total mesorectal excision surgery alone (11%) or non–total mesorectal excision surgery with radiotherapy (11%).34,35 Thus, in many types of cancer, lymph node involvement inversely correlated with LC, and effectively clearing regional disease may improve outcomes at nonregional sites.
We can only postulate as to the mechanism by which removal of nodal disease affected LC. Such mechanisms may include the biology of the tumor, immunologic consequences of compromised lymphatics, or other mechanisms. The beneficial effect of PRND may be more apparent in tumors that are less responsive to treatment and, therefore, inherently more likely to recur. Regional disease may act as a surrogate or even cause immune dysfunction that might be restored when the involved nodes are removed. In patients with head and neck cancer, tumor-infiltrating lymphocytes or lymph node lymphocytes were deficient in cytotoxic effector cells compared with the peripheral blood.36 Furthermore, CD8+ T cells in both hyperplastic and metastatic lymph nodes showed diminished responses to mitogenic stimuli.37 Similar immune dysfunction was observed in breast cancer lymph nodes and predicted worse outcomes.38 In preclinical models, lymph node metastasis induces immunologic tolerance due to inadequate costimulation.39 It is tempting to speculate that surgical clearance of these dysfunctional lymph nodes may improve systemic immune responses. Such a benefit would persist for those in cCR despite disease sterilization as demonstrated in this series. Indeed, Ma et al40 demonstrated that immune dysfunction in patients with HNSCC recovered after lymph node dissection but not radiotherapy. Finally, others have proposed that reseeding of the primary tumor from regional lymph node metastases might be important for LC.41 Therefore, PRND may have improved outcomes for tumors through clearance of involved lymphatics, which may restore immune function or prevent reseeding of the primary tumor.
Postradiotherapy neck dissection may increase morbidity and thereby negate any therapeutic benefit. Although patients undergoing PRND trended to an increased risk of tracheostomy, they did not have significantly increased risks of feeding tubes or osteoradionecrosis in our experience. Caution is warranted because PRND was associated with increased morbidities in some series. For example, Narayan et al16 observed that PRND was associated with significant complications in 17% of patients requiring either subsequent operation or long-term medical treatment. Therefore, patients who might benefit from PRND need to be carefully selected to derive meaningful therapeutic benefit.
Limitations of the current analysis include the retrospective nature and potential bias in selecting patients for PRND. Although we used CT-based imaging, our NPV was 91.1%, which is similar to the NPV of 86% to 100% for CT and PET-CT.6,13,15 Our regional control without PRND was similar to those reported in previous articles,3,5,6,9,11,20 even though our study had a lower incidence of oropharyngeal primary tumors compared with other series. In our series, patients undergoing PRND had a greater proportion of oropharyngeal primary tumors and fewer T4 tumors, factors that affect LC. Addressing this issue, we observed no difference in LC when comparing oropharyngeal and nonoropharyngeal primary tumors (2-year LC: 68.6% for oropharyngeal primary vs 64.2% for nonoropharyngeal primary; P = .41). Furthermore, PRND still benefited patients with T3 to T4 tumors with N2b or greater nodal disease and a cCR after chemoradiation (2-year LC: 87.5% for PRND vs 73.2% for non-PRND; P = .04). Furthermore, PRND remained the only significant factor on multivariate analysis predicting for improved LC and PFS. In addition, given that induction chemotherapy was more common in patients undergoing PRND, the extent to which this neoadjuvant approach affected disease control remains unclear. Nevertheless, induction chemotherapy was not significant for locoregional control or PFS on multivariate analysis, which is consistent with other studies.42 Finally, our study was limited by the relatively short follow-up time, and we await updated results with longer follow-up times. Thus, the effect of PRND remains robust after accounting for several variables that may affect LC or DC.
In conclusion, we identified a hypothesis-generating observation where PRND may improve LC and likely DC. The benefit of PRND on nonregional sites of disease persisted for patients with a cCR on imaging that had high predictive values. Currently, it remains unclear which patient, tumor, and molecular characteristics may predict improved LC with a PRND after a cCR. We propose that PRND should be reevaluated for patients with HPV-negative cancers and extensive nodal disease. Nevertheless, any potential benefit in PRND should be balanced with the increased morbidity after the procedure. Although these observations contradict the current trends in the treatment of patients achieving a cCR, our results suggest that addressing metastatic lymph nodes may play a larger role than just the regional control of disease.
Submitted for Publication: May 30, 2013; final revision received September 14, 2013; accepted September 30, 2013.
Corresponding Author: Michael T. Spiotto, MD, PhD, Department of Radiation and Cellular Oncology, The University of Chicago, Knapp Center for Biological Discovery 6142, 900 E 57th St, Chicago, IL 60637 (firstname.lastname@example.org).
Published Online: November 21, 2013. doi:10.1001/jamaoto.2013.5754.
Author Contributions: Dr Spiotto had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Spiotto.
Acquisition of data: Spiotto, Abundo, Jefferson.
Analysis and interpretation of data: Ranck, Kolokythas, Wenig, Weichselbaum, Spiotto.
Drafting of manuscript: Ranck, Abundo, Weichselbaum, Spiotto.
Critical revision of the manuscript for important intellectual content: Ranck, Jefferson, Kolokythas, Wenig, Weichselbaum, Spiotto.
Statistical analysis: Ranck, Spiotto.
Administrative, technical, and material support: Abundo, Wenig, Weichselbaum, Spiotto.
Study supervision: Weichselbaum, Spiotto.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study is supported by a grant from the Fanoni Anemia Research Foundation (Dr Spiotto) and the Burroughs Wellcome Career Award for Medical Scientists (Dr Spiotto).
Role of the Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Previous Presentation: This study was presented at the Annual Meeting for the American Society for Therapeutic Radiation Oncology; September 23, 2013; Atlanta, GA.