Published online 28 September 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed.23173

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1 ORIGINAL ARTICLE Residual nodal disease in patients with advanced-stage oropharyngeal squamous cell carcinoma treated with definitive radiation therapy and posttreatment neck dissection: Association with locoregional recurrence, distant metastasis, and decreased survival Vlad C. Sandulache, MD, PhD, 1 Thomas J. Ow, MD, 2 Shiva P. Daram, BS, 2 Jackson Hamilton, MD, 3 Heath Skinner, MD, PhD, 4 Diana Bell, MD, 5 David I. Rosenthal, MD, 4 Beth M. Beadle, MD, PhD, 4 K. Kian Ang, MD, PhD, 4 Merrill S. Kies, MD, 6 Faye M. Johnson, MD, PhD, 6 Adel K. El-Naggar, MD, PhD, 5 Jeffrey N. Myers, MD, PhD 2 * 1 Bobby R. Alford Department of Otolaryngology Head and Neck Surgery, Baylor College of Medicine, Houston, Texas, 2 Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, 3 Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 4 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, 6 Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Published online 28 September 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in frequency. We reviewed patients with advanced-stage OPSCC treated with chemoradiation to assess the impact of residual neck disease on survival. Methods. We reviewed 202 patients with OPSCC between 1990 and 2010 treated with primary chemoradiation followed by neck dissection. Imaging was analyzed using RECIST (Response Evaluation Criteria In Solid Tumors) 1.1 criteria. Survival was evaluated using both univariate and multivariate analyses. Results. Overall survival at 5 years was 89%. Forty-two patients (21%) had residual disease in the neck (pnþ). pnþ was associated with greater locoregional recurrence (LRR) and distant metastasis (DM) and decreased survival. No clinicopathologic factors were predictive of pnþ. Contrasted posttreatment CT had low sensitivity and specificity. Conclusions. In advanced OPSCC pnþ, patients have higher rates of LRR and DM. Neither clinicopathologic factors nor posttreatment imaging was predictive of pnþ, although increased use of modern imaging may reduce the rate of negative neck dissections. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: oropharynx, radiation, neck dissection, HPV, recurrence INTRODUCTION Head and neck squamous cell carcinoma affects over 40,000 patients annually in the United States. 1 As opposed to other head and neck subsites, squamous cell carcinoma in the oropharynx (OPSCC) is increasing in frequency, with an increased proportion of younger patients who are nonsmokers and are human papillomavirus (HPV) positive. 2 5 Definitive radiotherapy with or without systemic therapy is the mainstay of treatment for OPSCC Despite significant refinement of the delivery, dosing, and fractionation of external beam radiation for this disease during the last 3 decades, up to 30% to 40% of patients can have persistent or recurrent disease in regional lymph nodes Although planned neck dissection following definitive radiotherapy has been considered standard of Deceased *Corresponding author: J. N. Myers, Department of Head and Neck Surgery, University of Texas MD Anderson Cancer Center, Houston, Texas. jmyers@mdanderson.org Contract grant sponsor: National Institutes of Health/National Cancer Institute/ National Research Science Award Research Training; contract grant number: T32 CA care in the past, data suggest that patients who have a complete clinical and radiographic response to primary nonsurgical treatment can be observed without neck dissection and followed with imaging studies. 17,18 This change in practice is in part due to improved imaging modalities used for restaging and/or surveillance as well as evidence suggesting that patients with HPV-positive tumors tend to have a favorable response to treatment. 3,4,19 Nevertheless, it is still recommended that patients with evidence suggestive of persistent cervical nodal disease after radiation should undergo regional lymphadenectomy. Although it is generally accepted that patients with pathologic evidence of persistent disease after neck dissection are at higher risk for local, regional, or distant failure, 11,13,15,16 existing studies have failed to conclusively identify clinical parameters that correlate with an increased risk of residual viable tumor in cervical lymph node specimens after radiation treatment. 11,13,15,16 Despite multiple studies, the utility of a CT scan in predicting pathologic response after radiation or chemoradiation remains inconclusive. 6 Increased use of [ 18 F]fluorodeoxyglucose positron emission tomography (FDG PET) and PET CT have been advocated extensively in the last decade, and reports suggest that these tools can improve upon the ability of both clinical exam 1454 HEAD & NECK DOI /HED OCTOBER 2013

2 RESIDUAL NODAL DISEASE AND SURVIVAL IN OROPHARYNGEAL SCC and high-resolution CT to predict the presence of residual neck disease after definitive radiotherapy We hypothesize that despite improvements in chemoradiotherapy clinical protocols and increased use of posttreatment imaging, residual disease in the neck remains an important predictor of decreased survival, locoregional control, and distant metastasis (DM). To test this hypothesis, we reviewed survival and recurrence outcomes in a contemporary cohort of patients with stage III and IV OPSCC treated with radiation or chemoradiation followed by neck dissection. Clinical factors and available imaging modalities were evaluated to determine if there was concordance between clinical risk factors, imaging findings, and pathologically confirmed neck disease. MATERIALS AND METHODS Patients Following approval of The University of Texas MD Anderson Cancer Center Institutional Review Board, we reviewed all patients with previously untreated stage III or stage IV (American Joint Committee on Cancer [AJCC]) OPSCC (sites included tonsil, base of tongue, soft palate, glossopharyngeal sulcus, oropharyngeal wall) treated at MD Anderson Cancer Center between January 1, 1990, and December 31, 2010, who received primary treatment with radiation therapy or chemoradiotherapy followed by neck dissection. Exclusion criteria included second primary, previous treatment of disease, or incomplete treatment. Those patients treated with chemotherapy received either induction or concurrent therapy or both. Radiation therapy was carried out at the MD Anderson. The median radiation dose was 70 Gy (range, Gy). Following completion of radiation therapy, patients were evaluated clinically and radiographically for the presence of residual disease in the neck. Patients underwent neck dissection based on suspicion for residual disease as assessed by the treating radiation oncologist and head and neck surgeon, the latter of whom determined the extent of neck dissection in each case. Thus, the decision to perform a neck dissection was a result of pretreatment disease characteristics and posttreatment evaluation, and was ultimately a decision based on the assessment of the treating physicians. Due to the retrospective nature of this review and the number of treating physicians involved at MD Anderson, the exact criteria for each clinical decision to perform a neck dissection could not be clearly ascertained. Each neck dissection specimen was reviewed by a trained head and neck pathologist, and pathology reports were reviewed to establish either the presence or the absence of residual, viable tumor in the neck. Demographic information was recorded, including age, sex, race, smoking history, and alcohol consumption. Clinicopathologic features were evaluated including clinical stage in accord with the American Joint Committee on Cancer (AJCC) staging system and tumor grade of initial biopsy specimens. Results of diagnostic procedures, including imaging results and fine-needle aspirations were recorded, as well as the treatments rendered and the associated dates. Operative notes were reviewed, and the extent of neck dissection was recorded. Pathology reports were reviewed, and the presence and location of residual disease were also recorded. A subset of pathologic specimens readily available for additional analysis at the time this study was undertaken. These samples were evaluated forhpvstatususinginsituhybridization(ish)andp16 overexpression using immunohistochemistry (IHC) by a trained clinical pathologist (D.B.). In addition to reviewing the original radiology reports for 194 posttreatment CT scans, pre- and postoperative contrast-enhanced CT scans were evaluated by a head and neck trained radiologist (J.H.) blinded to the clinical outcomes using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria for lymph nodes. 22 Complete response (CR) was defined as regression of all nodal lesions to <10 mm in short-axis diameter. Partial response (PR) was defined as the measurable decrease in lymph node size by 25% or greater; progressive disease (PD) as an increase in lymph node size by 25%; and stable disease (SD) as changes of less than 25%. Study endpoints and statistical analysis Endpoints included time to locoregional recurrence (LRR), the development of DM, and death. Time to recurrence (locoregional or distant) was defined as the interval between date of diagnosis and date of biopsy-proven recurrence. In the absence of a pathologic report documenting recurrence, imaging was used as a surrogate. Disease-free survival (DFS: date of primary diagnosis to date of recurrence) and overall survival (OS: date of recurrence to last documented hospital note) were recorded as well. Patients suspected of recurrence were restaged using clinical exam and imaging. Recurrences after were diagnosed by biopsy (35 patients) or imaging (7 patients). Persistent disease was defined as biopsy-proven squamous cell carcinoma identified in a region of the initial disease less than 1 year postinitiation of definitive treatment. Recurrent disease was definedasbiopsy-provenopsccbetween1and5yearsafter initiation of definitive treatment. Actuarial survival rates were generated using the Kaplan Meier method, and comparisons between groups were made using log-rank statistics. Multivariate analysis was performed using forward stepwise Cox regression. Analysis variables included: patient age, sex, tobacco use, T classification, N classification, and the presence or the absence of residual disease at the time of neck dissection. All variables with p.1 on univariate analysis were used for multivariate analysis. Statistical calculations were performed with an SPSS software package (v. 16.0, SPSS, Inc., Chicago, IL). For all statistics, values of p were considered to be statistically significant if below a threshold of <.05 (2-sided). RESULTS Patient characteristics and treatment Table 1 summarizes relevant patient and treatment characteristics. A total of 210 patients were evaluated, with a mean age at diagnosis of 55.3 years and a male-to-female ratio of approximately 9:1. Median follow-up was 5 years (range, years) (Table 1). Primary tumors most commonly arose in the tonsil and base of tongue subsites, HEAD & NECK DOI /HED OCTOBER

3 SANDULACHE ET AL. TABLE 1. Summary of patient and treatment characteristics. Patient characteristics No. (%) Treatment summary Mean Median Total 210 Radiation dose, Gy Mean age, y (range) 55.31( ) Radiation course, days No. (%) Sex Induction chemotherapy Male % Concurrent chemotherapy Female % Induction þ concurrent chemotherapy Site No chemotherapy Tonsil % Mean Median Base of tongue % Follow-up, y Glossopharyngeal sulcus 6 2.9% Diagnosis to start of radiation, days Softpalate 4 1.9% Oropharyngeal wall 3 1.4% End radiation to neck dissection, days Tumor characteristics No. (%) Neck dissections Dissected Heminecks Positive T Classification Level Tx T T T T N classification N N2a N2b N2c N Stage III IV with fewer than 6.2% of tumors presenting on the soft palate, oropharyngeal wall, or glossopharyngeal sulcus. Equivalent patient numbers were treated with concurrent chemotherapy versus radiation only (86 and 85, respectively). Sixteen patients received induction chemotherapy followed by radiotherapy (XRT) and 23 patients received induction chemotherapy followed by chemo-xrt (Table 1). All 210 patients underwent neck dissection after definitive treatment was completed. Seven patients received bilateral neck dissections. The most commonly dissected levels were II and III. Residual disease was most commonly found in levels II, III, and IV (Table 1). (p ¼.11) compared with patients receiving radiotherapy alone, although this group presented with more advanced T and N classifications at the time of Survival outcomes Of 210 patients treated with definitive radiotherapy followed by neck dissection, 8 patients were removed from subsequent analysis because they had an extended disease-free interval between the end of radiation and the time of subsequent neck dissection (180 days or more). Among the 202 remaining patients, overall survival at 5 years was 89%, with 76% of patients free from disease progression/recurrence at 5 years (see Figure 1). A total of 42 patients (21%) were found to have pathologically confirmed residual disease in the neck, resulting in a locoregional control rate of 79% for all patients. Concurrent chemotherapy was not associated with improved disease-free (p ¼.31) or overall survival FIGURE 1. Overall (A) and disease-free (B) survival in the patient cohort studied. Overall (C) and disease-free (D) survival with stratification into patients with (pnþ) andwithout(pn ) residual disease. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] 1456 HEAD & NECK DOI /HED OCTOBER 2013

4 RESIDUAL NODAL DISEASE AND SURVIVAL IN OROPHARYNGEAL SCC TABLE 2. Survival Summary of clinical outcomes for pn1 and pn patients. No (%) by pathologic N classification pnþ Total no. (%) diagnosis, compared with the patients who did not receive chemotherapy. Persistent or recurrent regional disease is associated with decreased progression-free survival A total of 42 patients (21%) were found to have pathologically confirmed residual disease in the neck (pnþ) at pn Overall survival No evidence of disease 26 (54.2) 136 (84.0) Alive with disease 8 (16.7) 6 (3.7) Died with disease 8 (16.7) 12 (7.4) Died with other CA 0 (0.0) 4 (2.5) Died unknown reasons 0 (0.0) 1 (0.6) Disease-free survival Total noncure 19 (45.2) 24 (15.0) 43 (21.3) Persistent dx (<1 y) 7 (16.7) 7 (4.4) 14 (6.9) Recurrence (1 5 y) 12 (28.6) 17 (10.6) 29 (14.4) Abbreviations: CA, cancer; dx, disease. the time of neck dissection; 54% of these patients were alive at last contact, compared with 84% of patients that had no pathologically involved lymph nodes in their neck dissection specimens (pn ) (p ¼.075). Eight of 48 pnþ patients (17%) were alive with disease at last contact, compared with 5 of 162 pn patients (3.1%) (Table 2). Patients in the pnþ group had shorter disease-free survival (p <.001) (Figure 1, Table 2). Cox proportional hazards ratios were used to evaluate the association of T and N classifications, sex, age, tobacco use, and residual disease in the neck with LRR, the development of DM, disease-free and overall rates of survival (Table 3). T classification was strongly associated with decreased overall survival, whereas residual disease in the neck was the only variable significantly associated with decreased disease-free survival. Closer inspection showed that pnþ was associated with an increased rate of LRR as well as development of DM disease (Table 3). Multivariate analysis using stepwise Cox regression was conducted on 163 patients using collapsed T (T1 T2 and T3 T4) stage, residual disease in the neck, and tobacco use. T classification remained a significant factor associated with overall survival, whereas residual disease in the neck remained strongly associated with decreased disease-free survival. TABLE 3. Univariate and multivariate analyses were conducted using listed variables with targets of overall and disease-free survival, locoregional, and distant failure. Univariate analysis Multivariate analysis Variable Comparison p value Variable Comparison p value Overall survival Overall survival Nodal status post-xrt Negative vs positive.08 Nodal status post-xrt Negative vs positive.18 Tumor classification T1 2vsT Tumor classification T1 2vsT Nodal classification N1 N2b vs >N2b.92 Tobacco use Current/former vs never.10 Tobacco use Current/former vs never.08 Age, y <55 vs Sex Female vs male.31 Disease-free survival Disease-free survival Nodal status post-xrt Negative vs positive.00 Nodal status post-xrt Negative vs positive.00 Tumor classification T1 2vsT Tobacco use Current/former vs never.09 Nodal classification N1 N2b vs >N2b.62 Tobacco use Current/former vs never.08 Age, y <55 vs Sex Female vs male.40 Locoregional failure Locoregional failure Nodal status post- XRT Negative vs positive.00 Nodal status post-xrt Negative vs positive.00 Tumor classification T1 2vsT Nodal classification N1 N2b vs >N2b.48 Tobacco use Current/former vs never.09 Age, y <55 vs Sex Female vs male.41 Distant failure Distant failure Nodal status post-xrt Negative vs positive.00 Nodal status post-xrt Negative vs positive.00 Tumor classification T1 2vsT Nodal classification N1 N2b vs >N2b.95 Tobacco use Current/former vs never.36 Age, y <55 vs Sex Female vs male.69 Note: Significance was observed for T classification for overall survival and nodal status for disease-free survival. Nodal status was negatively associated with locoregional failure and distant failure on both univariate and multivariate analyses. HEAD & NECK DOI /HED OCTOBER

5 SANDULACHE ET AL. TABLE 4. Univariate analysis by linear regression was used to ascertain whether any of the listed variables were associated with residual disease in the neck. Variable Comparison p value Tumor stage T1 2vsT Nodal stage N1 N2b vs >N2b.11 Tobacco use Current/former vs never.18 Age, y <55 vs Clinicopathologic factors associated with residual disease in the neck Four parameters (T and N classifications, chemotherapy use, and tobacco use) were evaluated using linear regression to determine if any of these factors were significantly associated with the presence or the absence of residual disease in the neck (Table 4). Although T and N classifications approached significance, none of the tested parameters was predictive of residual disease in the neck. The rates of residual disease in the neck after radiation for N1, N2, and N3 disease were 35%, 17%, and 30%, respectively, and increased clinical N classification at diagnosis was not associated with the presence of residual disease in the linear regression analysis. Recurrence patterns following definitive radiotherapy for OPSCC A total of 43 patients experienced persistent or recurrent disease following treatment with curative doses of radiation followed by neck dissection. Of these patients, 18 developed LRR, 24 developed DM, and 1 patient developed both (Table 5). No significant differences were noted in the recurrence patterns of pnþ and pn patients. Postradiotherapy imaging did not predict residual disease in the neck The initial radiology reports for 194 posttreatment-contrasted CT scans were evaluated to determine the ability of postradiotherapy imaging to predict residual disease in the neck. Correlation of posttreatment CT scans with the results of neck dissections demonstrated a sensitivity of TABLE 5. Patterns of persistent disease and/or recurrence following curative doses of radiotherapy followed by neck dissection. Disease patterns Locoregional Distant Both Neck Total Persistent dx (<1 y) Recurrence (1 5y) pnþ Persistent dx (<1 y) Recurrence (1 5y) pn Persistent dx Recurrence (1 5y) pnþ indicates patients with residual disease in the neck at the time of neck dissection, and pn indicates patients free of residual disease in the neck at the time of neck dissection. 58%, a specificity of 48%, positive predictive value (PPV) of 80%, and negative predictive value (NPV) of 24%. A concurrent analysis of PET CT results is being conducted as part of a search for improved imaging algorithms. Only 28 posttreatment PET scans were available for this patient cohort. Sensitivity, specificity, NPV, and PPV were comparable with those of contrasted CT posttreatment CT scans (J. Hamilton, unpublished data). To correct for interreviewer variability, a subset of 145 patients with available pretreatment and posttreatment contrast-enhanced CT scans were reviewed by a trained head and neck radiologist (J.H.) blinded to clinical outcomes (Table 6). Among patients with pathologic residual disease in the neck, 42% of patients were determined to have had a CR based on posttreatment CT, resulting in a sensitivity of 58%. Among patients determined to be pn, 60% were thought to have had residual disease, classified as PR or SD by RECIST 1.1 CT criteria, resulting in a specificity of 40%. Although NPV was high (81%), PPV was low (17%). Among 14 patients deemed to have SD by CT, 86% were found to be pn. Together these data demonstrate that, although a finding of complete response per CT using RECIST criteria has a high likelihood of resulting in a negative neck dissection, CT cannot reliably predict the presence of residual disease in the neck. HPV1 tumors exhibit a lower rate of residual disease in the neck An increase in the incidence of OPSCC has been linked to the increased presence of HPV. Although prospective HPV testing by p16 IHC and HPV ISH is rapidly becoming standard of care at most institutions, the cohort reviewed here did not undergo routine testing. A total of 16 diagnostic primary site biopsies and 15 neck dissection samples were available for HPV testing. Of these, 11 were HPVþ/p16þ, 10 were HPV /p16þ, and 10 were HPV /p16. Although small, these numbers suggest that a significant percentage of the tumors in this cohort are in fact HPV positive. Overall, too few patients were available for analysis to conclusively determine whether HPV status correlated with overall and disease-free survival in this patient cohort. DISCUSSION We evaluated the impact of pathologic nodal (pn) status in patients treated for stage III or stage IV OPSCC TABLE 6. Results for CT with contrast were evaluated using RECIST 1.1 criteria. CT result pnþ pn Total Non-CR PR SD CR Total Abbreviations: RECIST, Response Evaluation Criteria in Solid Tumors; CR, complete response in the neck by CT imaging criteria; PR, partial response; SD, stable disease; pnþ indicates patients with residual disease in the neck at the time of neck dissection, and pn indicates patients free of residual disease in the neck at the time of neck dissection HEAD & NECK DOI /HED OCTOBER 2013

6 RESIDUAL NODAL DISEASE AND SURVIVAL IN OROPHARYNGEAL SCC with primary radiotherapy with or without chemotherapy followed by neck dissection. Overall, the locoregional control rate in 202 patients treated in this manner was found to be 80% at 5 years. Residual disease in the neck (pnþ) was identified in 20% of patients following definitive nonsurgical treatment. The finding of positive lymph nodes in the neck dissection is associated with decreased overall survival, as well as higher rates of LRR and DM, consistent with previous reports. 12,15,16 Among all tested clinical variables, only residual disease in the neck and T classification were predictive for reduced disease-free survival on multivariate analysis. These data are largely in agreement with prior studies by our group and others that typically included smaller patient cohorts. 11,12,15,16 Patterns of recurrence after definitive radiotherapy/chemoradiation followed by neck dissection were equally divided between locoregional and distant disease. Disease progression to distant sites may reflect the need for a trial of systemic adjuvant treatment for patients found to have pnþ disease. In this patient cohort, the addition of concurrent chemotherapy did not positively influence survival. However, patients receiving concurrent treatment were not matched by T or N classification to those who did not receive concurrent chemotherapy. The presence of residual disease in the neck did not significantly affect the ratio between locoregional and distant disease progression, which is puzzling given its profound effect on survival outcomes and rates of recurrence/progression. It is important to note that our study design, which excludes patients that did not undergo post-xrt neck dissections, represents one of the potential limitations of our analysis. By not evaluating recurrence rates and survival outcomes in the excluded patients there exists a potential bias toward increased importance of post-xrt neck dissection. Indeed, this cohort of patients underwent neck dissections based on clinical judgment, post-xrt clinical exam, and imaging findings as opposed to a standardized institutional protocol; thus, this group is likely inherently enriched for patients at higher risk for residual disease in the neck. Our intent was to retrospectively study this group that was at the highest risk of treatment failure who had pathologically confirmed positive neck dissection specimens available in an effort to identify which clinicoradiologic factors were most predictive of positive disease in this group of patients. Nevertheless, despite a large cohort size and relative uniformity within the patient population, we did not identify clinical predictors of residual disease in the neck. These results are concerning, particularly given that a larger patient cohort should provide increased discriminatory ability. 12,15,16 The lack of clinical predictors of residual disease in the neck described here as well as in previous studies remains an important clinical dilemma. It is clear that a planned neck dissection paradigm is not supported by outcome measures and morbidity data. However, to date, there exists no clinical paradigm for predicting which patients will benefit from a postradiotherapy neck dissection. Initially, it was hoped that improved imaging modalities would ameliorate this problem. Data from recent studies on both CT and PET/CT are mixed. 23 In 2002, Ojiri and colleagues 6 suggested that posttreatment restaging using CT can reach a sensitivity and negative predictive value of 100%. These results have been reproduced by more recent studies. 12,14 In our patient cohort, using RECIST 1.1 criteria to evaluate the CT data, the NPV of posttreatment CT was 81%. This value is likely more representative of the low disease prevalence than the accuracy of absolute nodal size as the only criterion for predicting residual disease. Together with previous studies, our data suggest that postradiotherapy imaging can potentially reduce the rate of negative neck dissections, but fails to provide significant insight into patients at high risk for residual disease in the neck. Given the importance of pnþ on patient survival, failure of both pretreatment clinical parameters and imaging to predict pnþ status suggests that there continues to exist a role of planned post-xrt neck dissections. Inclusion of patients with complete clinical and radiographic responses in the neck as well as long-term follow-up data regarding local, regional, and systemic recurrence and survival in an ongoing follow-up study will likely enhance the sensitivity, specificity, and predictive values of clinical and imaging data such as those included in this report to predict which patients would benefit the most from a postradiation neck dissection. In recent years, the role of HPV in the development of OPSCC has been increasingly clarified. 5 A recent study by Shoushtari et al 24 suggests that patients with OPSCC whose tumors stain positively on immunohistochemistry for p16, a surrogate marker for high-risk HPV, have improved survival outcomes compared with their p16 counterparts, as well as lower rates of residual disease at the time of neck dissection. Our study was not specifically designed to evaluate clinical outcomes based on HPV status, and retrospective analysis was not feasible because only a limited number of specimens were available for HPV/16 testing. However, our data suggest that HPVþ tumors were highly represented in our patient sample, HPV status is maintained during treatment, and HPV tumors exhibit a higher rate of residual disease in the neck. CONCLUSIONS Among those with advanced OPSCC, a significant proportion (20%) of patients deemed to have incomplete responses to radiation/chemoradiation will have residual disease in the neck. These patients exhibit worse survival outcomes than those of pn patients, which appears to be a result of increased rates of both locoregional and distant recurrence. Despite recent advances, post-xrt CT cannot adequately predict residual disease in the neck in this disease setting, although it can reduce the rate of negative neck dissections. In our opinion, only prospective randomized trials can conclusively address the role of post-xrt neck dissection in the OPSCC patient population. These trials will require standardized, prospective collection of HPV status along with other known risk factors. Homogeneous treatment protocols with respect to XRT dosing and the use of induction and adjuvant chemotherapy should be designed. Finally, prospective imaging analysis using currently available algorithms needs to be incorporated and critically assessed, to clearly demonstrate the utility of such methods. HEAD & NECK DOI /HED OCTOBER

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