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PURPOSE To provide evidence-based recommendations to practicing physicians and other health care providers on the diagnosis and management of squamous cell carcinoma of unknown primary in the head and neck (SCCUP). METHODS The American Society of Clinical Oncology convened an Expert Panel of medical oncology, surgery, radiation oncology, radiology, pathology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 2008 through 2019. Outcomes of interest included survival, local and regional disease control, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 100 relevant studies to inform the evidence base for this guideline. Four main clinical questions were addressed, which included subquestions on preoperative evaluations, surgical diagnostic and therapeutic procedures, appropriate pathology techniques, and adjuvant therapy. RECOMMENDATIONS Evidence-based recommendations were developed to address preoperative evaluation for patients with a neck mass, surgical diagnostic and therapeutic procedures, appropriate treatment options in unilateral versus bilateral SCCUP. Additional information is available at www.asco.org/head-neck-cancer-guidelines .

The soft palate contributes to deglutition, articulation, and respiration. Current reconstructive techniques focus on restoration of both form and function. The unique challenges of soft palate reconstruction include maintenance of complex upper aerodigestive tract function, with minimal local or donor site morbidity.To review the literature on soft palate reconstruction and present an algorithm on how to approach soft palate defects based on this review.A review of the literature for articles reporting studies on and that described concepts related to soft palate reconstruction was conducted in March 2017. In all, 1804 candidate titles and abstracts were independently reviewed. English-language articles that discussed acquired soft palate defect reconstruction were included. Non-English language studies without available translations, studies on primary soft palate defect reconstruction (ie, cleft palate repair) and primary cleft palate repair, studies in which the soft palate was not the focus of the article, and studies involving animals were excluded.The following observations were made from the review of 92 included articles. Soft palate anatomy is a complex interplay of multiple structures working in a 3-dimensional area. Three of the authors created an initial algorithmic framework based on the selected studies. After this, a round table discussion among 3 authors considered experts was used to refine the algorithm based on their expert opinion. The 4 most important factors were determined to be defect size, defect extension to other subsites, defect thickness, and history of radiotherapy or planned radiotherapy. This algorithm includes both surgical and nonsurgical options. Defects in the soft palate not only affect the size and shape of the organ but, more critically, the function. The reconstructive ladder is used to help maximize the remaining soft palate functional tissue and minimize the effect of nonfunctional implanted tissue. Partial-thickness defects or defects less than one-fourth of the soft palate may not require locoregional tissue transfer. Patients with a history of radiotherapy or defects of up to 75% of the soft palate may require locoregional tissue transfer. Defects greater than 75% of the soft palate, defects that include exposure of the neck vasculature, or defects that include significant portions of the hard palate or adjacent oropharyngeal subsites may require free tissue transfer. Obturation should be considered a second-line option in most cases.Ideal reconstruction of the soft palate relies on a comprehensive understanding of soft palate anatomy, a full consideration of the armamentarium of surgical techniques, consideration for adjacent subsite deficits, and a detailed knowledge of various intrinsic and extrinsic patient factors to optimize speech, swallowing, and airway outcomes. The included algorithm may serve as a useful starting point for the surgeon when considering reconstruction.

To determine the prognostic role of extranodal extension (ENE) among patients with human papilloma virus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) through a systematic review and meta-analysis of institutional studies.MEDLINE, Embase, Scopus, and PubMed.Two independent authors searched the databases on December 3, 2019, to identify studies of HPV+ OPSCC comparing prognostic outcomes stratified by ENE. TheEighteen observational studies met inclusion criteria, yielding 3603 patients with HPV+ OPSCC (1521 ENE+ and 2082 ENE-) with a median follow-up of 49 months. The presence of pathologic ENE (pENE) and radiologic ENE (rENE) was associated with decreased overall survival (pENE HR, 1.89 [95% CI, 1.15-3.13],pENE and rENE are moderately associated with an increased risk of all-cause mortality and recurrence with distant metastasis in a cohort of patients with HPV+ OPSCC. These findings may be used to inform exclusion criteria for deintensification trials and assist in refined risk stratification.

The optimal management of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) with primary surgical versus non-surgical treatment is unclear. The objective of this systematic review was to evaluate the literature and compare survival for primary surgical versus non-surgical treatment of HPV-positive OPSCC. We performed a comprehensive literature search of multiple electronic databases for relevant articles up to February, 2017. Studies reporting mortality or hazard ratio (HR) for overall survival (OS) in primary HPV-positive OPSCC patients were eligible. Seventy-three articles were eligible, of which 66 included single-modality (19 surgical, 47 non-surgical), and 7 included both surgical and non-surgical modalities. There were no randomized studies comparing outcomes between both modalities. In a meta-analysis of both-modality studies, OS with surgical treatment was not significantly different from non-surgical treatment (pooled HR 1.12; 95% CI: 0.35, 3.57). There was significant heterogeneity between studies (I2 = 82.4%). Among single-modality studies, the mortality rate was lower with surgical [pooled proportion 0.15 (95% CI: 0.09, 0.21)] versus non-surgical treatment [0.20 (95% CI:0.15, 0.24)]. In a subgroup analysis, OS was higher for HPV-positive versus HPV-negative OPSCC, irrespective of the treatment modality. We conclude that there is an absence of high-quality studies that compare survival for HPV-positive OPSCC treated with primary surgical versus non-surgical approach. The available data suggest no statistical or clinically meaningful difference in survival between the two approaches. HPV-positivity was a key prognostic factor irrespective of treatment modality. Further high-quality studies with consistent data reporting are needed to inform the choice for optimal treatment modality for HPV-positive OPSCC.

Background Oncologic outcomes of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (SCC) requiring resection of major muscular or neurovascular tissue during neck dissection for invasive nodal disease remain uncertain. Methods Patients with HPV-related oropharyngeal SCC requiring resection of major muscular or neurovascular tissue during their neck dissections were retrospectively identified. Results Seventy-two patients were included. Regional and distant recurrences occurred in 6% and 17% of patients. Advanced T classification, pathological node number of 5 or more, and omission of adjuvant therapy were associated with decreased disease-free survival (DFS). The addition of adjuvant chemotherapy was not associated with improved survival. Conclusion Patients with invasive nodal disease from HPV-related oropharyngeal SCC can be managed with up-front surgery and adjuvant therapy, as indicated with good regional control. Although distant recurrence was the primary site of failure, adjuvant chemotherapy was not associated with improved outcomes. The T classification, node number, and adjuvant radiotherapy are independent prognostic factors in this patient population.

BACKGROUND The authors hypothesized that unilateral intensity-modulated radiotherapy (IMRT) would decrease toxicity compared with bilateral IMRT for patients with lateralized palatine tonsillar cancer and a neck classification of N0 to N2b, with similar oncological outcomes. METHODS A total of 154 patients were treated with postoperative IMRT from 1997 through 2013. Data were collected prospectively from 2005 to 2013 and retrospectively collected before 2005. Of those patients with lateralized primary and N0 to N2b disease, 48 received unilateral IMRT (group 1) and 59 received bilateral IMRT (group 2); a total of 47 patients had nonlateralized primary or N2c to N3 disease and received bilateral IMRT (group 3). RESULTS The median follow-up was 5.5 years. The 5-year locoregional control rates were similar in group 1, group 2, and group 3 (100%, 96%, and 94%, respectively; pooled comparison: P = .39 and group 1 vs group 2 comparison: P = .19). The 5-year overall survival rates were similar in group 1, group 2, and group 3 (85%, 79%, and 76%, respectively; pooled comparison: P = .60 and group 1 vs group 2 comparison: P = .25). There were no contralateral neck recurrences noted among unilaterally treated patients. Unilateral IMRT reduced acute toxicity and improved patient-reported quality of life compared with bilateral IMRT. CONCLUSIONS Unilateral IMRT appears to reduce acute toxicity and achieves oncological outcomes similar to those of bilateral IMRT in selected patients with lateralized palatine tonsillar cancer with a neck classification of N0 to N2b. Cancer 2017;123:4594-4607. © 2017 American Cancer Society.

Purpose The most common surgical method to remove benign parotid tumors remains the prograde approach. We examined if a retrograde surgical technique offers better outcomes than historical prograde controls. Materials and methods A retrospective chart review at Stanford Hospital was conducted to identify retrograde parotidectomies between February 2012 and October 2014 that were staffed by the senior author (DS) with resident involvement. Facial nerve (FN) outcomes and other post-surgical parameters were recorded. Results We identified 44 consecutive cases and found that 18.2% (n = 8) of patients experienced temporary paresis and 2.3% (n = 1) experienced minor (HB 2) permanent paresis limited to one branch. The average hospital length of stay was 0.64 days and complication rate was 6.8%. Conclusion The retrograde technique has complication rates comparable to historical rates for the prograde technique and is amenable to minimally invasive outpatient superficial parotidectomy.

Objective: The entity of primary mandibular paraganglioma (PGL) is not well accepted within the head and neck. Mandibular PGLs hitherto reported in literature are malignant metastatic lesions, mostly from a pheochromocytoma. Methods: We report a case of mandibular lytic lesion in a young female with multifocal PGLs but no family history of PGLs. We also performed a literature search to identify published cases of mandibular PGL. Results: Lack of established criteria for malignancy in a PGL made diagnosis and treatment challenging. Testing was negative for a pheochromocytoma and positive for mutation of succinate dehydrogenase gene encoding subunit D (SDHD), thus rendering a diagnosis of familial PGL syndrome type I. Due to the absence of prior published reports of nonmalignant, primary mandibular PGL, patient was treated with surgery and postoperative radiotherapy. Our literature search revealed 4 published cases of mandibular PGL, all of which had an osteoblastic appearance and were malignant. Conclusions: Isolated mandibular PGL does not always indicate a malignant metastatic lesion. Genetic testing is recommended in patients with early onset of PGL and/or multifocality even without a positive family history. Surgical resection alone with surveillance can be offered for such isolated lesions in the presence of familial PGL syndrome type I.

Purpose Pharyngocutaneous fistula (PCF) after laryngectomy continues to be a serious complication, especially after radiation. Recruitment of non-radiated tissue into the surgical defect may decrease the risk of fistula. These techniques however have significant morbidity and increases operative time. We hypothesized that using acellular dermal graft to reinforce the pharyngeal closure could decrease the risk of fistula, without the added morbidity of a vascularized flap. Methods We performed a retrospective chart review of all patients that underwent a laryngectomy between 2005 and 2015 at an acedemic tertiary referral center. Patients who underwent primary pharyngeal closure with Alloderm® reinforcement without any other flap reconstruction were identified. Basic demographics, previous treatment, operative technique and fistula were extracted from the medical records. The primary outcome was PCF rate. The time to closure, margin status and disease recurrence was also evaluated. Results Among 16 patients with AlloDerm® augmentation, eight had primary laryngectomy and eight had salvage laryngectomy. A total of three in the salvage laryngectomy with prior history of radiation developed PCF. The fistula closed in all three cases with conservative treatment. There was no PCF in the primary laryngectomy group without prior history of radiation. Conclusion The rate of PCF among the salvage laryngectomy group with previous radiation did not differ from historical data. AlloDerm® can however, provide a simple alternative for repair in radiation patients where flap cannot be performed for pharyngeal reconstruction. In non-radiated patients, AlloDerm® augmentation may have a protective effect on fistula formation.

Background: The indications, techniques, and outcomes for a minimally invasive surgical approach in oropharyngeal squamous cell carcinoma (OPSCC) unsuitable for transoral resection are not well-described. Methods: A retrospective case series was performed using a prospectively assembled database of transoral surgery–treated OPSCC patients who also underwent a “hybrid” approach of combined transoral and limited pharyngotomy for tumor resection. Disease and functional outcomes were evaluated. Results: Twenty patients underwent complete tumor resection using the hybrid approach. Median follow-up was 48 months. No postoperative pharyngocutaneous fistula occurred. One patient (5%) had a local recurrence. Kaplan-Meier estimates for disease-specific survival at 2 and 5 years were 94.4% (95% CI, 84%-100%) and 87% (95% CI, 70%-100%). All but 1 patient (due to chemoradiotherapy-related chondroradionecrosis) were decannulated, and 2 required long-term gastrostomy. Conclusion: In the absence of a favorable transoral access, the “hybrid” approach of combined transoral and limited pharyngotomy can accomplish margin-negative primary tumor resection, with a high degree of disease control and functional recovery in selected OPSCC patients.

Objectives/Hypothesis To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival. Study Design Retrospective case series with chart review. Methods This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates. Results Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2–147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%–99%), 87% (95% CI: 75%–99%), and 84% (95% CI: 72%–96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS. Conclusions Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence. Level of Evidence 4. Laryngoscope, 127:2033–2037, 2017

Objective Transoral surgery (TOS) for oropharyngeal carcinoma (OPC) is steadily becoming more routine. Expected posttreatment swallow function is a critical consideration for preoperative counseling. The objective of this study was to identify predictors of swallow dysfunction following TOS for advanced tumor (T)-stage (T3-T4) OPC. Methods A retrospective review from 1997 to 2016 at a single institution was performed. Eighty-two patients who underwent primary transoral resection of locally advanced OPCs with at least 1 year of postoperative follow-up were included. The primary outcome measure was swallow function, as measured by the Functional Outcomes Swallowing Scale (FOSS) at 1 year postoperatively. Operative reports were reviewed, and the extent of resection and type of reconstruction were documented. Conjunctive consolidation was then performed to incorporate multiple variables and their impact on swallow function into a clinically meaningful classification system. Results Fifty-six patients (68%) had acceptable swallowing at 1 year. T4 tumor stage and receipt of adjuvant chemoradiation therapy (CRT) were strongly associated with poor swallowing but did not reach statistical significance. Only base of tongue (BOT) resection ≥50% (odds ratio [OR] 3.19, 95% confidence interval [CI] 1.21-8.43) and older age (OR 1.06, 95% CI 1.00-1.12) were significantly associated. Utilizing T-stage, adjuvant CRT, and BOT resection, a conjunctive consolidation was performed to develop a classification system for swallow dysfunction at 1 year. Conclusion This study provides risk stratification for swallow function at 1 year following primary transoral resection of locally advanced OPCs. BOT resection ≥50%, especially when coupled with T4 tumor stage or adjuvant CRT, was associated with poor long-term swallow outcomes. Level of evidence 3 Laryngoscope, 130:94-100, 2020.

Objectives To examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease. Study design Multi-institutional retrospective review. Methods Two institutional databases of patients with HPV-related OPSCC were reviewed to identify patients with clinical (c) N1-N3 neck disease who underwent SND ± adjuvant therapy. Results Three hundred and twenty-four patients were identified with a median follow-up of 49 months (range 3-199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II-IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9-29.4). On multivariable analysis, adjuvant radiation was associated with improved disease-free survival (DFS) (OR 0.27, 95% CI 0.14-0.53) but lost significance for overall (OS) and disease-specific survival (DSS) (P > 0.05). Five-year Kaplan-Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%-92%), 93% (95% CI 89%-96%), and 83% (95% CI 78%-87%), respectively. Conclusion In HPV-related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long-term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection. Level of evidence 4. Laryngoscope, 127:623-630, 2017.

Objectives/Hypothesis Evaluate the oncologic outcomes of patients with early and select advanced primary glottic squamous cell carcinoma (SCCa) managed by transoral laser microsurgery (TLM). Study Design Retrospective cohort study. Methods Ninety cases of TLM-managed primary glottic SCCa were identified retrospectively using a prospectively collected database. Results Outcomes of patients with pTis–pT2a disease (n = 65) and pT2b–pT4a disease (n = 25) were, respectively: 5-year local control, 86.2% and 67.5%; 5-year disease-free survival, 64.9% and 44.9%; 5-year disease-specific survival, 96.4% and 59.0%; laryngeal preservation, 96.9% and 80%. Five of nine patients (56%) with supraglottic–glottic–subglottic tumors were local recurrence-free compared to the 70 of 81 (86%) patients with glottic, supraglottic–glottic, and glottic–subglottic tumors. Seven of 13 patients (54%) with positive or indeterminate margins were local recurrence-free compared to 68 of 77 (88%) patients with negative margins. Conclusions Given sample size considerations, this study highlights the satisfactory oncologic outcomes of TLM-treated glottic cancer and the potential importance of margin management and disease extension within the larynx. Level of Evidence 4 Laryngoscope, 127:597–604, 2017

Background The purpose of this study was to compare outcomes of patients with p16-positive oropharyngeal squamous cell carcinoma (SCC) treated with postoperative intensity-modulated radiotherapy (IMRT) before and after an institutional dose reduction policy effective on February 2009. Methods Between 1998 and 2013, 175 consecutive patients with p16-positive oropharyngeal SCC with extracapsular extension (ECE) and/or close or positive margins were treated postoperatively to 66 Gy (n = 109) or 60 Gy (n = 66) in 2 Gy/fx. Results Between the 66 and 60 Gy groups, there was no difference in tumor classification (pT4 vs pT1–T3; p = .181) and nodal classification (pN2c–N3 vs pN0–N2b; p = .704), and American Joint Committee on Cancer (AJCC) group stage (IV vs I–III; p = .473). Median follow-up was 5.9 years overall (66 Gy: 7.4 years; 60 Gy: 4.0 years). There was no difference in locoregional recurrence-free survival (2-year: 98.1% vs 98.5%; p = .421). Conclusion This study suggests that treating p16-positive oropharyngeal SCC with ECE and/or close or positive margins with postoperative IMRT to 60 Gy may not compromise locoregional recurrence-free survival compared to 66 Gy. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708–1716, 2016

Objective We observed high survival in a previous report of a p16-positive, oropharyngeal carcinoma (OPC) cohort treated primarily with transoral laser microsurgery (TLM) ± adjuvant therapy and followed for ≥ 12 months. To address long-term outcomes of primary transoral surgery for this unique disease, we present an updated analysis of our cohort with extended follow-up. Methods A prospectively assembled TLM cohort of 171 OPC patients was analyzed for disease-free, disease-specific, and overall survival (disease-free survival [DFS], disease-specific survival [DSS], overall survival [OS]) and functional outcomes, with a minimum follow-up of 60 months or to death. Results Median follow-up was 103 (60-201) months. Five-year DFS, DSS, and OS estimates were 85% (95% confidence interval [CI]: 80%-91%), 93% (95% CI: 89%-97%), and 90% (95% CI: 86%-95%). Recurrence occurred in 20 (12%; 7 locoregional, 13 distant); median time to recurrence was 18.8 months; and 90% occurred within 48 months. Age, smoking, American Joint Committee on Cancer 8th edition clinical tumor-category, pathologic tumor (pT)-category, pathologic tumor-node-metastasis (pTNM), and any adjuvant were significantly associated with disease-free survival in multivariable analyses, whereas pT-category, pN-category, TNM grouping, and angioinvasion were associated with DSS. A second primary developed in six (3.5%) patients. Indications for gastrostomy were recurrence/second primary (11), postadjuvant esophageal stenosis (6), comorbidities (3), and osteo/chondroradionecrosis (3); only seven (4%) had a gastrostomy tube in the absence of these factors, all of whom received adjuvant therapy. Two had a tracheostomy tube [chondoradionecrosis (1), recurrence (1)]. Conclusion High 5-year survival and locoregional control were observed, with recurrence occurring more commonly as distant metastasis. The observed time to recurrence suggests posttreatment oncologic surveillance for at least 48 months. Identified prognosticators will inform adjuvant treatment considerations, trial planning, and patient counseling for long-term outcomes. Laryngoscope, 2018 LEVEL OF EVIDENCE: 2b Laryngoscope, 129:1141-1149, 2019.

These NCCN Guidelines Insights focus on recent updates to the 2015 NCCN Guidelines for Head and Neck (HN the small number of patients in the United States who currently receive this treatment; and concerns that the toxicity of neutron therapy may offset potential disease control advantages.

Objectives To review the indications, techniques, and outcomes for a series of patients in whom the lower trapezius flaps was used for repair of complex posterior scalp and neck defects after posterior occipital-cervical surgeries. Design Retrospective case series. Setting Tertiary academic hospital. Participants A retrospective review of cases that required complex occipital-cervical repair was performed to identify patients who underwent reconstruction using the lower trapezius flap. Data collected included demographics, clinical presentations, surgical anatomy, operative techniques, and outcomes with review of the pertinent literature. Outcomes Nine patients who underwent reconstruction using the lower trapezius flap were identified. Prior surgical interventions included five complex tumor resections, two patients with multiple instrumented cervical spine surgeries, one patient with a craniotomy for attempted extracranial to intracranial arterial bypass for a basilar aneurysm repair, and a posterior occipital-cervical decompression after trauma. During the median follow-up period of 7 months, all nine single-stage reconstructions resulted in successful healing without major surgical complications. Conclusion Lower trapezius island flaps provide a reliable option for the reconstruction of complex scalp and neck defects that develop after complex occipital-cervical surgeries.

Summary Background Due to unique biology and prognosis, precise identification of predictive parameters is critical for p16+ oropharyngeal squamous cell carcinoma (OPSCC). Prior studies showing absence of prognostication from extracapsular spread (ECS) and/or high N-classification in surgically-treated p16+ OPSCC necessitate new, evidence-based prognosticators. Methods A prospectively assembled cohort of 220, transoral surgery + neck dissection ± adjuvant therapy-treated, p16+ OPSCC patients was analyzed. Disease recurrence and disease-specific survival (DSS) were primary endpoints. Results Median follow-up was 59 (12–189) months. Distribution of metastatic node numbers was: 0 in 9.5% (n = 21), 1 in 33.6% (n = 74), 2 in 17% (n = 38), 3 in 14.5% (n = 32), 4 in 8.2% (n = 18), and ⩾ 5 in 17% (n = 37). ECS was recorded in 80% (n = 159), and N2c–N3 in 17% (n = 38). Adjuvant radiotherapy and chemoradiotherapy was administered in 44% and 34%. Recurrence developed in 22 patients (10%); 4 local, 5 regional, 2 regional and distant, and 11 distant. The 3- and 5-year DSS estimates were 94.6% and 93%. Multivariable logistic regression identified ⩾ 5 nodes and T3–T4 classification as predictors for recurrence. In multivariable Cox analyses, ⩾ 5 nodes, T3–T4 classification and margins were prognostic for DSS. ECS, N2c–N3 classification and smoking were not prognostic. Conclusions Metastatic node number, not ECS or high N-classification is an independent nodal predictor of outcomes in surgically-treated p16+ OPSCC patients. Despite high DSS (~80%), closer surveillance for recurrence is recommended for patients with ⩾ 5 metastatic nodes.

The BRAF mutation occurs commonly in papillary thyroid carcinoma (PTC). Previous investigations of its utility to predict recurrence-free survival (RFS) and disease-specific survival (DSS) have reported conflicting results and its role remains unclear. The purpose of this retrospective study was to determine the incidence of the BRAF mutation and analyze its relationship to clinicopathologic risk factors and long-term outcomes in the largest, single-institution American cohort to date. BRAF mutational status was determined in 508 PTC patients using RFLP analysis. The relationships between BRAF mutation status, patient and tumor characteristics, RFS, and DSS were analyzed. The BRAF mutation was present in 67% of patients. On multivariate analysis, presence of the mutation predicted only for capsular invasion (HR, 1.7; 95% CI, 1.1–2.6), cervical lymph node involvement (HR, 1.7; 95% CI, 1.1–2.7), and classic papillary histology (HR, 1.8; 95% CI 1.1–2.9). There was no significant relationship between the BRAF mutation and RFS or DSS, an observation that was consistent across univariate, multivariate, and Kaplan–Meier analyses. This is the most extensive study to date in the United States to demonstrate that BRAF mutation is of no predictive value for recurrence or survival in PTC. We found correlations of BRAF status and several clinicopathologic characteristics of high-risk disease, but limited evidence that the mutation correlates with more extensive or aggressive disease. This analysis suggests that BRAF is minimally prognostic in PTC. However, prevalence of the BRAF mutation is 70% in the general population, providing the opportunity for targeted therapy.

The National Comprehensive Cancer Network (NCCN) describes the presence of extracapsular spread and/or positive margins in oropharynx cancer (OPC) as an indication for the addition of chemotherapy to postoperative radiation. The guideline's category 1 consensus is based on what they term high-level evidence. For this study, the authors performed a critical appraisal of the research upon which the NCCN guideline is based and assessed its relevance in the era of human papillomavirus (HPV)/p16-positive OPC. Multiple shortcomings were identified, including patient exclusion after randomization and the use of unplanned subgroup analyses without multivariate adjustment, which undermined internal validity. Indeterminate HPV/p16 status limited external validity. Given the unique biology of HPV/p16-positive tumors and the problems of internal and external validity, the authors concluded that the literature upon which the recommendation for the addition of chemotherapy to adjuvant radiation was based does not generate high-level evidence, and its relevance for the postoperative management of patients with HPV/p16-positive OPC remains unknown.

With the rise of oropharyngeal squamous cell carcinoma associated with human papillomavirus (HPV), appropriate treatment strategies continue to be tailored toward minimizing treatment while preserving oncologic outcomes. This study aimed to compare the outcomes for those undergoing transoral resection with or without adjuvant therapy for HPV-related oropharyngeal carcinoma. A case-match cohort analysis was performed at two institutions on patients with HPV-related oropharyngeal squamous cell carcinoma. All the subjects underwent transoral surgery and neck dissection. The patients treated with surgery alone were matched 1:1 to those treated with surgery and adjuvant therapy using two groups identified as confounders: T-stage (T1/2 or T3/4) and number of pathologically positive lymph nodes (≤4 or >4). The study identified 105 matched pairs, with a median follow-up period of 42 months (range 3.1–102.3 months). The patients were staged as T1/T2 (86%) or T3/4 (14%). Each group had five patients with more than four positive lymph nodes. Adjuvant therapy significantly improved disease-free survival (hazard ratio [HR] 0.067; 95% confidence interval [CI] 0.01–0.62) and was associated with a lower risk of local and regional recurrence (risk ratio [RR] 0.096; 95% CI 0.02–0.47). No difference in disease-specific survival (HR 0.22; 95% CI 0.02–2.57) or overall survival (HR 0.18; 95% CI 0.01–2.4) was observed with the addition of adjuvant therapy. The risk of the gastrostomy tube was higher for those receiving adjuvant therapy (RR 7.3; 95% CI 2.6–20.6). Transoral surgery is an effective approach for the treatment of HPV-related oropharyngeal carcinoma. The addition of adjuvant therapy appears to decrease the risk of recurrence and improve disease-free survival but may not significantly improve overall survival.

Objectives This study compares the outcomes of patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) treated with surgery followed by adjuvant radiotherapy (aRT) or chemoradiotherapy (aCRT).

Copyright © 2014 by the National Comprehensive Cancer Network. All rights reserved. This selection from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers focuses on glottic laryngeal cancer, which is the most common type of laryngeal cancer and has an excellent cure rate. The lymphatic drainage of the glottis is sparse, and early stage primaries rarely spread to regional nodes. Because hoarseness is an early symptom, most glottic laryngeal cancer is early stage at diagnosis. Updates to these guidelines for 2014 include revisions to "Principles of Radiation Therapy" for each site and "Principles of Surgery," and the addition of a new section on "Principles of Dental Evaluation and Management."

Background Amidst a rising incidence of p16-positive (p16+) oropharyngeal cancer, a significant number of cases present as regionally metastatic disease with an “unknown” primary. Preliminary data support transoral surgery as an effective method of primary detection/treatment. Methods An observational cohort study of 65 p16+ unknown primary patients treated with transoral surgery and neck dissection (2001–2012) was performed. Adjuvant therapy and recurrence data were collected. Kaplan–Meier estimates were computed for disease-specific survival (DSS) and overall survival (OS). Results The primary detection rate was 89% (58 of 65). Five-year DSS and OS were 98% and 97% for the detected group and 100% for the undetected, respectively. Seventeen patients were treated with surgery alone. Of the 47 patients receiving adjuvant therapy, radiation to the pharynx was spared in 36. Conclusion The transoral approach was highly effective for the diagnosis and treatment of the p16+ unknown primary and laid the foundation for deescalated radiation by elimination of the pharyngeal field. © 2014 Wiley Periodicals, Inc. Head Neck 37: 1603–1611, 2015

The tongue is a vital organ that is integral to many basic human functions, such as speech and deglutition. The primary challenges in tongue reconstruction lie in its unique form and function, and complete functional rehabilitation is equally dependent on restoring sensory and motor functions. This review article discusses the background, history, and future of tongue reconstruction in the era of human tissue allotransplantation.

The clinical benefit of combined intraoperative magnetic resonance imaging (iMRI) and endoscopy for transsphenoidal pituitary adenoma resection has not been completely characterized. This study assessed the impact of microscopy, endoscopy, and/or iMRI on progression-free survival, extent of resection status (gross-, near-, and sub-total resection), and operative complications. Retrospective analyses were performed on 446 transsphenoidal pituitary adenoma surgeries at a single institution between 1998 and 2012. Multivariate analyses were used to control for baseline characteristics, differences during extent of resection status, and progression-free survival analysis. Additional surgery was performed after iMRI in 56/156 cases (35.9 %), which led to increased extent of resection status in 15/156 cases (9.6 %). Multivariate ordinal logistic regression revealed no increase in extent of resection status following iMRI or endoscopy alone; however, combining these modalities increased extent of resection status (odds ratio 2.05, 95 % CI 1.21–3.46) compared to conventional transsphenoidal microsurgery. Multivariate Cox regression revealed that reduced extent of resection status shortened progression-free survival for near- versus gross-total resection [hazard ratio (HR) 2.87, 95 % CI 1.24–6.65] and sub- versus near-total resection (HR 2.10; 95 % CI 1.00–4.40). Complication comparisons between microscopy, endoscopy, and iMRI revealed increased perioperative deaths for endoscopy versus microscopy (4/209 and 0/237, respectively), but this difference was non-significant considering multiple post hoc comparisons (Fisher exact, p = 0.24). Combined use of endoscopy and iMRI increased pituitary adenoma extent of resection status compared to conventional transsphenoidal microsurgery, and increased extent of resection status was associated with longer progression-free survival. Treatment modality combination did not significantly impact complication rate.

Background Appreciable local recurrence rates observed in patients with margin-negative, transoral laser microsurgery (TLM)-treated oral cavity squamous cell carcinoma (SCC) necessitate identification of new prognosticators for local control and survival. A histopathologic index (Brandwein–Gensler score [BGS]) and intrinsic/iatrogenic/chronic conditions causing immune compromise are investigated. Methods From a prospectively assembled database of TLM-treated oral cavity SCC, specimens for 60 patients with a minimum of 2-years follow-up could undergo BGS assignment. Local control, disease-specific survival (DSS), and overall survival (OS) were study endpoints. Results “Low-BGS” was recorded in 28 patients (47%) and “high-BGS” in 32 patients (53%), whereas immune compromise was observed in 18%. In multivariate analyses, immune compromise was the only predictor for local control. T classification and immune compromise were prognostic for DSS and OS. “High-BGS” was prognostic only for OS. Conclusion “High-BGS” was associated with recurrences but immune compromise was the most significant predictor of local control and survival in margin-negative, TLM-treated oral cavity SCC. Strategies that maintain/restore tumor-specific immune responses in immune compromised oral cavity SCC hosts need to be developed. © 2014 Wiley Periodicals, Inc. Head Neck 37: 52–63, 2015

Background Modest survival rates are published for treatment of oral squamous cell carcinoma (OSCC) using conventional approaches. Few cohort studies are available for transoral resection of OSCC. Methods Analysis for recurrence, survival, and prognosis of patients with OSCC treated with transoral laser microsurgery (TLM) ± neck dissection was obtained from a prospective database. Results Ninety-five patients (71 patients had stages T1–T2 and 24 had stages T3–T4 disease) with minimum follow-up of 24 months met criteria and demonstrated negative margins in 95%. Five-year local control (LC) and disease-specific survival (DSS) were 78% and 76%, respectively. Surgical salvage achieved an absolute final locoregional control of 92%. Immune compromise and final margins were prognostic for LC, whereas T classification, N classification, TNM stage, comorbidity, and perineural invasion were also significant for DSS. Conclusion We document a large series of patients with OSCC treated with TLM, incorporating T1 to T4 primaries. A significant proportion of stage III/IV cases demonstrates feasibility of TLM in higher stages, with final margin positivity of 5%, LC greater than 90%, and comparable survival outcomes. © 2013 Wiley Periodicals, Inc. Head Neck 36: 340–351, 2014

OBJECTIVE Internal carotid artery (ICA) injury is a rare but severe complication of endonasal surgery. The authors describe their endovascular experience managing ICA injuries after transsphenoidal surgery; they review and summarize the current literature regarding endovascular techniques; and they propose a treatment algorithm based on the available evidence. METHODS A retrospective review of 576 transsphenoidal pituitary adenoma resections was performed. Cases of ICA injury occurring at our institution and transfers from other hospitals were evaluated. Endovascular treatments for ICA injury reported in the literature were also reviewed and summarized. RESULTS Seven cases were identified from the institutional cohort (mean age 46.3 years, mean follow-up 43.4 months [1–107 months]) that received endovascular treatment for ICA injury. Five injuries occurred at our institution (5 [0.9%] of 576), and 2 injuries occurred at outside hospitals. Three patients underwent ICA sacrifice by coil placement, 2 underwent lesion embolization (coil or stent-assisted coil placement), and 2 underwent endoluminal reconstruction (both with flow diversion devices). Review of the literature identified 98 cases of ICA injury treated with endovascular methods. Of the 105 total cases, 46 patients underwent ICA sacrifice, 28 underwent lesion embolization, and 31 underwent endoluminal reconstruction. Sacrifice of the ICA proved a durable solution in all cases; however, the rate of persistent neurological complications was relatively high (10 [21.7%] of 46). Lesion embolization was primarily performed by coil embolization without stenting (16 cases) and stent-assisted coiling (9 cases). Both techniques had a relatively high rate of at least some technical complication (6 [37.5%] of 16 and 5 [55.6%] of 9, respectively) and major technical complications (i.e., injury, new neurological deficit, or ICA sacrifice) (5 [31.3%] of 16 and 2 [22.2%] of 9, respectively). Endoluminal reconstruction was performed by covered stent (24 cases) and flow diverter (5 cases) placement. Covered stents showed a reasonably high rate of technical complications (10 [41.7%] of 24); however, 8 of these problems were resolved, leaving a small percentage with major technical complications (2 [8.3%] of 24). Flow diverter placement was also well tolerated, with only 1 minor technical complication. CONCLUSIONS Endovascular treatments including vessel sacrifice, coil embolization (with or without stent assistance), and endoluminal reconstruction offer a tailored approach to ICA injury management after endonasal surgery. Vessel sacrifice remains the definitive treatment for acute, uncontrolled bleeding; however, vessel preservation techniques should be considered carefully in select patients. Multiple factors including vascular anatomy, injury characteristics, and risk of dual antiplatelet therapy should guide best treatment, but more study is needed (particularly with flow diverters) to refine this decision-making process. Ideally, all endovascular treatment options should be available at institutions performing endonasal surgery.

Importance Further investigation is needed in the outcomes of currently available treatment for T3 glottic squamous cell carcinoma (SCC), a unique type of laryngeal cancer. Objective To compare overall survival (OS) and functional outcomes among patients with T3 glottic SCC receiving nonsurgical and surgical management. Design, Setting, and Participants This secondary analysis used data from the Surveillance, Epidemiology, and End Results (SEER) registry and Medicare databases. All patients with T3 glottic SCC who received a diagnosis from January 1, 1992, to December 31, 2010, were included. Data were analyzed from April 2014 to August 2015. Interventions Surgery with or without adjuvant radiotherapy and/or chemotherapy. Main Outcomes and Measures Five-year OS and functional outcomes. Results Among the 487 patients identified with T3 glottic SCC (418 men [85.8%]; 69 women [14.2%]; median age, 74.3 [interquartile range, 70.4-80.6] years), the 5-year OS for nonsurgical management, surgery alone, and surgery plus adjuvant treatment were 36% (95% CI, 30%-42%), 41% (95% CI, 30%-53%), and 41% (95% CI, 32%-51%), respectively. Multivariable analyses revealed an adjusted hazard ratio for OS of 0.68 (95% CI, 0.49-0.94) for patients receiving surgery alone vs nonsurgical management and 0.75 (95% CI, 0.57-0.98) for patients receiving surgery plus adjuvant treatment vs nonsurgical management. Gastrostomy tube dependence was highest in patients receiving surgery plus adjuvant treatment (30 of 98 patients [30.6%]). Tracheostomy dependence was highest in patients receiving chemoradiotherapy (34 of 92 patients [37.0%]). Conclusions and Relevance Overall survival showed a statistically significant and clinically meaningful improvement in patients with T3 glottic SCC who underwent surgery compared with a nonsurgical treatment. Furthermore, the data suggest that adjuvant and nonsurgical treatment result in a dysfunctional larynx; however, this association needs further study.

The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC.Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases.A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort.Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC.

Objective The purpose of our study is to compare oncologic and functional outcomes of p16-positive oropharyngeal squamous cell carcinoma (OPSCC) patients, in the presence and absence of planned radiation to the primary bed following transoral surgery (TOS), stratified by T-classification. Methods Retrospective cohort study of 261, T1-T4, consecutively TOS-treated OPSCC patients. Results At a median follow-up of 61 months, local recurrence (LR) occurred in 6 (2.3%) patients (3 each in T1-T2 and T3-T4 groups), of which 5 had tumors in the tongue base and one in the tonsil. Of patients not receiving planned primary bed radiation, LR occurred in 3% of T1-T2s versus 17% of T3-T4s. In patients with T1-T2 tumors, Absolute Risk Reduction of LR with primary bed radiation was 3.26% (95% CI: −0.37%, 7%); Number Needed to Treat to prevent one LR was 31 (95% CI: 14.5, 271). Absolute Risk Increase for gastrostomy-tube with primary bed radiation was 34.4% (95% CI: 24%, 45%); Number Needed to Harm was 3 (95% CI: 2.2, 4.2), i.e., for every three patients with T1-T2 tumors receiving primary bed radiation, one had a gastrostomy-tube. Conclusions Elimination of primary bed radiation in margin-negative resected, T1-T2 p16-positive OPSCC was not associated with significant compromise of local control, and correlated with superior swallowing preservation, assessed using gastrostomy rate as a surrogate. Lack of primary bed radiation in T3-T4 tumors associated with significantly increased LR rates.

Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (preoperative) trial to determine the biomarker and tumor response of OCSCC to MEK inhibition with trametinib. Experimental Design: Patients with stage II–IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemical staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity [maximum standardized uptake values (SUVmax) by F-18 fluorodeoxyglucose positron emission tomography/CT), and in tumor downstaging. Drug-related adverse events (AE) and surgical/wound complications were evaluated. Results: Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n = 2: nausea, duodenal perforation) or unrelated (n = 1: constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and posttrametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14%–74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6%–52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients. Conclusions: Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in patients with OCSCC. Clin Cancer Res; 23(9); 2186–94. ©2016 AACR.

To examine outcomes of selective neck dissection (SND) in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) who present with clinical neck disease.Multi-institutional retrospective review.Two institutional databases of patients with HPV-related OPSCC were reviewed to identify patients with clinical (c) N1-N3 neck disease who underwent SND ± adjuvant therapy.Three hundred and twenty-four patients were identified with a median follow-up of 49 months (range 3-199 months). All patients underwent transoral resection of the primary tumor and SND, including levels II-IV and ± levels I or V, with resection of additional nonlymphatic tissue (extended SND) as indicated by extent of disease, including the spinal accessory nerve (7%), the internal jugular vein (13%), and the sternocleidomastoid muscle (8%). Two hundred and seventy (83%) patients underwent adjuvant radiation. There were 13 (4%) regional recurrences and 19 (6%) distant recurrences. Regional control following salvage was 98%. On univariable analysis, absence of radiation was associated with regional recurrence (odds ratio [OR] 9.2, 95% confidence interval [CI] 2.9-29.4). On multivariable analysis, adjuvant radiation was associated with improved disease-free survival (DFS) (OR 0.27, 95% CI 0.14-0.53) but lost significance for overall (OS) and disease-specific survival (DSS) (P0.05). Five-year Kaplan-Meier estimates for OS, DSS, and DFS were 88% (95% CI 84%-92%), 93% (95% CI 89%-96%), and 83% (95% CI 78%-87%), respectively.In HPV-related OPSCC presenting with clinical neck disease, a SND ± additional tissue resection and adjuvant therapy, when indicated, provides excellent long-term regional control. Omission of radiotherapy increases the risk of regional recurrence, although it may not significantly impact OS or DSS. It appears unnecessary to routinely perform a comprehensive neck dissection.4. Laryngoscope, 127:623-630, 2017.

Evaluate the oncologic outcomes of patients with early and select advanced primary glottic squamous cell carcinoma (SCCa) managed by transoral laser microsurgery (TLM).Retrospective cohort study.Ninety cases of TLM-managed primary glottic SCCa were identified retrospectively using a prospectively collected database.Outcomes of patients with pTis-pT2a disease (n = 65) and pT2b-pT4a disease (n = 25) were, respectively: 5-year local control, 86.2% and 67.5%; 5-year disease-free survival, 64.9% and 44.9%; 5-year disease-specific survival, 96.4% and 59.0%; laryngeal preservation, 96.9% and 80%. Five of nine patients (56%) with supraglottic-glottic-subglottic tumors were local recurrence-free compared to the 70 of 81 (86%) patients with glottic, supraglottic-glottic, and glottic-subglottic tumors. Seven of 13 patients (54%) with positive or indeterminate margins were local recurrence-free compared to 68 of 77 (88%) patients with negative margins.Given sample size considerations, this study highlights the satisfactory oncologic outcomes of TLM-treated glottic cancer and the potential importance of margin management and disease extension within the larynx.4 Laryngoscope, 127:597-604, 2017.

Context: Parathyroid oxyphil cells, whose function is unknown, are thought to be derived from chief cells. Oxyphil cells increase in number in parathyroid glands of patients with chronic kidney disease (CKD) and are even more abundant in patients receiving treatment for hyperparathyroidism with calcitriol and/or the calcimimetic cinacalcet. Objective: We examined oxyphil and chief cells of parathyroid glands of CKD patients for differential expression of genes important to parathyroid function. Design/Setting/Participants: Parathyroid tissue from CKD patients with refractory hyperparathyroidism was immunostained for gene expression studies. Main Outcome Measure: Immunostaining for PTH, PTHrP, calcium-sensing receptor, glial cells missing 2, vitamin D receptor, 25-hydroxyvitamin D-1α-hydroxylase, and cytochrome c was quantified and expression reported for oxyphil and chief cells. Results: Expression of all proteins analyzed, except for the vitamin D receptor, was higher in oxyphil cells than in chief cells. Conclusion: Human parathyroid oxyphil cells express parathyroid-relevant genes found in the chief cells and have the potential to produce additional autocrine/paracrine factors, such as PTHrP and calcitriol. Additional studies are warranted to define the secretory properties of these cells and clarify their role in parathyroid pathophysiology.

3582–3589. 5. Feng FY, Kim HM, Lyden TH, et al. Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: clinical and functional results. J Clin Oncol 2010;28:2732–2738. 6. Chronowski G, Garden A, Morrison W, et al. Unilateral radiotherapy for the treatment of tonsillar cancer. Int J Radiat Oncol Biol Phys 2011 Oct 2. [Epub ahead of print] 7. Bourhis J, Le Maitre A, Baujat B, Audry H, Pignon JP. Individual patients' data meta-analyses in head and neck cancer. Curr Opin Oncol 2007;19:188–194. 8. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 2006;368: 843–854. 9. Eisbruch A, Harris J, Garden AS, et al. Multi-institutional trial of accelerated hypofractionated intensity-modulated radiation therapy for early-stage oropharyngeal cancer (RTOG 00-22). Int J Radiation Oncol Biol Physics 2009;76:1333–1338. 10. Kies MS, Holsinger FC, Lee JJ, et al. Induction chemotherapy and cetuximab for locally advanced squamous cell carcinoma of the head and neck: results from a phase II prospective trial. J Clin Oncol 2010;28:8–14.