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Purpose: To evaluate the influence of socioeconomic and demographic factors which might predict for excessive delays in the receipt of adjuvant radiotherapy for head and neck cancer., Methods and Materials: The medical records of 430 consecutive patients referred for adjuvant radiation after surgical resection for squamous cell carcinoma of the head and neck were reviewed. The number of days from surgery to initiation of radiation was recorded. To study the variability in which adjuvant radiation was delivered, descriptive statistics were used to determine the percentage of patients who deviated from starting treatment beyond the recommended benchmark of 42 days. The chi-square statistic was used to compare differences in proportion among subsets. A Cox proportional hazards model was constructed to perform a multi-variate analysis to identify factors which independently influenced the likelihood for non-adherence., Results: The interval between surgery and the start of radiation therapy ranged from 5 to 128 days (mean, 36 days). The mean number of days from surgery to radiation therapy was 31 days, 35 days, 40 days, and 42 days for Caucasians, Asians, Latino, and Black patients (p = 0.01). In all, 359 of 430 patients (83 %) started adjuvant radiation within 42 days. The proportion of patients who initiated radiation therapy within 42 days of surgery was 91 %, 86 %, 71 %, 65 %, and 80 % for Caucasians, Asians, Latinos, Blacks, and Native Hawaiian/Pacific Islanders, respectively (p < 0.001). Patient characteristics associated with higher odds of non-adherence to the timely receipt of adjuvant radiation therapy within then 42-day benchmark from surgery to radiation included race ([OR] = 4.23 95 % CI (1.30-7.97), non-English speaking status ([OR] = 2.38, 95 % CI: 0.61-4.50), and low socioeconomic status ([OR] = 1.21, 95 % CI: 1.01-1.86)., Conclusion: Underrepresented minorities are more likely to experience delays in the receipt of adjuvant radiation for head and neck cancer. The potential underlying reasons are discussed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Importance: The role of surveillance imaging after treatment for head and neck cancer is controversial and evidence to support decision-making is limited., Objective: To determine the use of surveillance imaging in asymptomatic patients with head and neck cancer in remission after completion of chemoradiation., Design, Setting, and Participants: This was a retrospective, comparative effectiveness research review of adult patients who had achieved a complete metabolic response to initial treatment for head and neck cancer as defined by having an unequivocally negative positron emission tomography (PET) scan using the PET response criteria in solid tumors (PERCIST) scale within the first 6 months of completing therapy. The medical records of 501 consecutive patients who completed definitive radiation therapy (with or without chemotherapy) for newly diagnosed squamous cell carcinoma of the head and neck between January 2014 and June 2022 were reviewed., Exposure: Surveillance imaging was defined as the acquisition of a PET with computed tomography (CT), magnetic resonance imaging (MRI), or CT of the head and neck region in the absence of any clinically suspicious symptoms and/or examination findings. For remaining patients, subsequent surveillance after the achievement of a complete metabolic response to initial therapy was performed on an observational basis in the setting of routine follow-up using history-taking and physical examination, including endoscopy. This expectant approach led to imaging only in the presence of clinically suspicious symptoms and/or physical examination findings., Main Outcome and Measures: Local-regional control, overall survival, and progression-free survival based on assignment to either the surveillance imaging or expectant management cohort., Results: This study included 340 patients (mean [SD] age, 59 [10] years; 201 males [59%]; 88 Latino patients [26%]; 145 White patients [43%]) who achieved a complete metabolic response during this period. There was no difference in 3-year local-regional control, overall survival, progression-free survival, or freedom from distant metastasis between patients treated with surveillance imaging vs those treated expectantly., Conclusions and Relevance: In this comparative effectiveness research, imaging-based surveillance failed to improve outcomes compared with expectant management for patients who were seemingly in remission after completion of primary radiation therapy for head and neck cancer.

Human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (SCC), which accounts for an increasing proportion of all head and neck cancers, represents a specific entity with distinct clinical and molecular characteristics. It is now firmly established that patients with HPV-positive oropharyngeal SCC have a significantly improved prognosis because this variant has exquisite radiosensitivity compared with HPV-negative oropharyngeal SCC; thus, it can be targeted with de-escalated approaches using reduced doses of radiation and/or chemotherapy. The overriding goal of de-escalation is to maintain the high cure and survival rates associated with traditional approaches while reducing the incidence of both short- and long-term toxicity. Although the exact reason for the improved radiosensitivity of HPV-positive oropharyngeal carcinoma is unclear, prospective studies have now been published demonstrating that de-escalated radiation can successfully maintain high rates of cure and preserve the quality of life for appropriately selected patients with this disease. However, these studies have been complicated by such factors as the relatively limited sample sizes, as well as the variability in treatment, inclusion criteria, and follow-up. How treatment paradigms will evolve, particularly in the era of precision medicine, is a provocative question and is the subject of this review.

Background: We evaluated priorities, expectations, and regret among patients treated on a phase II trial of de-escalated chemoradiation for human papillomavirus (HPV)-positive oropharyngeal cancer., Methods: Eligibility included stage III/IV squamous cell carcinoma of the oropharynx, p16-positivity, age ≥18 years, and Zubrod score 0-1. Participants were surveyed with validated measures evaluating their treatment experience., Results: Twenty-four of 27 (89%) patients participated with a median follow-up of 24 months. Twenty-three subjects (96%) selected "being cured" or "living as long as possible" as top priority. No patient reported any regret about the decision to enroll on a de-escalation protocol. Sixteen participants (67%) found retrospectively reported long-term swallowing function to be either better than or as originally expected., Conclusions: These data offer a baseline landscape of perspectives and priorities for patients treated with de-escalation for HPV-positive oropharyngeal carcinoma and provide support to the fundamental premise underlying ongoing efforts to establish a new standard of care., (© 2019 Wiley Periodicals, Inc.)

Background: Triweekly high-dose cisplatin (100 mg/m 2 ) with concurrent radiation therapy is the current standard of care in the definitive or appropriate postoperative setting in head and neck squamous cell carcinoma (HNSCC). We compared triweekly 100 mg/m 2 with alternative weekly 40 mg/m 2 and weekly <40 mg/m 2 cisplatin regimens., Methods: From 2011 to 2016, 163 patients received concurrent cisplatin and intensity-modulated radiotherapy for locally advanced HNSCC. Primary endpoints were overall survival (OS) and progression-free survival., Results: Cisplatin weekly <40 mg/m 2 showed inferior OS outcomes when compared to weekly 40 mg/m 2 (P = 0.084) and triweekly 100 mg/m 2 (P = 0.04) regimens., Conclusion: Our study displayed inferior outcomes with weekly cisplatin doses under 40 mg/m 2 , suggesting the inferiority of low-dose weekly chemotherapy and the need for ongoing randomized trials to further explore 40 vs 100 mg/m 2 chemotherapy regimens., (© 2019 Wiley Periodicals, Inc.)

Purpose: To evaluate the prognostic significance of human papillomavirus (HPV) status among patients treated by salvage radiation therapy for local-regional recurrences and second primary cancers of the head and neck arising in a previously irradiated field., Methods and Materials: The medical records of 54 consecutive patients who underwent re-irradiation for squamous cell carcinoma of the head and neck occurring in a previously irradiated field were reviewed. Only patients with biopsy-proven evidence of recurrent disease that had previously been treated with doses of radiation therapy of at least 60 Gy were included. Determination of HPV status at the time of recurrence was performed by p16 immunohistochemistry. The median age at re-irradiation was 58.5 years (range, 27.9 to 81.5 years). Thirty patients (55.5%) were lifelong never-smokers. The Kaplan Meier method was used to calculate overall survival, progression-free survival, and local-regional control, and distant metastasis-free survival with comparisons between groups performed using the log-rank test., Results: HPV status among tumors that were re-irradiated was as follows: 16 positive (29.7%); 7 negative (12.9%); 31 unknown (57.4%). The median overall survival in the entire cohort was 11.7 months (range, 8 to 27 months), with the 1-year and 2-year estimates of overall survival being 47.2% and 38.4%, respectively. A statistical trend was identified favoring patients with HPV-positive cancers with respect to the endpoints of overall survival (p = 0.06) and progression-free survival (p = 0.08) after re-irradiation when compared to the HPV-negative/unknown population. There was no significant difference in distant control between the two cohorts (p = 0.40)., Conclusions: The favorable prognostic significance of HPV seemingly extends to patients treated by re-irradiation suggesting that this biomarker may be useful in risk stratification in this setting., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: To analyze functional outcomes for patients treated on a phase 2 trial of de-escalated chemoradiation therapy for human papillomavirus-positive oropharyngeal cancer., Methods and Materials: Patient eligibility included p16-positive, stage III or IV oropharyngeal squamous cell carcinoma and a Zubrod performance status of 0 to 1. Treatment was induction chemotherapy with paclitaxel, 175 mg/m 2 , and carboplatin, area under the curve (AUC) of 6 mg/ml/min, for 2 cycles every 21 days, followed by concurrent paclitaxel, 30 mg/m 2 , every 7 days with dose-reduced radiation therapy of 54 or 60 Gy. Trends in body weight and body mass index (BMI) were analyzed with gastrostomy tube and narcotic use rates. Functional outcomes were assessed using the University of Washington Quality of Life Scale and the Functional Assessment of Cancer Therapy-Head and Neck Scale., Results: Forty-five patients were registered, of whom 40 were evaluable. Only 1 patient had a BMI deemed unhealthy at the completion of treatment. For the 15 patients (38%) with a normal BMI (18-25 kg/m 2 ) before treatment, recovery back to baseline occurred at approximately 18 months (average BMI, 23.2 kg/m 2 vs 22.3 kg/m 2 ; P=.09). In 2 patients (5%), gastrostomy tubes were placed during treatment. No patient was enteral feeding tube-dependent at 6 months after treatment. Ninety-five percent of patients tolerated a normal regular diet at last follow-up., Conclusions: De-escalated chemoradiation therapy may improve functional outcomes as indicated by the relatively low incidence of gastrostomy tube placement and long-term dysphagia. In patients with a normal BMI prior to chemoradiation therapy, BMI recovered to baseline levels., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin., Methods: Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%)., Results: The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting., Conclusion: Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation., (© 2017 Wiley Periodicals, Inc.)

Purpose: To report a single-institutional experience with the use of magnetic resonance imaging (MRI)-guided radiotherapy for cancers of the head and neck., Materials and Methods: Between October 2014 and October 2016, 18 patients with newly diagnosed cancers of the head and neck were prospectively enrolled on an institutional registry trial investigating the feasibility and efficacy of external-beam radiotherapy delivered using on-board MRI. All patients had biopsy-proven evidence of malignancy, measurable disease, and the ability to provide consent. None had previously received any treatment. Median dose was 70 Gy (range 54-70 Gy). MRI scans were obtained as part of an image-guided registration protocol for alignment prior to and during each treatment. Concurrent chemotherapy was administered to 14 patients (78%). Patient-reported outcomes were assessed using the University of Washington quality of life instrument., Results: Seventeen of 18 patients completed the planned intensity-modulated radiotherapy (IMRT) treatment of which 15 (83%) had a complete response and 2 (11%) had a partial response based on initial post-therapy positron emission tomography (PET) at 3 months. The 1-year estimates of progression-free survival, overall survival, and local-regional control were 95, 96, and 95%, respectively. There were no treatment-related fatalities. The incidence of grade 3+ acute toxicity was 44%. The proportion of patients rating their health-related quality of life as "very good" or "outstanding" at 6 months and 1 year after completion of radiation therapy was 60 and 70%, respectively., Conclusions: MRI-guided radiotherapy achieves clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Treatment of squamous cell carcinoma of the head and neck is rapidly evolving due to changing patient populations, an emphasis on quality of life-related outcomes, and advances in radiotherapy concepts and techniques to meet these new demands. This review includes recent and ongoing studies that are potentially practice changing, including improvements in intensity-modulated radiotherapy planning, the use of deintensified regimens in the human papilloma virus-related setting, and adjuvant therapy after transoral robotic surgery. Additionally, recent studies of modern proton therapy are reviewed., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To compare patterns of care for elderly patients aged ≥70 years with locally advanced head and neck cancer versus those of younger patients treated for the same disease., Methods and Materials: The medical records of 421 consecutive patients over the age of 50 years treated at a single institution between April 2011 and June 2016 for stage III/IV squamous cell carcinoma of the head and neck were reviewed. The primary treatment approach was compared using a t test statistic among 3 age cohorts: 50 to 59 years (118 patients); 60 to 69 years (152 patients); and 70 years and older (151 patients). Logistical regression was used to determine variables that influenced the likelihood of receiving surgery versus nonsurgical treatment, as well as radiation alone versus chemoradiation., Results: There was no difference in sex, T stage, N stage, Karnofsky performance status, or the number of chronic comorbid conditions among the 3 age cohorts (P>.05 for all). A greater proportion of elderly patients aged ≥70 years were treated by radiation alone compared with those aged 50 to 59 and 60 to 69 years (44% vs 16% and 24%, P=.01). Increasing age was associated with a greater likelihood of receiving primary nonsurgical versus surgical treatment (odds ratio 1.023, 95% confidence interval 1.004-1.042) and radiation alone compared with chemoradiation (odds ratio 1.054; 95% confidence interval 1.034-1.075). Ten chemotherapy regimens were used concurrently with radiation for patients aged ≥70 years, including carboplatin/paclitaxel (19%), carboplatin/cetuximab (19%), cisplatin (17%), and cetuximab (17%)., Conclusions: Despite similar performance status and comorbidity burden compared with their younger counterparts, patients aged ≥70 years were more commonly treated with less-aggressive strategies, including radiation alone. The variability of concurrent chemotherapy regimens used further suggests that the standard of care remains to be defined for this population., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine the effect of fraction size on laryngoesophageal dysfunction among patients treated by chemoradiotherapy for laryngeal and hypopharyngeal cancer., Methods: Forty patients underwent chemoradiotherapy for stage III/IV squamous cell carcinomas of the larynx and hypopharynx. Median radiation dose was 70 Gy (range, 69.3-70.4 Gy) with daily fractionation ranging from 2 Gy to 2.2 Gy., Results: When comparing 2 Gy versus >2 Gy daily fractionation, there was no difference in 2-year overall survival (71% vs 72%; p = .68), locoregional control (79% vs 77%; p = .43), or laryngectomy-free survival (60% vs 61%; p = .72). Use of 2 Gy versus >2 Gy fractionation improved laryngoesophageal dysfunction-free survival (2-year estimates, 49% vs 27%; p = .07). Patient-reported voice and swallowing were improved with the former., Conclusion: As the importance of a functional larynx becomes recognized as an endpoint for patients treated by voice preservation, the results of our study help refine treatment guidelines. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1322-1326, 2017., (© 2017 Wiley Periodicals, Inc.)

Background: Head and neck cancers positive for human papillomavirus (HPV) are exquisitely radiosensitive. We investigated whether chemoradiotherapy with reduced-dose radiation would maintain survival outcomes while improving tolerability for patients with HPV-positive oropharyngeal carcinoma., Methods: We did a single-arm, phase 2 trial at two academic hospitals in the USA, enrolling patients with newly diagnosed, biopsy-proven stage III or IV squamous-cell carcinoma of the oropharynx, positive for HPV by p16 testing, and with Zubrod performance status scores of 0 or 1. Patients received two cycles of induction chemotherapy with 175 mg/m 2 paclitaxel and carboplatin (target area under the curve of 6) given 21 days apart, followed by intensity-modulated radiotherapy with daily image guidance plus 30 mg/m 2 paclitaxel per week concomitantly. Complete or partial responders to induction chemotherapy received 54 Gy in 27 fractions, and those with less than partial or no responses received 60 Gy in 30 fractions. The primary endpoint was progression-free survival at 2 years, assessed in all eligible patients who completed protocol treatment. This study is registered with ClinicalTrials.gov, numbers NCT02048020 and NCT01716195., Findings: Between Oct 4, 2012, and March 3, 2015, 45 patients were enrolled with a median age of 60 years (IQR 54-67). One patient did not receive treatment and 44 were included in the analysis. 24 (55%) patients with complete or partial responses to induction chemotherapy received 54 Gy radiation, and 20 (45%) with less than partial responses received 60 Gy. Median follow-up was 30 months (IQR 26-37). Three (7%) patients had locoregional recurrence and one (2%) had distant metastasis; 2-year progression-free survival was 92% (95% CI 77-97). 26 (39%) of 44 patients had grade 3 adverse events, but no grade 4 events were reported. The most common grade 3 events during induction chemotherapy were leucopenia (17 [39%]) and neutropenia (five [11%]), and during chemoradiotherapy were dysphagia (four [9%]) and mucositis (four [9%]). One (2%) of 44 patients was dependent on a gastrostomy tube at 3 months and none was dependent 6 months after treatment., Interpretation: Chemoradiotherapy with radiation doses reduced by 15-20% was associated with high progression-free survival and an improved toxicity profile compared with historical regimens using standard doses. Radiotherapy de-escalation has the potential to improve the therapeutic ratio and long-term function for these patients., Funding: University of California., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Importance: There is a significant need to find biomarkers of response to radiotherapy and cetuximab in locally advanced head and neck squamous cell carcinoma (HNSCC) and biomarkers that predict altered immunity, thereby enabling personalized treatment., Objectives: To examine whether the Kirsten rat sarcoma viral oncogene homolog (KRAS)-variant, a germline mutation in a microRNA-binding site in KRAS, is a predictive biomarker of cetuximab response and altered immunity in the setting of radiotherapy and cisplatin treatment and to evaluate the interaction of the KRAS-variant with p16 status and blood-based transforming growth factor β1 (TGF-β1)., Design, Setting, and Participants: A total of 891 patients with advanced HNSCC from a phase 3 trial of cisplatin plus radiotherapy with or without cetuximab (NRG Oncology RTOG 0522) were included in this study, and 413 patients with available samples were genotyped for the KRAS-variant. Genomic DNA was tested for the KRAS-variant in a CLIA-certified laboratory. Correlation of the KRAS-variant, p16 positivity, outcome, and TGF-β1 levels was evaluated. Hazard ratios (HRs) were estimated with the Cox proportional hazards model., Main Outcomes and Measures: The correlation of KRAS-variant status with cetuximab response and outcome, p16 status, and plasma TGF-β1 levels was tested., Results: Of 891 patients eligible for protocol analyses (786 male [88.2%], 105 [11.2%] female, 810 white [90.9%], 81 nonwhite [9.1%]), 413 had biological samples for KRAS-variant testing, and 376 had plasma samples for TGF-β1 measurement. Seventy patients (16.9%) had the KRAS-variant. Overall, for patients with the KRAS-variant, cetuximab improved both progression-free survival (PFS) for the first year (HR, 0.31; 95% CI, 0.10-0.94; P = .04) and overall survival (OS) in years 1 to 2 (HR, 0.19; 95% CI, 0.04-0.86; P = .03). There was a significant interaction of the KRAS-variant with p16 status for PFS in patients treated without cetuximab. The p16-positive patients with the KRAS-variant treated without cetuximab had worse PFS than patients without the KRAS-variant (HR, 2.59; 95% CI, 0.91-7.33; P = .07). There was a significant 3-way interaction among the KRAS-variant, p16 status, and treatment for OS (HR, for KRAS-variant, cetuximab and p16 positive, 0.22; 95% CI, 0.03-1.66; HR for KRAS-variant, cetuximab and p16 negative, 1.43; 95% CI, 0.48-4.26; HR for KRAS-variant, no cetuximab and p16 positive, 2.48; 95% CI, 0.64-9.65; and HR for KRAS-variant, no cetuximab and p16 negative, 0.61; 95% CI, 0.23-1.59; P = .02). Patients with the KRAS-variant had significantly elevated TGF-β1 plasma levels (median, 23 376.49 vs 18 476.52 pg/mL; P = .03) and worse treatment-related toxic effects., Conclusions and Relevance: Patients with the KRAS-variant with HNSCC significantly benefit from the addition of cetuximab to radiotherapy and cisplatin, and there is a significant interaction between the KRAS-variant and p16 status. Elevated TGF-β1 levels in patients with the KRAS-variant suggests that cetuximab may help these patients by overcoming TGF-β1-induced suppression of antitumor immunity., Trial Registration: clinicaltrials.gov Identifier: NCT00265941.

Purpose: To evaluate the prognostic significance of p16 expression among patients with squamous cell carcinoma of the larynx (LSCC) and hypopharynx (HSCC)., Methods: The medical records of all patients with locally advanced, non-metastatic LSCC/HSCC were reviewed. p16 INK4A (p16) protein expression was evaluated on pathological specimens by immunohistochemistry (IHC), and the Kaplan-Meier method was used to estimate overall survival (OS) and locoregional control (LRC). In select cases, p16 expression was correlated to high-risk and low-risk HPV genotypes using in situ hybridization (ISH)., Results: Thirty-one patients (23 LSCC; 8 HSCC) were identified. Seventeen (54.8%) patients were p16 negative; 14 (45.2%) were p16-positive. The primary treatment modality was radiation therapy for 22 (71.0%) patients and surgery for 9 (29.0%). Nineteen (61.3%) patients were evaluated for high-risk HPV and low-risk HPV genotypes by IHC, of whom 2 (10.5%) patients were positive for high-risk HPV and 1 (5.3%) was positive for low-risk HPV. For high-risk HPV, the positive predictive value (PPV), sensitivity, and specificity of p16 was 20.0%, 100%, and 52.9%. There was no significant difference in the 2-year actuarial rates of OS (91% vs. 64%, p=0.34) or LRC (51% vs. 46%, p=0.69) between the p16-positive and p-16 negative patients., Conclusion: In this small cohort of 31 LSCC and HSCC patients, p16 was not a significant predictive of either LRC or OS. Furthermore, p16 was poorly correlated with HPV genotyping as identified by ISH., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To test the hypothesis that the radiation response of cancer stem cells (CSCs) in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC) differs and is not reflected in the radiation response of the bulk tumor populations, that radiation therapy (RT) can dedifferentiate non-stem HNSCC cells into CSCs, and that radiation-induced dedifferentiation depends on the HPV status., Methods and Materials: Records of a cohort of 162 HNSCC patients were reviewed, and their outcomes were correlated with their HPV status. Using a panel of HPV-positive and HPV-negative HNSCC cell lines expressing a reporter for CSCs, we characterized HPV-positive and HPV-negative lines via flow cytometry, sphere-forming capacity assays in vitro, and limiting dilution assays in vivo. Non-CSCs were treated with different doses of radiation, and the dedifferentiation of non-CSCs into CSCs was investigated via flow cytometry and quantitative reverse transcription-polymerase chain reaction for re-expression of reprogramming factors., Results: Patients with HPV-positive tumors have superior overall survival and local-regional control. Human papillomavirus-positive HNSCC cell lines have lower numbers of CSCs, which inversely correlates with radiosensitivity. Human papillomavirus-negative HNSCC cell lines lack hierarchy owing to enhanced spontaneous dedifferentiation. Non-CSCs from HPV-negative lines show enhanced radiation-induced dedifferentiation compared with HPV-positive lines, and RT induced re-expression of Yamanaka reprogramming factors., Conclusions: Supporting the favorable prognosis of HPV-positive HNSCCs, we show that (1) HPV-positive HNSCCs have a lower frequency of CSCs; (2) RT can dedifferentiate HNSCC cells into CSCs; and (3) radiation-induced dedifferentiation depends on the HPV status of the tumor., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Importance: There is no consensus whether primary surgery followed by either adjuvant radiotherapy (RT) or adjuvant chemoradiation (CRT) or definitive CRT should be the standard treatment approach to advanced-stage hypopharyngeal squamous cell carcinoma (HP SCC)., Objectives: To determine survival outcomes for patients with advanced-stage HP SCC treated at a single institution with either primary surgery plus RT or CRT or definitive CRT., Evidence and Data Acquisition: We conducted a retrospective analysis of prospectively collected medical records in an institutional database for patients with HP SCC newly diagnosed between January 1999 and April 2013. Overall survival (OS) and recurrence-free survival (RFS) were calculated and compared between treatment groups using the Kaplan-Meier method, with multivariate Cox regression analysis used to control for demographic and clinicopathologic features., Results: We identified 166 consecutively treated patients, 90 of whom did not meet study criteria. Of the 76 included patients, 48 (63%) had undergone definitive CRT, and 28 (37%) had undergone primary surgery with adjuvant RT or CRT. The groups were well balanced by age, smoking history, and alcohol use. Five-year OS and RFS for patients treated surgically were 66.3% and 53.6%, respectively; for patients treated with definitive CRT, OS and RFS were 41.3% and 34.5%, respectively. Multivariate Cox regression analysis showed that surgical management was associated with clinically improved OS (hazard ratio [HR], 4.78; 95% CI, 0.91-25.03; P = .06) and RFS (HR, 2.97; 95% CI, 0.76-11.53; P = .12), although the difference was not statistically significant., Conclusions and Relevance: Patients with advanced-stage HP SCC treated surgically with adjuvant RT or CRT showed a trend toward clinically improved OS and RFS compared with patients treated with definitive CRT. However, the difference was not statistically significant, and further investigation with larger controlled trials using modern approaches should be undertaken to optimize the initial management of advanced-stage HP SCC.

Objectives/hypothesis: Submandibular gland-sparing intensity-modulated radiotherapy (SMG-sparing IMRT) has been proposed to reduce xerostomia following head and neck irradiation. However, the safety of this practice has been questioned. Data from a large surgical series of oropharyngeal carcinoma patients were extracted to identify clinicopathological correlates for submandibular involvement and to create a risk stratification scheme to guide decision making to refine selection guidelines for SMG-sparing IMRT., Study Design: Clinicopathologic analysis., Methods: The medical records of 153 consecutive patients with squamous cell carcinoma of the oropharynx treated by primary surgery and neck dissection were reviewed. Univariate and multivariate analysis was performed with logistic regression to identify factors predictive of submandibular involvement. Recursive partitioning was used to develop risk stratification schemas based on preoperative data alone and in combination with pathologic data to guide treatment decisions in the definitive and postoperative settings, respectively., Results: Submandibular (level IB) nodal dissection was performed in 119 heminecks (85 ipsilateral and 17 contralateral). The incidence of submandibular involvement was 18%. Young age, T3-4 disease, N2b-3 disease, and perineural invasion were identified as risk factors for submandibular nodal involvement on multivariate analysis (P < .01). Three distinct risk groups for submandibular involvement were identified: age >60 years and N0-2a disease (low risk, 2%), age ≤60 years and T1-2N2b-3 (intermediate risk, 16%), age ≤60 years and T3-4N2b-3 disease (high risk, 57%)., Conclusions: These data provide assurances that SMG-sparing IMRT can reasonably be offered to appropriately selected patients. Risk stratification schemas were successfully developed for SMG-sparing IMRT in both the definitive and adjuvant settings., (© 2014 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: The purpose of this study was to compare outcomes among patients treated by intensity-modulated radiotherapy (IMRT) with daily image-guided radiotherapy (IGRT) for head and neck cancer according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV)., Methods: Three hundred sixty-seven consecutive patients were treated with IMRT for squamous cell carcinoma of the head and neck. The first 103 patients were treated with 5-mm CTV-to-PTV margins. The subsequent 264 patients were treated using reduced (3 mm) margins., Results: The 3-year locoregional control for patients treated using 5-mm and 3-mm CTV-to-PTV margins, respectively, was 78% and 80% (p = .75). The incidence of gastrostomy-tube dependence at 1 year was 10% and 3%, respectively (p = .001). The incidence of posttreatment esophageal stricture was 14% and 7%, respectively (p = .01)., Conclusion: The use of reduced (3 mm) CTV-to-PTV margins was associated with reduced late toxicity while maintaining locoregional control., (© 2014 Wiley Periodicals, Inc.)

Background: The purpose of this study was to determine the effect of adaptive replanning on clinical outcome among patients treated by intensity-modulated radiotherapy (IMRT) for head and neck cancer., Methods: Three hundred seventeen patients underwent IMRT with daily image-guidance for newly diagnosed squamous cell carcinoma of the head and neck to a median dose of 66 Gy (range, 60-74 Gy). Of these 317 patients, 51 (16%) underwent adaptive radiotherapy with modification of the original IMRT midway during treatment., Results: The 2-year local-regional control was 88% for patients treated with adaptive replanning compared with 79% for patients treated without (p = .01). The median time to local-regional recurrence for the 4 patients treated by adaptive radiotherapy was 7 months (range, 3-15 months) with all failures occurring within the high-dose planning target volume (PTV)., Conclusion: Although the use of routine replanning is probably not necessary, our findings do suggest a significant benefit in appropriately selected patients., (© 2014 Wiley Periodicals, Inc.)

Objectives/hypothesis: To examine functional and quality-of-life outcomes for patients treated by reirradiation to the head and neck for recurrent or new primary cancers., Study Design: Retrospective review., Methods: The University of Washington Quality of Life Instrument (UW-QOL) scores were reviewed with swallow evaluations for 17 patients with biopsy-proven recurrent or new primary squamous cell carcinoma of the head and neck treated with reirradiation who were clinically without evidence of disease at a minimum follow-up of 1 year. All patients had received their initial radiation therapy to a median dose of 66 Gy (range, 60-72 Gy). The median interval between radiation courses was 30 months (range, 6-132 months). The median reirradiation dose was 60 Gy (range, 54-70 Gy)., Results: At 1 year after reirradiation, the mean UW-QOL composite score was 67.0 (range, 22.1-83.5), which did not differ significantly from baseline (P = .57). The proportion of patients who rated their global quality of life as "very good" or "outstanding" at 1 year after reirradiation was 35%. The percentage of patients who reported their global quality of life as "good/fair" and "poor/very poor" were 59% and 6%, respectively., Conclusions: The majority of survivors in this highly selected series were devoid of new impairment after reirradiation and were satisfied with their functional status. Although nearly all patients had side effects from their prior radiation course prior to reirradiation, no patient reported a decline in global quality of life from before reirradiation to 1 year post-treatment., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Objective: To demonstrate the feasibility of helical tomotherapy (HT)-based intensity-modulated radiotherapy (IMRT) for the treatment of synchronous primary cancers arising from the head and neck., Methods: 14 consecutive patients with histologically proven squamous cell carcinoma of the head and neck were determined to have a second primary cancer in the upper aerodigestive tract on further evaluation and were treated with HT using simultaneous integrated boost IMRT. Megavoltage CT scans were acquired daily as part of an image-guided registration protocol. Concurrent platinum-based systemic therapy was given to nine patients (64%)., Results: HT resulted in durable local control in 21 of the 28 primary disease sites irradiated, including a complete clinical and radiographic response initially observed at 17 of the 20 sites with gross tumour. The mean displacements to account for interfraction motion were 2.44 ± 1.25, 2.92 ± 1.09 and 2.31 ± 1.70 mm for the medial-lateral (ML), superior-inferior (SI) and anteroposterior (AP) directions, respectively. Table shifts of >3 mm occurred in 19%, 20% and 22% of the ML, SI and AP directions, respectively. The 2-year estimates of overall survival, local-regional control and progression-free survival were 58%, 73% and 60%, respectively., Conclusion: The effectiveness of HT for the treatment of synchronous primary cancers of the head and neck was demonstrated., Advances in Knowledge: HT is a feasible option for synchronous primary cancers of the head and neck and can result in long-term disease control with acceptable toxicity in appropriately selected patients.

Objectives/hypothesis: To analyze outcomes among patients with residual positron-emission tomography (PET)-negative lymphadenopathy after chemoradiotherapy for head and neck cancer based on whether or not they underwent neck dissection., Study Design: Retrospective review., Methods: Fifty-five patients with stage III/IV squamous cell carcinoma of the head and neck were identified with residual PET-negative lymphadenopathy based on standardized uptake value of <3. All patients had been treated with chemoradiotherapy to a median dose of 70 Gy (range, 60-4 Gy)., Results: With a median follow-up of 30 months (range, 6-67 months), the 3-year overall survival (85% vs. 81%, P = .57), progression-free survival (88% vs. 88%, P = .42), and local-regional control (96% vs. 100%, P = .68), did not differ between patients treated by neck dissection or observation., Conclusions: Omission of neck dissection appears to be reasonable for patients with residual lymphadenopathy but negative PET after chemoradiotherapy for head and neck cancer., Level of Evidence: 4., (© 2013 The American Laryngological, Rhinological and Otological Society, Inc.)

Importance: Survival of patients with head and neck cancer can be affected by competing causes of mortality, as well as comorbidities that result in radiation treatment interruptions., Objective: To discern how differences in preexisting medical and psychosocial comorbidities potentially influence adherence to radiation therapy according to human papillomavirus (HPV) status., Design, Setting, and Participants: Retrospective analysis at a comprehensive cancer center of 162 consecutive patients with locally advanced squamous cell carcinoma of the oropharynx treated with primary chemoradiation (n = 95) or primary surgery followed by adjuvant radiation (n = 67). Immunostaining for p16 was used to determine HPV status., Main Outcomes and Measures: Difference in alcohol, tobacco, and marijuana use was compared between patients with HPV-positive and HPV-negative tumors, as well as the prevalence of the following comorbidities: diabetes mellitus, chronic obstructive pulmonary disease (COPD), anxiety disorder, and major depression. The number of total missed treatment days was analyzed as both a continuous and categorical variable., Results: Rates of self-reported heavy alcohol use (47% vs 16%; P = .02) and any marijuana use (47% vs 23%; P = .003) were significantly higher among HPV-negative patients. Fifty-four percent of HPV-positive patients self-identified as never smokers, compared with only 12% of HPV-negative patients (P < .001). HPV-negative patients had more missed treatment days (mean, 2.8 vs 1.7 days; P = .02), as well as an increased rate of at least 5 missed days (24% vs 10%; P = .04), and higher prevalences of COPD (12% vs 7%; P = .37) and anxiety disorder (12% vs 6%; P = .35)., Conclusions and Relevance: Pronounced differences exist in lifestyle habits between patients with HPV-negative and HPV-positive oropharyngeal cancer at diagnosis. These differences, as well as those of medical and psychosocial burden, may contribute to observed discrepancies in treatment adherence and need to be considered in outcomes reporting and clinical trial design.

Purpose: Data from a prospective screening protocol administered for patients previously irradiated for head-and-neck cancer was analyzed to identify dosimetric predictors of brachial plexus-associated neuropathy., Methods and Materials: Three hundred fifty-two patients who had previously completed radiation therapy for squamous cell carcinoma of the head and neck were prospectively screened from August 2007 to April 2013 using a standardized self-administered instrument for symptoms of neuropathy thought to be related to brachial plexus injury. All patients were disease-free at the time of screening. The median time from radiation therapy was 40 months (range, 6-111 months). A total of 177 patients (50%) underwent neck dissection. Two hundred twenty-one patients (63%) received concurrent chemotherapy., Results: Fifty-one patients (14%) reported brachial plexus-related neuropathic symptoms with the most common being ipsilateral pain (50%), numbness/tingling (40%), and motor weakness and/or muscle atrophy (25%). The 3- and 5-year estimates of freedom from brachial plexus-associated neuropathy were 86% and 81%, respectively. Clinical/pathological N3 disease (P<.001) and maximum radiation dose to the ipsilateral brachial plexus (P=.01) were significantly associated with neuropathic symptoms. Cox regression analysis revealed significant dose-volume effects for brachial plexus-associated neuropathy. The volume of the ipsilateral brachial plexus receiving >70 Gy (V70) predicted for symptoms, with the incidence increasing with V70 >10% (P<.001). A correlation was also observed for the volume receiving >74 Gy (V74) among patients treated without neck dissection, with a cutoff of 4% predictive of symptoms (P=.038)., Conclusions: Dose-volume guidelines were developed for radiation planning that may limit brachial plexus-related neuropathies., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: The objective of this study is to determine the prevalence of tobacco consumption (i.e., cigarette use) among survivors of head and neck cancer after treatment with radiation therapy (RT)., Methods and Materials: A longitudinal study was conducted with 230 patients previously treated with RT for squamous cell carcinoma of the head and neck. All patients were clinically without evidence of disease and had a minimum of 1 year follow-up. Patients were summarily asked about the use of tobacco products at each follow-up visit. To explore for associations between potential predictors of post-RT smoking, the Chi-square test and Spearman's correlation coefficient were employed., Results: The percentage of patients who were actively smoking was 21%, 21%, and 20%, at 1, 2, and 3 years post-RT, respectively. When the analysis was limited to patients with a former smoking history (i.e., excluding all never-smokers), these percentages increased to 32%, 27%, and 25%, respectively. The intensity of smoking at follow-up ranged from one cigarette daily to 2.5 packs daily. Forty-two of 76 (55%) patients who were smoking at diagnosis were found to be smoking at 1-year follow-up compared to 7 of 154 patients who were not (p < 0.001). The only factor that significantly predicted for persistent smoking at follow-up was the presence of a preexisting psychiatric condition (most commonly, a mood disorder) at initial cancer diagnosis., Conclusions: A significant proportion of former smokers are actively smoking during follow-up despite having completed intensive RT and having their cancers evidently under control. Innovative interventional approaches to target those at highest risk for continued smoking are warranted., (Copyright © 2013 John Wiley & Sons, Ltd.)

Importance: Radiation therapy to the head and neck has traditionally been associated with adverse effects that can affect oral health and physical functioning. Although intensity-modulated radiotherapy (IMRT) has been widely adopted as a means of decreasing toxic effects, limited clinical data exist on its potential effect on long-term quality of life., Objective: To analyze quality of life among long-term survivors of head and neck cancer treated with IMRT., Design, Setting, and Participants: This cross-sectional analysis studied 50 consecutive long-term survivors of head and neck cancer from a comprehensive cancer center who had previously undergone IMRT that required bilateral neck irradiation for locally advanced disease. All patients were clinically without evidence of recurrent disease and had at least 5 years of follow-up., Main Outcomes and Measures: The University of Washington Quality of Life (UW-QOL) scores were reviewed for all study participants. The UW-QOL questionnaire consists of 12 domains that pertain to the degree of quality of life in the categories of pain, appearance, activity, recreation, swallowing, chewing, speech, shoulder function, taste, saliva, mood, and anxiety., Results: Five years after completion of IMRT, 42 patients (84%) reported that their health-related quality of life was "much better" or "somewhat better" than at the time of cancer diagnosis. With respect to recent health-related quality of life during the preceding 7 days at the time of completing the UW-QOL questionnaire, 40 patients (80%) treated with IMRT reported "outstanding" or "very good" levels of functioning. Five years after completion of treatment, 41 (82%) rated their overall quality of life as "outstanding" or "very good." The lowest domain score on the UW-QOL questionnaire at 5 years pertained to salivary dysfunction. However, 42 patients (84%) reported saliva "of normal consistency" or "less saliva than normal but enough" compared with 8 (16%) reporting "too little saliva." No patient reported having "no saliva.", Conclusions and Relevance: Our findings add to the body of literature that supports the acceptance of IMRT as standard treatment for head and neck cancer. The fact that most 5-year survivors were satisfied with their quality of lives points to the ability of IMRT to preserve long-term functioning.

Purpose: The purpose of this study is to identify factors predictive of treatment interruptions during radiation therapy (RT) for head and neck cancer., Methods and Materials: The medical records of 280 consecutive patients who completed a 6- or 7-week course of RT for squamous cell carcinoma of the head and neck were reviewed. The number of missed treatment days, excluding those due to holidays or machine downtime, was determined for each patient. All patients were treated to a median dose of 63 Gy (range, 60 to 70 Gy)., Results: The proportion of patients who missed 0, 3-5, 6-10, and greater than 10 days was 25, 59, 12, and 5 %, respectively. The percentage of patients who missed greater than 5 days was 62 % among the 39 patients with Karnofsky Performance Status (KPS) score of 70 or less compared to 10 % among those with a KPS score of greater than 70 (p < 0.01). Among the 33 patients identified with a preexisting psychiatric condition, the percentage that subsequently missed greater than 5 days of treatment was 48 % compared to 13 % among those without a psychiatric condition. When missed RT days were analyzed as a continuous variable, the correlations with both KPS and preexisting psychiatric condition remained highly significant (p < 0.01, for both)., Conclusion: Poor performance status and preexisting psychiatric condition predicted for treatment interruptions during RT for head and neck cancer. In view of the possible detrimental effect on treatment outcome, appropriate social programs should be initiated to overcome potential barriers to RT for these particular populations.

Background: To report a single institutional experience with definitive radiation therapy alone for human papillomavirus (HPV)-positive head and neck cancer., Methods: A total of 67 patients were treated by radiation therapy alone to a median dose of 70 Gy (range, 66-72 Gy) for squamous cell carcinoma of the head and neck. Paraffin-embedded, formalin-fixed pretreatment tumor tissues were used to establish HPV-positivity using standardized techniques of immunohistochemistry for p16 and polymerase chain reaction for HPV., Results: In all, 23 patients with HPV-positive cancers were identified. With a median follow-up of 28 months (range, 6-85 months), the 3-year actuarial rates of overall survival, locoregional control, and distant metastasis-free survival were 83%, 90%, and 88%, respectively., Conclusion: These findings attest to the exquisite radiosensitivity of HPV-positive head and neck cancer. The clinical outcomes observed from this selected series compare favorably with historical controls treated by more intensive chemoradiotherapy strategies., (Copyright © 2013 Wiley Periodicals, Inc.)

Objectives/hypothesis: To evaluate the responsiveness of human papillomavirus (HPV) -positive and HPV-negative oropharyngeal cancer to intensity-modulated radiotherapy (IMRT), using axial imaging obtained daily during the course of image-guided radiotherapy (IGRT)., Study Design: Observational cohort study with matched-pair analysis of patients irradiated for HPV-positive and HPV-negative oropharygeal cancer., Methods and Materials: Ten patients treated by IMRT to 70 Gy for locally advanced, HPV-positive squamous cell carcinoma of the oropharynx were matched to one HPV-negative control subject by age, gender, performance status, T-category, tumor location, and the use of concurrent chemotherapy. The gross tumor volume (GTV) was delineated on daily IGRT scans obtained via kilovoltage cone-beam computed tomography (CBCT). Mathematical modeling using fitted mixed-effects repeated measure analysis was performed to quantitatively and descriptively assess the trajectory of tumor regression., Results: Patients with HPV-positive tumors experienced a more rapid rate of tumor regression between day 1 of IMRT and the beginning of week 2 (-33% Δ GTV) compared to their counterparts with HPV-negative tumors (-10% Δ GTV), which was statistically significant (p<0.001). During this initial period, the average absolute change in GTV was -22.9 cc/week for HPV-positive tumors and -5.9 cc/week for HPV-negative tumors (p<0.001). After week 2 of IMRT, the rates of GTV regression were comparable between the two groups., Conclusions: HPV-positive oropharyngeal cancers exhibited an enhanced response to radiation, characterized by a dramatically more rapid initial regression than those with HPV-negative tumors. Implications for treatment de-intensification in the context of future clinical trials and the possible mechanisms underlying this increased radiosensitivity will be discussed., (Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.)

Purpose: To compare the long-term quality of life among patients treated with and without intensity-modulated radiotherapy (IMRT) for head-and-neck cancer., Methods and Materials: The University of Washington Quality of Life instrument scores were reviewed for 155 patients previously treated with radiation therapy for locally advanced head-and-neck cancer. All patients were disease free and had at least 2 years of follow-up. Eighty-four patients (54%) were treated with IMRT. The remaining 71 patients (46%) were treated with three-dimensional conformal radiotherapy (3D CRT) by use of initial opposed lateral fields matched to a low anterior neck field., Results: The mean global quality of life scores were 67.5 and 80.1 for the IMRT patients at 1 and 2 years, respectively, compared with 55.4 and 57.0 for the 3D CRT patients, respectively (p < 0.001). At 1 year after the completion of radiation therapy, the proportion of patients who rated their global quality of life as "very good" or "outstanding" was 51% and 41% among patients treated by IMRT and 3DCRT, respectively (p = 0.11). At 2 years, the corresponding percentages increased to 73% and 49%, respectively (p < 0.001). On multivariate analysis accounting for sex, age, radiation intent (definitive vs. postoperative), radiation dose, T stage, primary site, use of concurrent chemotherapy, and neck dissection, the use of IMRT was the only variable independently associated with improved quality of life (p = 0.01)., Conclusion: The early quality of life improvements associated with IMRT not only are maintained but apparently become more magnified over time. These data provide powerful evidence attesting to the long-term benefits of IMRT for head-and-neck cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to analyze voice quality among patients treated by definitive radiotherapy for laryngeal cancer., Methods: Ten patients with laryngeal cancer who had completed radiotherapy were involved in this pilot study. A standardized protocol was administered assessing: (1) sustained vowel production following maximal inspiration, (2) sustained vowel production for a 7-second duration repeated 5 times, and (3) spontaneous speech for 10 seconds., Results: The acoustic parameters among patients with early-stage cancer were not statistically different from healthy age-corresponding controls, except for shimmer (0.20 vs 0.16 dB, ρ = 0.01) and maximum phonation duration (24.37 vs 30.10 seconds, ρ = 0.04). For patients with locally advanced cancer, differences with controls were observed with shimmer (2.29 vs 0.16 dB, ρ = 0.01), jitter (7.49% vs 1.04%, ρ = 0.01), harmonics-to-noise ratio (2.67 vs 9.22, ρ = 0.01), and maximum phonation duration (14.12 vs 30.10 seconds, ρ = 0.01)., Conclusions: Despite the subtle differences in voice quality that existed, radiotherapy as a curative treatment for laryngeal cancer allows maintenance of a functional voice., (Copyright © 2011 Wiley Periodicals, Inc.)

Purpose: To compare patterns of disease failure among patients treated with intensity-modulated radiotherapy (IMRT) in conjunction with daily image-guided radiotherapy (IGRT) for head and neck cancer, according to the margins used to expand the clinical target volume (CTV) to create a planning target volume (PTV)., Methods and Materials: Two-hundred and twenty-five patients were treated with IMRT for squamous cell carcinoma of the head and neck. Daily IGRT scans were acquired using either kilovoltage or megavoltage volumetric imaging prior to each delivered fraction. The first 95 patients were treated with IMRT with 5-mm CTV-to-PTV margins. The subsequent 130 patients were treated using 3-mm PTV expansion margins., Results: Two-year estimates of overall survival, local-regional control, and distant metastasis-free survival were 76%, 78%, and 81%, respectively. There were no differences with respect to any of these endpoints among patients treated with 5-mm and 3-mm PTV expansion margins (p > 0.05, all). The 2-year local-regional control rate for patients treated with IMRT with 5-mm and 3-mm PTV margins was 78% and 78%, respectively (p = 0.96). Spatial evaluation revealed no differences in the incidences of marginal failures among those treated with 5-mm and 3-mm PTV margins., Conclusions: The use of 3-mm PTV expansion margins appears adequate and did not increase local-regional failures among patients treated with IMRT for head and neck cancer. These data demonstrate the safety of PTV reduction of less than 5 mm and support current protocols recommending this approach in the setting of daily IGRT., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To determine how the addition of cisplatin-based concurrent chemotherapy to radiation therapy influences outcomes among a cohort of patients treated for head-and-neck cancer of unknown primary origin., Methods and Materials: The medical records of 60 consecutive patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Thirty-two patients (53%) were treated by concurrent chemoradiation, and 28 patients (47%) were treated by radiation therapy alone. Forty-five patients (75%) received radiation therapy after surgical resection, and 15 patients (25%) received primary radiation therapy. Thirty-five patients (58%) were treated by intensity-modulated radiotherapy., Results: The 2-year estimates of overall survival, local-regional control, and progression-free survival were 89%, 89%, and 79%, respectively, among patients treated by chemoradiation, compared to 90%, 92%, and 83%, respectively, among patients treated by radiation therapy alone (p > 0.05, for all). Exploratory analysis failed to identify any subset of patients who benefited from the addition of concurrent chemotherapy to radiation therapy. The use of concurrent chemotherapy was associated with a significantly increased incidence of Grade 3+ acute and late toxicity (p < 0.001, for both)., Conclusions: Concurrent chemoradiation is associated with significant toxicity without a clear advantage to overall survival, local-regional control, and progression-free survival in the treatment of head-and-neck cancer of unknown primary origin. Although selection bias cannot be ignored, prospective data are needed to further address this question., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To describe the spatial distribution of local-regional recurrence (LRR) among patients treated postoperatively with intensity-modulated radiotherapy (IMRT) for head and neck cancer., Methods and Materials: The medical records of 90 consecutive patients treated by gross total resection and postoperative IMRT for squamous cell carcinoma of the head and neck from January 2003 to July 2009 were reviewed. Sites of disease were the oral cavity (43 patients), oropharynx (20 patients), larynx (15 patients), and hypopharynx (12 patients). Fifty patients (56%) received concurrent chemotherapy., Results: Seventeen of 90 patients treated with postoperative IMRT experienced LRR, yielding a 2-year estimate of local regional control of 80%. Among the LRR patients, 11 patients were classified as in-field recurrences, occurring within the physician-designated clinical target volume, and 6 patients were categorized as marginal recurrences. There were no out-of-field geographical misses. Sites of marginal LRRs included the contralateral neck adjacent to the spared parotid gland (3 patients), the dermal/subcutaneous surface (2 patients), and the retropharyngeal/retrostyloid lymph node region (1 patient)., Conclusions: Although the incidence of geographical misses was relatively low, the possibility of this phenomenon should be considered in the design of target volumes among patients treated by postoperative IMRT for head and neck cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: An increasing proportion of patients with head and neck cancer have no history of smoking. The purpose of this analysis was to compare the clinical outcomes between patients without a history of smoking (never-smokers) and those with a previous history of smoking (ever-smokers) treated by radiation therapy., Methods and Materials: Seventy patients with newly diagnosed squamous cell carcinoma of the oropharynx or oral cavity without a previous history of smoking were matched to a control ever-smoker with a positive tobacco history (>10 pack-years) based on age, gender, ethnicity, Karnofsky Performance Status, primary tumor site, disease stage, primary treatment, radiation dose, and start date. Outcome was compared using Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer radiation toxicity criteria., Results: With a median follow-up of 33 months, lifelong never-smokers had an increased 3-year overall survival (86% vs. 69%), disease-free survival (82% vs. 65%), and local-regional control (85% vs. 70%) compared with the ever-smoker control population (P < 0.05, for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of grade 3+ complications was also significantly lower among never-smokers compared with ever-smokers (10% vs. 29%, P = 0.01)., Conclusions: Prognosis differed significantly between never-smokers and ever-smokers with head and neck cancer treated by radiation therapy. Further studies analyzing the biologic and molecular reasons underlying these differences are planned.

Currently, the most common method of delivering intensity-modulated radiotherapy (IMRT) is through step-and-shoot, segmental multi-leaf collimator (SMLC)-based techniques. Although rotational delivery methods such as helical tomotherapy (HT) have been proposed as offering advantages in the treatment of head and neck cancer, a lack of clinical data exists on its potential utility. This study compared dosimetric, clinical, and quality-of-life endpoints among 149 patients treated by HT and SMLC-IMRT for head and neck cancer. Dosimetric analysis revealed that the use of HT resulted in significant improvements with respect to mean dose (23.5 versus 27.9 Gy, p = 0.03) and V30 (30.1 versus 43.9 Gy, p = 0.01) to the contralateral (spared) parotid gland. However, the incidence of grade 3+ xerostomia in the late setting was 10% and 8% among patients treated by HT and SMLC-IMRT, respectively (p = 0.46). There were no significant differences in any of the quality of life endpoints among patients treated by HT and SMLC-IMRT (p > 0.05, for all). Acknowledging the biases inherent in this retrospective analysis, we found that the dosimetric advantages observed with HT compared to SMLC-IMRT failed to translate into significant improvements in clinical outcome. Prospective studies are needed to further evaluate how HT may affect the therapeutic ratio.

Purpose: To compare differences in dosimetric, clinical, and quality-of-life endpoints among a cohort of patients treated by intensity-modulated radiotherapy (IMRT) and conventional radiotherapy (CRT) for head-and-neck cancer of unknown primary origin., Methods and Materials: The medical records of 51 patients treated by radiation therapy for squamous cell carcinoma of the head and neck presenting as cervical lymph node metastasis of occult primary origin were reviewed. Twenty-four patients (47%) were treated using CRT, and 27 (53%) were treated using IMRT. The proportions of patients receiving concurrent chemotherapy were 54% and 63%, respectively., Results: The 2-year estimates of overall survival, local-regional control, and disease-specific survival for the entire patient population were 86%, 89%, and 84%, respectively. There were no significant differences in any of these endpoints with respect to radiation therapy technique (p>0.05 for all). Dosimetric analysis revealed that the use of IMRT resulted in significant improvements with respect to mean dose and V30 to the contralateral (spared) parotid gland. In addition, mean doses to the ipsilateral inner and middle ear structures were significantly reduced with IMRT (p<0.05 for all). The incidence of severe xerostomia in the late setting was 58% and 11% among patients treated by CRT and IMRT, respectively (p<0.001). The percentages of patients who were G-tube dependent at 6 months after treatment were 42% and 11%, respectively (p<0.001)., Conclusions: IMRT results in significant improvements in the therapeutic ratio among patients treated by radiation therapy for head-and-neck cancer of unknown primary origin., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the effect of continued cigarette smoking among patients undergoing radiation therapy for head-and-neck cancer by comparing the clinical outcomes among active smokers and quitters., Methods and Materials: A review of medical records identified 101 patients with newly diagnosed squamous cell carcinoma of the head and neck who continued to smoke during radiation therapy. Each active smoker was matched to a control patient who had quit smoking before initiation of radiation therapy. Matching was based on tobacco history (pack-years), primary site, age, sex, Karnofsky Performance Status, disease stage, radiation dose, chemotherapy use, year of treatment, and whether surgical resection was performed. Outcomes were compared by use of Kaplan-Meier analysis. Normal tissue effects were graded according to the Radiation Therapy Oncology Group/European Organization for the Treatment of Cancer toxicity criteria., Results: With a median follow-up of 49 months, active smokers had significantly inferior 5-year overall survival (23% vs. 55%), locoregional control (58% vs. 69%), and disease-free survival (42% vs. 65%) compared with the former smokers who had quit before radiation therapy (p < 0.05 for all). These differences remained statistically significant when patients treated by postoperative or definitive radiation therapy were analyzed separately. The incidence of Grade 3 or greater late complications was also significantly increased among active smokers compared with former smokers (49% vs. 31%, p = 0.01)., Conclusions: Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcomes. Further studies analyzing the biologic and molecular reasons underlying these differences are planned., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The two currently acceptable treatment options for locally advanced laryngeal cancer are total laryngectomy and organ preservation using chemoradiation. To facilitate therapeutic decision making, the accurate pre-treatment evaluation of cartilage invasion is of paramount importance. The purpose of this study was to evaluate the positive predictive value (PPV) and negative predictive value (NPV) of detecting neoplastic cartilage invasion in laryngeal cancer patients using fast-speed multidetector CT (MDCT)., Methods: 61 consecutive patients with clinically staged T3 or T4 squamous cell carcinoma of the larynx or hypopharynx who underwent total laryngectomy were analysed. All patients had MDCT of the neck within 2 weeks prior to surgery. Central radiographic and pathological review was performed in an attempt to correlate findings. MDCT invasion of cartilage was graded based on objective criteria., Results: MDCT scan was found to have a PPV of 78% and an NPV of 100% for detection of invasion through cartilage, with sensitivity being 100% and specificity 96%. For detection of any cartilage invasion (minor, major or through cartilage invasion), PPV and NPV were 63% and 92%, respectively. The sensitivity was 85% and specificity was 75%. For the detection of tumour invasion through cartilage or major cartilage invasion, MDCT scan had a PPV of 53% and an NPV of 95%. 47% (9/19) patients were down-staged from T4 to T3 after central pathology review., Conclusion: The low PPV for cartilage destruction using MDCT suggests that a significant proportion of patients who were treated by total laryngectomy could have been appropriately offered organ preservation if more accurately staged at initial diagnosis.

Purpose: To analyze outcomes after radiation therapy for head-and-neck cancer among a cohort of patients with human immunodeficiency virus (HIV)., Methods and Materials: The medical records of 12 patients with serologic evidence of HIV who subsequently underwent radiation therapy to a median dose of 68 Gy (range, 64-72 Gy) for newly diagnosed squamous cell carcinoma of the head and neck were reviewed. Six patients (50%) received concurrent chemotherapy. Intensity-modulated radiotherapy was used in 6 cases (50%). All patients had a Karnofsky performance status of 80 or 90. Nine patients (75%) were receiving antiretroviral therapies at the time of treatment, and the median CD4 count was 460 (range, 266-800). Toxicity was graded according to the Radiation Therapy Oncology Group / European Organization for the Treatment of Cancer toxicity criteria., Results: The 3-year estimates of overall survival and local-regional control were 78% and 92%, respectively. Acute Grade 3+ toxicity occurred in 7 patients (58%), the most common being confluent mucositis (5 patients) and moist skin desquamation (4 patients). Two patients experienced greater than 10% weight loss, and none experienced more than 15% weight loss from baseline. Five patients (42%) experienced treatment breaks in excess of 10 cumulative days, although none required hospitalization. There were no treatment-related fatalities., Conclusions: Radiation therapy for head-and-neck cancer seems to be relatively well tolerated among appropriately selected patients with HIV. The observed rates of toxicity were comparable to historical controls without HIV., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: To compare intensity-modulated radiotherapy (IMRT) treatment plans generated by segmental multileaf collimator (SMLC) and helical tomotherapy (HT) techniques for patients with unresectable sinonasal cancer., Methods and Materials: SMLC-IMRT and HT-IMRT plans for 5 patients with cancer of the paranasal sinuses and nasal cavity were independently optimized using the Eclipse treatment planning system (Varian Medial Systems, Palo Alto, CA) and Tomotherapy HI-ART treatment planning system (Tomotherapy, Inc, Madison, WI). The goal was to deliver a prescribed dose of 70 Gy to at least 95% of the planning target volume (PTV) encompassing gross tumor over 35 treatments whereas respecting constraints to organs at risk, notably the ocular structures., Results: HT-IMRT reduced the maximum doses to the optic chiasm, as well as to the ipsilateral optic nerve and retina (P < 0.05, for all). Maximum doses to these structures were reduced by 10%, 16%, and 14%, respectively, using HT-IMRT compared with SMLC-IMRT. Additionally, the mean dose to the ipsilateral lacrimal gland was reduced by 32% using HT-IMRT. With respect to conformality, HT-IMRT improved dose homogeneity by decreasing "hot-spots." The mean percentage of PTV70 receiving greater than 77 Gy (110% of the prescribed dose) was 4.0% for the HT-IMRT plans compared with 17.8% for the SMLC-IMRT plans (P = 0.001)., Conclusions: HT-IMRT has the potential to improve dose homogeneity to PTVs whereas reducing dose to the optic structures. Clinical implications are discussed.

Purpose: To determine the effect of prophylactic gastrostomy tube (GT) placement on acute and long-term outcome for patients treated with definitive chemoradiotherapy for locally advanced head and neck cancer., Methods and Materials: One hundred twenty consecutive patients were treated with chemoradiotherapy for Stage III/IV head and neck cancer to a median dose of 70 Gy (range, 64-74 Gy). The most common primary site was the oropharynx (66 patients). Sixty-seven patients (56%) were treated using intensity-modulated radiotherapy (IMRT). Seventy patients (58%) received prophylactic GT placement at the discretion of the physician before initiation of chemoradiotherapy., Results: Prophylactic GT placement significantly reduced weight loss during radiation therapy from 43 pounds (range, 0 to 76 pounds) to 19 pounds (range, 0 to 51 pounds), which corresponded to a net change of -14% (range, 0% to -30%) and -8% (range, +1% to -22%) from baseline, respectively (p < 0.001). However, the proportion of patients who were GT-dependent at 6- and 12-months after treatment was 41% and 21%, respectively, compared with 8% and 0%, respectively, for those with and without prophylactic GT (p < 0.001). Additionally, prophylactic GT was associated with a significantly higher incidence of late esophageal stricture compared with those who did not have prophylactic GT (30% vs. 6%, p < 0.001)., Conclusions: Although prophylactic GT placement was effective at preventing acute weight loss and the need for intravenous hydration, it was also associated with significantly higher rates of late esophageal toxicity. The benefits of this strategy must be balanced with the risks., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to compare the patterns of failure focusing on the distribution of local-regional recurrence among patients treated postoperatively with conventional radiotherapy (RT) and intensity-modulated radiotherapy (IMRT) for head and neck cancer., Methods: The records of 130 patients treated by surgery and postoperative radiation therapy for squamous cell carcinoma of the head and neck were reviewed. Seventy-eight patients (60%) were treated using conventional RT and 52 patients (40%) were treated using IMRT., Results: The 3-year estimates of local-regional control were 70% and 73% among patients treated by conventional RT and IMRT, respectively (p = .33). Among the local-regional recurrences in the IMRT group, 9 were in-field recurrences occurring within the physician-designated clinical target volume (CTV), and 4 were marginal recurrences involving the contralateral neck adjacent to the spared parotid gland (3 patients) and the retropharyngeal/retrostyloid lymph node region (1 patient)., Conclusion: Our study showed that conventional RT and IMRT result in similar rates of local-regional control. The implications for CTV design are discussed herein.

Background: The aim of this study was to determine the incidence of esophageal toxicity after radiation therapy for head and neck cancer., Methods: The records of 211 patients treated by radiation therapy for head and neck cancer were reviewed to identify those with dysphagia lasting more than 90 days after therapy. Late toxicity criteria established by the Radiation Therapy Oncology Group were used to score the symptoms., Results: The incidence of grade 3+ esophageal toxicity at 3 and 6 months was 30% and 19%, respectively. The rate of gastrotomy-tube dependence at 3 and 6 months was 20% and 11%, respectively. Hypopharyngeal and unknown primary site (p = .01, for both), T4 disease (p = .01), and the use of concurrent chemotherapy (p = .001) were associated with grade 3+ esophageal toxicity and stricture formation., Conclusion: A significant proportion of patients exhibit symptoms of esophageal toxicity after radiation therapy for head and neck cancer. Therefore, preventive strategies need further investigation., (Copyright 2009 Wiley Periodicals, Inc.)

Background: To report a single-institutional experience with the use of helical tomotherapy (HT)-based intensity-modulated radiotherapy (IMRT) for head and neck cancer., Methods: Seventy-seven consecutive patients were treated with HT for squamous cell carcinoma of the head and neck to a median dose of 66 Gy (range, 60 to 72 Gy). Megavoltage CT scans were obtained as part of an image-guided registration protocol for patient alignment before each treatment. Concurrent chemotherapy was administered to 48 patients (62%)., Results: The 2-year estimates of overall survival, local-regional control, and disease-free survival were 82%, 77%, and 71%, respectively. Spatial evaluation of local-regional failures revealed that 16 of the 18 patients who progressed in the primary site or neck failed in the high-dose planning target volume (PTV)., Conclusions: HT appears to achieve clinical outcomes comparable to contemporary series reporting on IMRT for head and neck cancer.

Purpose: To investigate the association between dose to various anatomical structures and dysphagia among patients with head and neck cancer treated by definitive intensity-modulated radiotherapy (IMRT) and concurrent chemotherapy., Methods and Materials: Thirty-nine patients with squamous cancer of the head and neck were treated by definitive concurrent chemotherapy and IMRT to a median dose of 70 Gy (range, 68 to 72). In each patient, a gastrostomy tube (GT) was prophylacticly placed prior to starting treatment. Prolonged GT dependence was defined as exceeding the median GT duration of 192 days. Dysphagia was scored using standardized quality-of-life instruments. Dose-volume histogram (DVH) data incorporating the superior/middle pharyngeal constrictors (SMPC), inferior pharyngeal constrictor (IPC), cricoid pharyngeal inlet (CPI), and cervical esophagus (CE) were analyzed in relation to prolonged GT dependence, dysphagia, and weight loss., Results: At 3 months and 6 months after treatment, 87% and 44% of patients, respectively, were GT dependent. Spearman's rho analysis identified statistical correlations (p < 0.05) between prolonged GT dependence or high grade dysphagia with IPC V65, IPC V60, IPC Dmean, and CPI Dmax. Logistic regression model showed that IPC V65 > 30%, IPC V60 > 60%, IPC Dmean > 60 Gy, and CPI Dmax > 62 Gy predicted for greater than 50% probability of prolonged GT dependence., Conclusion: Our analysis suggests that adhering to the following parameters may decrease the risk of prolonged GT dependence and dysphagia: IPC V65 < 15%, IPC V60 < 40%, IPC Dmean < 55 Gy, and CPI Dmax < 60 Gy.

Background: To analyze the efficacy of various fractionation schedules for the palliation of head and neck cancer with radiation therapy., Methods: Sixty patients completed palliative irradiation to primary head and neck sites. The most commonly used fractionation regimen was the one previously described by the Radiation Therapy Oncology Group (RTOG) protocol 85-02 and was designed to deliver 440 cGy using 370 cGy fractionation, administered twice a day for 2 consecutive days at 2- to 3-week intervals for 3 total cycles., Results: The rates of palliative response were 83%, 77%, 67%, 86%, and 60% among those treated using the RTOG regimen, 7000 cGy/35 fractions, 3000 cGy/10 fractions, 3750 cGy/15 fractions, and 2000 cGy/5 fractions, respectively (p = .42). Nine percent (2/23) of those treated with the RTOG regimen developed grade 3+ toxicity compared with 37% among those treated with other schedules (p = .01)., Conclusion: Although all of the analyzed schedules were effective at providing palliation, the RTOG 85-02 regimen was associated with less toxicity., ((c) 2008 Wiley Periodicals, Inc.)

Purpose: The intraparotid and periparotid lymph nodes are the most commonly involved when skin cancer of the head and neck metastasizes beyond the primary site. We sought to report the clinical outcome of patients treated with radiation therapy for parotid-area metastases from cutaneous squamous cell carcinoma of the head and neck., Methods and Materials: The records of 36 patients treated with radiation therapy for cutaneous squamous cell carcinoma involving the parotid-area lymph nodes were reviewed. All patients had clinically N0 necks and were without evidence of distant disease. Thirty patients (83%) were treated postoperatively after gross total tumor resection. Median dose to the parotid area was 60 Gy (range, 50-72 Gy). Treatment of clinically N0 necks consisted of surgical dissection (7 patients), irradiation (15 patients), and observation (14 patients)., Results: The 5-year estimate of local (parotid) control was 86% in patients treated using surgery with postoperative therapy and 47% in patients treated using radiation therapy alone. Three of 4 patients with tumors that relapsed locally after surgery and postoperative radiation received a dose of less than 60 Gy. Elective neck irradiation decreased the incidence of subsequent nodal failures from 50% to 0% and significantly improved neck control (p < 0.001). The 5-year overall survival rate was 63%., Conclusions: Surgery followed by radiation therapy to doses of at least 60 Gy results in effective local control for patients with parotid area metastasis from cutaneous squamous cell carcinoma. Routine irradiation of the clinically N0 neck is recommended.