Search

Background: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies., Methods: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, T TR , is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, T B for Blacks and T W for Whites, for risk stratification., Results: MuNI was statistically significantly different between Black (mean, 3.88e-4; median, 3.67e-04) and White patients (mean, 3.36e-04; median, 2.99e-04), with p = .0078. Using T TR , MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21-2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18-2.51). Population-specific cutoff, T W , yielded improved HR of 1.77 (p = .003; 95% CI, 1.21-2.58) for White patients, whereas T B did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2-1.80)., Conclusions: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background/aim: Definitive treatment for locally advanced head and neck squamous cell carcinoma (LAHNSCC) is often compromised in older adults due to concerns about potential treatment toxicity intolerance. We reviewed our institutional experience with definitive management of older adults with LAHNSCC., Patients and Methods: From our Institutional Review Board-approved registry, we identified patients aged >60 years with stage III-IV, M0 LAHNSCC (seventh/earlier editions of the American Joint Committee on Cancer classification) treated with definitive radiotherapy from 1993-2019. Indications for concurrent chemotherapy included T3-4 or N2-3 disease. Multivariable analysis using Fine and Gray regression was performed to identify risk factors associated with recurrence. The cumulative incidence method was used to calculate recurrence rates., Results: Overall, 350 patients were identified: 223 aged 60-69, 82 aged 70-74, and 45 aged ≥75 years. Median follow-up was 36.3 months. Two-year recurrence rates were 13.7%, 20.2% and 34.8%, respectively; human papillomavirus-positive disease was present in 190 (85%), 44 (54%), and 25 (56%), respectively; and systemic therapy was given to 194 (87%), 64 (88%), and 23 (56%) patients, respectively. Factors significantly associated with increased risk of recurrence included age ≥75 years, Karnofsky performance status 70-80, clinical N2c-N3, and Charlson score 2-3., Conclusion: Patients aged ≥75 years received less aggressive therapy and experienced increased recurrence compared to younger patients. Outcomes for those aged 70-74 years were similar to younger patients treated with aggressive therapy, despite their inferior performance status/comorbidity, and such patients should not routinely be excluded from standard-of-care therapy. Further study is needed to optimize therapy for a redefined older adult (age ≥75 years) population., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has excellent control rates compared to nonvirally associated OPSCC. Multiple trials are actively testing whether de-escalation of treatment intensity for these patients can maintain oncologic equipoise while reducing treatment-related toxicity. We have developed OP-TIL, a biomarker that characterizes the spatial interplay between tumor-infiltrating lymphocytes (TILs) and surrounding cells in histology images. Herein, we sought to test whether OP-TIL can segregate stage I HPV-associated OPSCC patients into low-risk and high-risk groups and aid in patient selection for de-escalation clinical trials., Methods: Association between OP-TIL and patient outcome was explored on whole slide hematoxylin and eosin images from 439 stage I HPV-associated OPSCC patients across 6 institutional cohorts. One institutional cohort (n = 94) was used to identify the most prognostic features and train a Cox regression model to predict risk of recurrence and death. Survival analysis was used to validate the algorithm as a biomarker of recurrence or death in the remaining 5 cohorts (n = 345). All statistical tests were 2-sided., Results: OP-TIL separated stage I HPV-associated OPSCC patients with 30 or less pack-year smoking history into low-risk (2-year disease-free survival [DFS] = 94.2%; 5-year DFS = 88.4%) and high-risk (2-year DFS = 82.5%; 5-year DFS = 74.2%) groups (hazard ratio = 2.56, 95% confidence interval = 1.52 to 4.32; P < .001), even after adjusting for age, smoking status, T and N classification, and treatment modality on multivariate analysis for DFS (hazard ratio = 2.27, 95% confidence interval = 1.32 to 3.94; P = .003)., Conclusions: OP-TIL can identify stage I HPV-associated OPSCC patients likely to be poor candidates for treatment de-escalation. Following validation on previously completed multi-institutional clinical trials, OP-TIL has the potential to be a biomarker, beyond clinical stage and HPV status, that can be used clinically to optimize patient selection for de-escalation., (© The Author(s) 2021. Published by Oxford University Press.)

Objectives: To explore the influence of treatment package time(TPT) in high-risk oral cavity squamous cell carcinoma(OCSCC) receiving adjuvant radiotherapy with concurrent chemotherapy(CRT)., Materials and Methods: We queried our multi-institutional OCSCC collaborative database for cases diagnosed between 2005 and 2015 who underwent surgery followed by adjuvant CRT. All patients had high-risk features: extranodal extension(ENE) and/or positive surgical margin(PM). TPT was days between surgery to last radiotherapy fraction. Kaplan-Meier curves, log-rank p-values and multivariate analysis(MVA) were used to investigate the impact of TPT on overall(OS), disease-free(DFS), locoregional failure-free(LRFS) and distant metastases-free(DMFS) survival., Results: We identified 187 cases: median age 58 (range, 24-87 years), males 66%, and ever smokers 69%. ENE and PM were detected in 85% and 32%, and oral tongue and floor of the mouth constituted 49% and 18%, respectively. Median radiotherapy and cisplatin doses received were 66 Gy and 200 mg/m2. Overall, median TPT was 98 (range, 63-162 days). OS was worse for TPT > 90-days (n = 134) than TPT ≤ 90 (n = 53) at two-(65% vs. 71%) and five-years (45% vs. 62%); p = 0.05, with similar results for DFS. No influence on LRFS or DMFS was noted. More lymph nodes(LN) dissected(P = 0.039), T3-4 disease(P = 0.017), and unplanned reoperations(P = 0.037) occurred with TPT > 90-days. On MVA, TPT in 10-day increments was independently detrimental for OS (Hazard Ratio: 1.14; 95 %Confidence Interval [1-1.28]; P = 0.043), perineural invasion, age and positive LN (p < 0.05 for all)., Conclusion: In one of the largest multi-institutional cohorts, TPT > 90-days predicted worse OS for high-risk OCSCC receiving adjuvant CRT. All efforts are needed to optimize perioperative care and baseline conditions for favorable outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Adjuvant chemoradiation (CRT), with high-dose cisplatin remains standard treatment for oral cavity squamous cell carcinoma (OCSCC) with high-risk pathologic features. We evaluated outcomes associated with different cisplatin dosing and schedules, concurrent with radiation (RT), and the effect of cumulative dosing of cisplatin. An IRB-approved collaborative database of patients (pts) with primary OCSCC (Stage I-IVB AJCC 7th edition) treated with primary surgical resection between January 2005 and January 2015, with or without adjuvant therapy, was established from six academic institutions. Patients were categorized by cisplatin dose and schedule, and resultant groups compared for demographic data, pathologic features, and outcomes by statistical analysis to determine disease free survival (DFS) and freedom from metastatic disease (DM). From a total sample size of 1282 pts, 196 pts were identified with high-risk features who were treated with adjuvant CRT. Administration schedule of cisplatin was not significantly associated with DFS. On multivariate (MVA), DFS was significantly better in patients without perineural invasion (PNI) and in those receiving ≥200 mg/m 2 cisplatin dose ( p < 0.001 and 0.007). Median DFS, by cisplatin dose, was 10.5 (<200 mg/m 2 ) vs. 20.8 months (≥200 mg/m 2 ). Our analysis demonstrated cumulative cisplatin dose ≥200 mg/m 2 was associated with improved DFS in high-risk resected OCSCC pts.

BACKGROUNDPatients with p16+ oropharyngeal squamous cell carcinoma (OPSCC) are potentially cured with definitive treatment. However, there are currently no reliable biomarkers of treatment failure for p16+ OPSCC. Pathologist-based visual assessment of tumor cell multinucleation (MN) has been shown to be independently prognostic of disease-free survival (DFS) in p16+ OPSCC. However, its quantification is time intensive, subjective, and at risk of interobserver variability.METHODSWe present a deep-learning-based metric, the multinucleation index (MuNI), for prognostication in p16+ OPSCC. This approach quantifies tumor MN from digitally scanned H&E-stained slides. Representative H&E-stained whole-slide images from 1094 patients with previously untreated p16+ OPSCC were acquired from 6 institutions for optimization and validation of the MuNI.RESULTSThe MuNI was prognostic for DFS, overall survival (OS), or distant metastasis-free survival (DMFS) in p16+ OPSCC, with HRs of 1.78 (95% CI: 1.37-2.30), 1.94 (1.44-2.60), and 1.88 (1.43-2.47), respectively, independent of age, smoking status, treatment type, or tumor and lymph node (T/N) categories in multivariable analyses. The MuNI was also prognostic for DFS, OS, and DMFS in patients with stage I and stage III OPSCC, separately.CONCLUSIONMuNI holds promise as a low-cost, tissue-nondestructive, H&E stain-based digital biomarker test for counseling, treatment, and surveillance of patients with p16+ OPSCC. These data support further confirmation of the MuNI in prospective trials.FUNDINGNational Cancer Institute (NCI), NIH; National Institute for Biomedical Imaging and Bioengineering, NIH; National Center for Research Resources, NIH; VA Merit Review Award from the US Department of VA Biomedical Laboratory Research and Development Service; US Department of Defense (DOD) Breast Cancer Research Program Breakthrough Level 1 Award; DOD Prostate Cancer Idea Development Award; DOD Lung Cancer Investigator-Initiated Translational Research Award; DOD Peer-Reviewed Cancer Research Program; Ohio Third Frontier Technology Validation Fund; Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering; Clinical and Translational Science Award (CTSA) program, Case Western Reserve University; NCI Cancer Center Support Grant, NIH; Career Development Award from the US Department of VA Clinical Sciences Research and Development Program; Dan L. Duncan Comprehensive Cancer Center Support Grant, NIH; and Computational Genomic Epidemiology of Cancer Program, Case Comprehensive Cancer Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, the US Department of VA, the DOD, or the US Government.

Background: Process-related measures have been proposed as quality metrics in head and neck cancer care. A recent single-institution study identified four key metrics associated with increased survival. This study sought to validate the association of these quality metrics with survival in a multi-institutional cohort., Methods: Multicenter retrospective study of patients with oral cavity squamous cell (1/2005-1/2015). Baseline patient and disease characteristics and compliance with quality metrics was evaluated. Association between compliance with quality metrics with overall survival (OS), disease-free survival (DFS), and disease-specific survival (DSS) was evaluated using Cox proportional hazards models., Results: Failure to comply with two or more of the quality metrics was associated with worse OS, DFS, and DSS. Adherence to all or all but one of the quality metrics was found to be associated with improved survival., Conclusions: Process-related quality metrics are associated with increased survival in patients with oral cavity squamous cell carcinoma in a multi-institutional cohort., (© 2020 Wiley Periodicals LLC.)

Background: The role of smoking among patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) is unclear., Methods: A retrospective cohort study of patients with HPV(+) OPSCC from 2001 to 2015 at a tertiary-care institution was conducted. The primary outcome was overall survival (OS)., Results: Among 484 included patients, 94 (19.4%) were active smokers, 226 (46.7%) were former smokers, and 164 (33.9%) never smoked. Among active smokers, 82 patients (87.2%) had a ≥10 pack-year and 69 (73.4%) had a ≥20 pack-year smoking history. After adjusting for covariates, active smoking was a significant predictor of inferior OS (HR 2.28, P < .001) and PFS (HR 2.26, P < .001). When including pack-years as the covariate, ≥20 pack-years predicted a decreased effect-size for inferior OS and PFS., Conclusions: For patients with HPV(+) OPSCC, active smoking at diagnosis is the most powerful covariate capturing smoking history to predict OS and PFS., (© 2019 Wiley Periodicals, Inc.)

Purpose: To determine which factors influence cost in head and neck cancer (HNC) to inform the development of a bundled payment model (BPM)., Methods: Patients with stages 0 to IVB (by American Joint Commission on Cancer, 7th edition) HNC of various sites and histology treated definitively at a single tertiary care center during 2013 were included. Clinical variables and direct cost data were obtained, and their associations were investigated using χ 2 , t , Wilcoxon rank sum, and analysis of variance testing. Results were used to develop a BPM., Results: One hundred fifty patients were included; 87% were white, 74% were men, 48% had oropharyngeal cancer, and 58% had stage IVA disease. Treatment consisted of surgery alone (17%), radiation alone (11%), surgery plus radiation (14%), chemoradiation (45%), and surgery plus chemoradiation (13%). On multivariable analysis, both increasing group stage and number of treatment modalities used were significantly associated with higher cost. Given that stage often dictates treatment, we developed three cost tiers that were based on overall treatment modality. Tier A, the least costly, consisted of single-modality therapy with either surgery alone or radiation alone (median cost divided by the median overall cost of treatment, 0.54; 25th to 75th percentile range, 0.29 to 1.02), followed by tier B, which consisted of bimodality therapy with either chemoradiation or surgery plus radiation (1.03; range, 0.81 to 1.35), followed by tier C, which consisted of trimodality therapy with surgery plus chemoradiation (1.43; range, 1.10 to 1.96)., Conclusion: The number of treatment modalities required is the primary driver of cost in HNC. These data can simplify development of a comprehensive HNC BPM.

Background/aim: There are limited data regarding survival, failure patterns, and factors associated with disease recurrence in patients with cutaneous squamous cell cancer of the head and neck (cSCC-HN) with nodal metastases., Patients and Methods: A retrospective analysis of patients with cSCC-HN metastatic to cervical and/or parotid lymph nodes treated with surgery and post-operative radiation therapy was performed., Results: This study included 76 patients (57 immunocompetent and 18 immunosuppressed) with a median follow-up of 18 months. Overall survival, disease-free survival (DFS), and disease recurrence (DR) at 2 years was 60%, 49%, and 40%, respectively. Immunosuppressed patients had significantly lower 2-year DFS (28% vs. 55%; p=0.003) and higher DR (61% vs. 34%; p=0.04) compared to immunocompetent patients. Analysis of immunocompetent patients demonstrated extracapsular extension (ECE) as the only factor associated with DR (p<0.0001)., Conclusion: Patients with nodal metastases from cSCC-HN have suboptimal outcomes. ECE and immunosuppression were significantly associated with DR., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC)., Methods: Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively., Results: Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P = .038) or ≥ 70 days (odds ratio, 2.04; P < .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality (P < .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P = .023)., Conclusions: Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018;124:1400-14. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Purpose The American Society for Radiation Oncology (ASTRO) produced an evidence-based guideline on radiation therapy in oropharyngeal squamous cell carcinoma (OPSCC) that was determined to be relevant to the American Society of Clinical Oncology (ASCO) membership. After applying standard critical appraisal policy and endorsement procedures, ASCO chose to endorse the ASTRO guideline. Methods The ASTRO guideline was reviewed by ASCO content experts for clinical accuracy and by ASCO methodologists for developmental rigor. On favorable review, an ASCO Expert Panel was convened to review the guideline contents and recommendations. The ASCO guideline approval body, the Clinical Practice Guidelines Committee, approved the final endorsement. Results The ASCO Expert Panel determined that the ASTRO guideline recommendations, published in July 2017, are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the ASTRO guideline and added minor qualifying statements. Recommendations Recommendations for the addition of systemic therapy to definitive radiotherapy in the treatment of OPSCC, postoperative radiotherapy with and without systemic therapy following primary surgery of OPSCC, induction chemotherapy in the treatment of OPSCC, and the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the treatment of OPSCC are outlined for a variety of disease stages and clinical scenarios. ASCO Endorsement Panel qualifying statements and minor modifications were made to the ASTRO recommendations. The staging system that is referenced in these guidelines is the American Joint Committee on Cancer Staging Manual, 7th edition. Additional information is available at: www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

Objective: Nivolumab is the first drug to demonstrate a survival benefit for platinum-refractory recurrent or metastatic head and neck cancer. We performed a cost-utility analysis to assess the economic value of nivolumab as compared to alternative standard agents in this context., Materials and Methods: Using data from the CheckMate 141 trial, we constructed a Markov simulation model from the US payer's perspective to evaluate the cost-effectiveness of nivolumab compared to physician choice of either cetuximab, methotrexate or docetaxel. Alternative strategies considered included: single-agent cetuximab, methotrexate or docetaxel, or first testing for PD-L1 to select for nivolumab. Costs were extracted from Medicare and utilities from the literature and CheckMate. Probabilistic sensitivity analysis (PSA) was used to evaluate parameter uncertainty. $100,000/QALY was the primary threshold for cost-effectiveness., Results: When comparing nivolumab to the standard arm of CheckMate, nivolumab demonstrated an incremental cost-effectiveness ratio (ICER) of $140,672/QALY. When comparing standard therapies, methotrexate was the most cost-effective with similar results for docetaxel. Nivolumab was cost-effective compared to single-agent cetuximab (ICER $89,786/QALY). Treatment selection by PD-L1 immunohistochemistry did not markedly improve the cost-effectiveness of nivolumab. Factors likely to positively impact the cost-effectiveness of nivolumab include better baseline quality-of-life, poor tolerability of standard treatments and/or a lower cost of nivolumab., Conclusions: Nivolumab is preferred to single-agent cetuximab but requires a willingness-to-pay of at least $150,000/QALY to be considered cost-effective when compared to docetaxel or methotrexate. Selection by PD-L1 does not markedly improve the cost-effectiveness of nivolumab. This informs patient selection and clinical care-path development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: To determine the patterns of adjuvant chemoradiotherapy use in elderly patients treated with definitive surgical resection for squamous cell carcinoma of the head and neck with extracapsular extension (ECE) or positive margins and determine whether an association with overall survival (OS) exists with adjuvant concurrent chemoradiotherapy (CRT)., Methods and Materials: The National Cancer Database was queried to identify patients with SCC of the oral cavity, oropharynx, larynx, and hypopharynx who were treated with primary definitive surgery and adjuvant radiation therapy between 2004 and 2012. For elderly patients (aged >70 years) with pathology revealing ECE or positive margin, the benefit of concurrent chemotherapy was explored using multivariable Cox proportional hazards modeling., Results: A total of 7349 patients were identified meeting study criteria, of whom 1187 were elderly (aged >70 years) with a median follow-up of 30.6 months. Of these elderly patients, 445 had ECE or positive margin and represent the study population, of whom 187 (42%) received CRT. Delivery of CRT in this cohort increased over the study period, and intensity modulated radiation therapy was associated with increased use of CRT (odds ratio 2.07; P=.004). Increasing age was associated with reduced use of CRT (odds ratio 0.88; P<.001). Chemoradiotherapy was associated with a significant improvement in OS on multivariable analysis (hazard ratio 0.74; P=.04) and a trend toward significance on inverse propensity score analysis (hazard ratio 0.78; P=.051). Three-year OS was 53.8% in the CRT group, compared with 44.6% in the adjuvant radiation therapy-alone patients., Conclusions: The use of adjuvant CRT is increasing among elderly patients with resected squamous cell carcinoma of the head and neck exhibiting ECE or positive margins. Chemoradiotherapy was associated with an improvement in OS on multivariable analysis but not propensity-weighted analysis. Among fit elderly patients with ECE or positive margins after definitive surgical resection, concurrent chemotherapy can be carefully considered., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Severe late dysphagia is common after chemoradiotherapy for cancers of the larynx and oropharynx. Options for reduction of severe late dysphagia are limited for human papillomavirus (HPV)-negative patients. In this study, the role of feeding tube choice in severe late dysphagia is investigated., Methods: Patients disease-free after chemoradiotherapy for HPV-negative cancers of the laryngopharynx who received a feeding tube on-treatment were identified. The incidence of severe late dysphagia after reactive nasogastric (R-NG), proactive or reactive percutaneous gastrostomy (P-PEG or R-PEG) was assessed using log-rank and Cox analyses., Results: Seventy-eight patients received a feeding tube on-treatment and remained disease-free. Median follow-up was 64 months. The 5-year incidence of severe late dysphagia was 30.8% in the R-NG cohort (n = 36), 56.4% in the R-PEG (n = 17; p = .193), and 60.9% in the P-PEG (n = 25; p = .016) cohorts. On multivariate analysis, percutaneous gastrostomy (PEG) feeding was independently associated with an increased rate of severe late dysphagia., Conclusion: R-NG use during chemoradiotherapy is associated with less severe late dysphagia and is preferred over PEG. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1054-E1060, 2016., (© 2015 Wiley Periodicals, Inc.)

Background: Achieving locoregional control in high-risk patients with head and neck cancer who are poor candidates for standard continuous-course (chemo) radiotherapy due to advanced age, comorbidities, or very advanced disease is challenging. At our Institution, we have significant experience with a regimen of split-course, accelerated, hypofractionated radiotherapy (SCAHRT) for these patients., Patients and Methods: The SCAHRT regimen consisted of 60-72 Gy in 20-24 fractions separated by several weeks mid-course to allow for toxicity recovery and disease reassessment. It was used for patients with advanced age, significant co-morbidities, anticipated intolerance to definitive (chemo)radiation, and those with oligometastatic disease. Disease-free and overall survival rates were calculated using Kaplan-Meier analysis., Results: Fifty-eight out of 65 patients (89%) completed both courses of treatment. Patients without metastatic or recurrent disease were evaluated for treatment response and survival (n=39). Among this group, total tumor response was 91%, and median locoregional failure-free survival and overall survival were 25.7 and 8.9 months, respectively., Conclusion: In high-risk patients unable to tolerate continuous-course definitive (chemo)radiation, SCAHRT is a safe, well-tolerated and effective method of achieving durable locoregional disease control. In properly selected patients, this regimen is preferable to purely palliative approaches., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: The purpose of the present study was to identify variables associated with high risk of failure in patients with locally advanced squamous cell carcinoma of the oral cavity (SCC-OC)., Patients and Methods: This retrospective study included 191 patients with stage III-IVb SCC-OC treated with post-operative radiotherapy (RT) or chemoradiotherapy (CRT) between 1995 and 2013. Disease-free (DFS) and overall survival (OS) were analyzed; variables associated with inferior DFS were identified., Results: Seventy-five patients (39%) recurred. DFS and five-year OS were 52% and 54%, respectively. Poorly differentiated tumors (p=0.03), recurrent tumors (p=0.02) and high nodal ratio (p=0.02) were associated with an increased risk of recurrence. CRT was associated with improved DFS in patients with positive margins and/or extracapsular extension (p=0.021)., Conclusion: Tumors that are recurrent, high grade, or have high nodal ratio are at risk of recurrence. Presence of these disease features should be taken into consideration for better risk stratification., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Chemoradiotherapy results in excellent outcomes in locally advanced head and neck squamous cell carcinoma (HNSCC). This trial compared 2 chemoradiotherapy regimens., Methods: Patients with locally advanced HNSCC were treated with radiation (70-74.4 Gy), and randomized to arm A: cisplatin 100 mg/m(2) on radiotherapy (RT) days 1, 22, and 43, or arm B: cisplatin (20 mg/m(2) /day) and 5-fluorouracil (5-FU; 1000 mg/m(2) /day) continuous 96-hour infusions on RT weeks 1 and 4. The primary endpoint was relapse-free survival (RFS)., Results: Between February 2008 and October 2011, 69 patients were enrolled in this study. The study prematurely closed when a scheduled interim analysis showed superior outcomes in both arms and futility of continuation. Eighty-three percent of patients had oropharyngeal cancer, of these, 86% were human papillomavirus (HPV)/p16+. The 3-year Kaplan-Meier outcome estimates (median follow-up, 41 months) for arms A and B were: RFS 87% versus 80% (p = .24), overall survival 97% versus 85% (p = .013), locoregional control 96% versus 94% (p = .52), and distant metastatic control 91% versus 87% (p = .9)., Conclusion: Multiagent was not superior to single-agent chemoradiotherapy. Overrepresentation of HPV/p16+ patients resulted in better than expected outcomes., (© 2014 Wiley Periodicals, Inc.)

Introduction: The last few years have seen significant increase in the number of available clinical trials in head and neck cancer. It has been difficult to stay abreast of these efforts because multiple cooperative groups and institutions are engaged in their recruitment. This review presents the state of the art of available clinical trials organized around major research themes., Data Sources: Published literature, published cooperative group monographs, expert review., Review Methods: Initial themes in head and neck cancer clinical trial development were first identified along with examples. Opinions from an international panel of multidisciplinary experts were then solicited., Results/discussion: Current major themes of head and neck clinical trials centered on 5 major themes: (1) recognition of human papillomavirus oropharynx cancer and optimal treatment strategies, (2) defining the role of transoral surgery in head and neck cancer treatment, (3) improving postoperative adjuvant treatment, (4) investigation of rare malignancies, and (5) the importance of biomarker-driven, innovative, and targeted therapy investigation., Conclusions: A number of exciting clinical trials are currently in development or accrual with the potential for tremendous impact and improvement of the treatment of head and neck cancer., Implications for Practice: Awareness by practicing otolaryngologists and trainees of these current themes will be essential for study accrual, success, and improvement in the care of head and neck cancer., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2015.)

Background: Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (SCC) is associated with high cure rates and distant metastases are rare., Methods and Results: We report a case of a 61-year-old man presenting with acute left-sided weakness. An enhancing dural mass was noted and resected. Histology revealed p16-positive SCC. Further workup revealed a p16-positive right tonsillar primary with ipsilateral nodal disease and was classified as T2N2bM1. The patient underwent whole brain irradiation and definitive chemoradiation with curative intent. Complete clinical response was achieved and the patient continues to be disease-free 6 months posttreatment., Conclusion: HPV-associated oligometastatic oropharyngeal SCC is a rare entity that may have a unique natural history and behavior. Given the excellent treatment response and prognosis of HPV-positive disease in general, these patients may be appropriate for definitive treatment approaches., (© 2014 Wiley Periodicals, Inc.)

Head and neck squamous cell carcinoma is the fifth most common cancer worldwide. Patients who present with locally advanced disease are usually treated with a combined modality approach, often including chemotherapy, and frequently using the platinum agents cisplatin or carboplatin. In locally advanced head and neck squamous cell carcinoma, carboplatin and cisplatin have both been found to produce a survival benefit when added to radiation therapy. Although it appears that cisplatin may be more active, carboplatin is better tolerated. Cisplatin has been given concurrently with radiation every 3 weeks, weekly or daily. There have been no prospective trials comparing the different cisplatin dose schedules, but a dose of 100 mg/m(2) administered every 3 weeks on days 1, 22 and 43 with concurrent standard fractionation radiation therapy is the most widely used and tested regimen. The required total dose of cisplatin is also not known, although a necessary dose threshold of 200 mg/m(2) has been suggested.

Background: This phase II study tested the addition of the oral epidermal growth factor receptor gefitinib to multiagent concurrent chemoradiotherapy regimen in head and neck squamous cell cancer (HNSCC)., Methods: Patients with stage III-IV HNSCC received hyperfractionated radiation (72-74.4 Gy at 120 cGy twice daily), with concurrent 96-hour infusions of cisplatin 20 mg/m(2) /day and fluorouracil 1000 mg/m(2) /day given during weeks 1 and 4. Daily gefitinib 250 mg was started on day 1 of radiation and continued for 2 years. Results were retrospectively compared with our previous study using identical chemoradiotherapy without gefitinib., Results: Sixty patients were enrolled in the study; 80% had stage IV disease and 68% had oropharyngeal primary tumors. The full course of gefitinib was not tolerated by 42%; there were 5 treatment-related deaths (8%). With a median follow-up of 54 months, 2- and 3-year overall survival estimates were 80% and 71%, respectively. Projected distant metastatic control at 2 and 3 years was 88%. When compared with our historical cohort, acute toxicities including renal dysfunction and unplanned rehospitalization were worse in the study patients. Projected outcome estimates did not differ between the 2 cohorts., Conclusions: Addition of gefitinib to concurrent chemoradiotherapy was difficult to complete, did not improve outcomes, and increased toxicity., (Copyright © 2011 Wiley Periodicals, Inc.)

Definitive chemoradiation therapy has evolved as the preferred organ preservation strategy in the treatment of locally advanced head-and-neck cancer (LA-HNC). Dry mouth and dysphagia are among the most common and most debilitating treatment-related toxicities that frequently necessitate the placement of enteral feeding tubes (FT) in these patients to help them meet their nutritional requirements. The use of either a percutaneous endoscopic gastrostomy tube or a nasogastric tube, the choice of using a prophylactic vs a reactive approach, and the effects of FTs on weight loss, hospitalization, quality of life, and long-term functional outcomes are areas of continued controversy. Considerable variations in practice patterns exist in the United States and abroad. This critical review synthesizes the current data for the use of enteral FTs in this patient population and clarifies the relative advantages of different types of FTs and the timing of their use. Recent developments in the biologic understanding and treatment approaches for LA-HNC appear to be favorably impacting the frequency and severity of treatment-related dysphagia and may reduce the need for enteral tube feeding in the future., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: The reported decreasing benefit with increasing age from concurrent chemoradiotherapy in head and neck cancer patients prompted this retrospective review., Methods: Two courses of cisplatin-based concurrent chemoradiotherapy were given to fit patients ≥70 years with locoregionally advanced cancers. Clinical characteristics, treatment, and outcomes were compared with those for an identically treated cohort <70 years., Results: There were 44 patients ≥70 and 137 patients <70 years. Clinical characteristics, treatment and toxicities were similar except that the elderly were less likely to receive both chemotherapy courses, experienced more myelosuppression, required more unplanned hospitalization, and were feeding-tube dependent longer. Projected 5-year disease-specific survival (71% vs 74%) and freedom from recurrence (69% v. 71%) were nearly identical., Conclusions: Although these selected elderly patients experienced greater myelosuppression and supportive care requirements, outcomes were the same as in younger patients. Age alone should not be considered a contraindication to aggressive chemoradiotherapy for this disease., (Copyright © 2011 Wiley Periodicals, Inc.)

Chemotherapy has assumed an important role in multidisciplinary management of patients with head and neck cancer. Much recent progress is attributable to successful design and careful implementation of clinical trials. In addition to showing the efficacy of chemotherapy, trials also instruct about how to improve experimental design so that we can make the most of what is learned. In this Personal View, several important studies in head and neck cancer are reviewed, with focus on issues raised by their design, potential solutions to these difficulties, and challenges that future investigations of this disease will face., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: The management of initially bulky nodal disease after primary nonsurgical treatment for stage IV head and neck squamous cell carcinoma (HNSCC) continues to be a subject of debate., Methods: A retrospective chart review of neck management in patients after chemoradiation was performed., Results: Of the initially positive necks analyzed, 210/329 (65%) had a complete clinical response to treatment and 161 necks underwent neck surgery. Patients were pathologically positive 13.8% and 39.6% of the time after clinical complete or partial response, respectively. Regional recurrence was more frequent in necks with partial clinical (p = .04) or pathologic responses (p < .01) and with primary site recurrences (p < .01)., Conclusions: It is still safest at our institution to perform selective neck dissection on patients with > or = N2 neck disease when initially observed to prevent unsalvageable regional recurrence until more accurate interval assessment tools are confirmed.

Background: In an effort to optimize nonoperative therapy in patients with locoregionally advanced head and neck squamous cell cancer, the Southwest Oncology Group conducted a phase II trial combining 3-drug taxane-containing induction chemotherapy with accelerated fractionation/concomitant boost radiation and concomitant single-agent cisplatin., Methods: Two induction courses using docetaxel (75 mg/m(2) on day 1), cisplatin (100 mg/m(2) on day 1), and fluorouracil (1000 mg/m(2)/day continuous intravenous infusion days 1-4) were given, with an interval of 21 days. Patients who were stable or responded to the chemotherapy received definitive accelerated fractionation/concomitant boost radiation with concurrent cisplatin (100 mg/m(2)) on days 1 and 22 of radiation., Results: There were 74 eligible and evaluable patients enrolled between March 1, 2003, and August 15, 2004; 52 (70%) had stage IV disease. At least 1 grade 3-4 toxicity was experienced by 63 patients (85%) during induction. A total of 61 patients completed induction and began concurrent chemoradiotherapy; 50 (68%) completed all planned treatment. At least 1 grade 3-4 toxicity was noted in 53 of the 58 patients (91%) evaluated for toxicity from concurrent chemoradiotherapy. Two patients died during induction, and 2 during chemoradiation. With a median follow-up of 36 months (range, 14-50), the 2-year and 3-year overall survival estimates were 70% and 64%, with 2-year and 3-year progression-free survival estimates of 66% and 61%, respectively., Conclusions: Three-drug induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin is toxic but feasible within a cooperative group. In this patient cohort with advanced head and neck squamous cell cancer, overall and progression-free survivals were encouraging, justifying further study of this approach., (Copyright 2009 Wiley Periodicals, Inc.)

Several different approaches have been tested in an effort to integrate chemotherapy into definitive non-operative management of squamous cell head and neck cancer. In phase III randomized trials and in meta-analyses, the concomitant use of chemotherapy and radiation has proven to be the most consistently successful, and to produce both locoregional control and survival benefits, when compared to radiation therapy alone. Large, multi-institutional and cooperative group studies have now established high-dose single-agent cisplatin and concurrent radiation therapy as the standard of care for patients with advanced nasopharynx cancer, for patients with unresectable head and neck tumors, and as a postoperative adjuvant for patients with high-risk pathologic features. This same treatment regimen also has been demonstrated to be the most effective multi-modality treatment strategy for larynx preservation. Future investigation will focus on optimizing the concomitant chemotherapy and radiotherapy schedules used, integrating targeted agents into these established treatment schedules, addressing the problem of distant metastases, minimizing both acute and late toxicities, and identifying the most appropriate patient populations for this kind of aggressive treatment.

Objective: To report our experience using the neck examination, computed tomography (CT), and positron emission tomography (PET) to clinically evaluate node-positive patients with head and neck squamous cell cancer for residual neck node disease after definitive chemoradiotherapy., Design: Retrospective review of all Cleveland Clinic patients with head and neck squamous cell cancer and N2 or N3 neck node involvement at presentation who were treated with definitive concurrent chemoradiotherapy and who underwent clinical restaging after treatment using the neck examination, CT, and PET., Setting: Tertiary care referral institution., Patients: Forty-eight patients with 72 positive necks at diagnosis were followed up for a median of 20 months., Main Outcome Measures: Palpable nodes on examination, nodes larger than 1 cm, nodes with central necrosis on CT, or any hypermetabolic lymph nodes on PET were considered clinical evidence of residual nodal disease. The true rate of pathologic involvement was determined by histologic examination after planned neck dissection or if regional recurrence developed. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated for all 3 clinical assessment tools., Results: Planned neck dissection was performed in 33 necks and was positive for residual neck node disease in 5 necks. A delayed neck dissection was performed in 5 necks and was positive in 3 necks. The positive predictive value was low for all 3 clinical assessment tools. The addition of PET did not significantly improve the negative predictive value or positive predictive value of CT and the clinical examination., Conclusions: Residual neck node disease after definitive chemoradiotherapy was infrequent and was not well predicted by PET. A positive PET finding in this setting is of little utility. Although a negative PET finding was highly predictive for control of neck disease after chemoradiotherapy, it added little to the clinical neck examination and CT.

Background: Concurrent chemoradiation therapy has been demonstrated to be effective as an organ-sparing treatment for select advanced head and neck squamous cell carcinoma (HNSCC). However, this treatment modality is not without side effects. One side effect is the formation of upper esophageal strictures. As concurrent chemoradiation treatment is used more frequently, it is important to identify risk factors associated with stricture formation., Methods: A retrospective chart review of all patients who had undergone definitive concurrent chemoradiation treatment between 1989 and 2002 was performed. Exclusion criteria included death within 1 year or persistent/recurrent disease that required surgical salvage at the primary site. The outcome measure was stricture formation as determined by both objective findings (barium swallow or endoscopy) and the need for dilation after treatment., Results: Of the 222 patients in this cohort, there were enough data for 199 patients to assess for stricture formation. Strictures developed in a total of 41 patients (21%). Significant predictive factors were a twice-daily (BID) radiation fractionation (p = .007), female sex (p = .015), and a hypopharyngeal primary site (p = .01). Age and tumor extent were not significant factors in stricture formation (p = .15 and p = .23, respectively)., Conclusions: Symptomatic strictures occur in 21% of patients undergoing concurrent chemoradiation for HNSCC. Female sex, BID radiation fractionation, and a hypopharyngeal primary site are significant predictive factors for stricture formation., ((c) 2006 Wiley Periodicals, Inc.)

The use of systemic chemotherapy before definitive locoregional management, or induction chemotherapy, has been a theoretically attractive and well-studied approach in the management of squamous cell head and neck cancer. Although a decrease in distant metastases has frequently been observed, an improvement in survival from induction has been difficult to demonstrate. When chemotherapy and radiation are used concomitantly, however, an improvement in both survival and locoregional control can be identified, and this has led to the adoption of concurrent chemoradiotherapy as a standard of care for these patients. With this improvement in locoregional control, distant metastases have become a more frequently recognized cause of treatment failure, suggesting that an intervention, such as induction chemotherapy, directed at improving distant control might now be of some importance in improving overall treatment success. The recent development of taxane-containing, three-drug induction regimens that are capable of producing significantly better response rates than the older cisplatin and fluorouracil combination has also raised the possibility of a new and more important role for induction. The results of phase II investigations using this kind of a sequential schedule of induction chemotherapy followed by concurrent chemoradiotherapy have been encouraging, and phase III trials are now underway. This treatment approach remains investigational however, and these phase III studies are critical. The current randomized trials are reviewed and discussed.

Purpose: A retrospective review with long-term follow-up is reported from the Cleveland Clinic Foundation studying radiation and concurrent multiagent chemotherapy in patients with locoregionally advanced squamous cell head and neck cancer., Patients and Methods: Between 1989 and 2002, 222 patients were treated with 4-day continuous infusions of fluorouracil (1,000 mg/m2/d) and cisplatin (20 mg/m2/d) during weeks 1 and 4 of either once daily or twice daily radiation therapy. Primary site resection was reserved for patients with residual or recurrent primary site disease after chemoradiotherapy. Neck dissection was considered for patients with N2 or greater disease, irrespective of clinical response, and for patients with residual or recurrent neck disease., Results: With a median follow-up of 73 months, the Kaplan-Meier 5-year projected overall survival rate is 65.7%, freedom from recurrence rate is 74.0%, local control without the need for surgical resection rate is 86.7%, and overall survival rate with organ preservation is 62.2%. Including patients undergoing primary site resection as salvage therapy, the overall local control rate is 92.4%. Regional control rate at 5 years is 92.4%. Among patients with N2-3 disease, regional control was significantly better if a planned neck dissection was performed. Distant control at 5 years was achieved in 85.4% of patients and was significantly worse in patients with hypopharyngeal primary sites and patients with poorly differentiated tumors., Conclusion: Concurrent multiagent chemoradiotherapy can result in organ preservation and cure in the majority of appropriately selected patients with locoregionally advanced, nonmetastatic, squamous cell head and neck cancer. Distant metastatic disease was the most common cause of treatment failure. Late functional outcomes will require further investigation.

Squamous cell head and neck cancer is a relatively uncommon malignancy in North America. Nonetheless, it has been of considerable interest to medical oncologists because of its remarkable sensitivity to systemic chemotherapy. Even in patients with relapsed or metastatic disease, meaningful tumour shrinkage can be achieved with systemic therapy. This has led to the performance of carefully conducted clinical trials exploring the role of systemic chemotherapy, not only in the palliative setting, but as part of definitive multi-modality treatment. Chemotherapy has been used as the initial (or induction) treatment, as an adjuvant treatment after definitive surgery and/or radiation, and concurrent with both definitive and adjuvant radiation therapy. Evidence-based conclusions have been drawn from these clinical trials and have led to significant changes in the current standards of care for this disease. In this article, the available data supporting the use of systemic chemotherapy as palliative treatment, and as part of the definitive management for this disease will be reviewed.

Background: The role of neck dissection (ND) after definitive chemoradiotherapy for squamous cell head and neck cancer is incompletely defined. We retrospectively reviewed 109 patients with N2-N3 disease treated with chemoradiotherapy to identify predictors of a clinical complete response in the neck (CCR-neck), pathologic complete response after ND (PCR-neck), and regional failure., Method: All patients were given 4-day continuous infusions of 5-fluorouracil (1000 mg/m2/d) and cisplatin (20 mg/m2/d) during the first and fourth weeks of either once daily (n = 68) or twice daily (n = 41) radiation therapy. ND was considered for all patients after completion of chemoradiotherapy and was performed in 32 of the 65 patients achieving a CCR-neck after chemoradiotherapy and in all 44 patients with residual clinical evidence of neck disease. CCR-neck, PCR-neck, and regional failure were then correlated with potential predictors, including T, N, largest lymph node size (<3 cm, > or =3 cm), primary tumor site, and radiation fractionation schedule., Results: Achievement of a CCR-neck was predicted by N, N2 vs N3 (53 of 80 vs 12 of 29, p =.019) and by largest lymph node size, <3 cm vs > or =3 cm (19 of 25 vs 46 of 84, p =.06). Achievement of a PCR-neck could not be predicted by any clinical parameter. Regional failure occurred both in patients undergoing ND and those not dissected (5 of 76 vs 4 of 33, p =.33) and proved more likely only in the ND patients with residual positive pathology compared with those achieving a PCR-neck (5 of 25 vs 0 of 51, p <.001). Primary site was not a useful predictor of CCR-neck, PCR-neck, or regional failure. Most importantly, CCR-neck (vs

Purpose: The Head and Neck Intergroup conducted a phase III randomized trial to test the benefit of adding chemotherapy to radiation in patients with unresectable squamous cell head and neck cancer., Patients and Methods: Eligible patients were randomly assigned between arm A (the control), single daily fractionated radiation (70 Gy at 2 Gy/d); arm B, identical radiation therapy with concurrent bolus cisplatin, given on days 1, 22, and 43; and arm C, a split course of single daily fractionated radiation and three cycles of concurrent infusional fluorouracil and bolus cisplatin chemotherapy, 30 Gy given with the first cycle and 30 to 40 Gy given with the third cycle. Surgical resection was encouraged if possible after the second chemotherapy cycle on arm C and, if necessary, as salvage therapy on all three treatment arms. Survival data were compared between each experimental arm and the control arm using a one-sided log-rank test., Results: Between 1992 and 1999, 295 patients were entered on this trial. This did not meet the accrual goal of 362 patients and resulted in premature study closure. Grade 3 or worse toxicity occurred in 52% of patients enrolled in arm A, compared with 89% enrolled in arm B (P <.0001) and 77% enrolled in arm C (P <.001). With a median follow-up of 41 months, the 3-year projected overall survival for patients enrolled in arm A is 23%, compared with 37% for arm B (P =.014) and 27% for arm C (P = not significant)., Conclusion: The addition of concurrent high-dose, single-agent cisplatin to conventional single daily fractionated radiation significantly improves survival, although it also increases toxicity. The loss of efficacy resulting from split-course radiation was not offset by either multiagent chemotherapy or the possibility of midcourse surgery.

Purpose: Results are reported from an aggressive chemoradiotherapy protocol for advanced squamous cell head and neck cancer., Patients and Methods: Patients with advanced squamous cell head and neck cancer were treated with hyperfractionated radiation therapy (72 Gy at 1.2 Gy twice per day) and two courses of concurrent chemotherapy with fluorouracil (1,000 mg/m(2)/d) and cisplatin (20 mg/m(2)/d), both given as 96-hour continuous intravenous infusions during weeks 1 and 4 of radiation therapy. Primary-site resection was reserved for residual or recurrent primary-site disease after chemoradiotherapy. Neck dissection was considered for N2 or greater disease, irrespective of clinical response, and for residual or recurrent neck disease after nonoperative treatment., Results: Forty-one patients with stage IV disease were treated. Toxicity was significant, with grade 3 to 4 mucositis in 98%, dysphagia in 88%, and skin reaction in 85%. Neutropenic fever requiring hospitalization occurred in 51%. Despite feeding tube placement in 35 patients (85%), the mean weight loss during chemoradiotherapy was 13.3% of initial body weight. One patient died during treatment as a result of a pulmonary embolus. At a median follow-up period of 30 months, the 3-year Kaplan-Meier projected overall survival was 59%, disease-specific survival 69%, likelihood of local control without surgical resection 91%, and local control with surgical resection 97%. The likelihood of distant disease control at 3 years was 74%, and distant metastases were present in eight of 13 patients who died., Conclusion: This chemoradiotherapy schedule produces considerable but manageable toxicity. Survival and organ preservation are excellent for this poor-prognosis patient cohort. Distant metastases are the most common cause of treatment failure.