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Background Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer. Patients and Methods This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes’ B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes’ B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes’ B2 colon cancer with no additional chemotherapy. Results From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03–20.3 years). Among patients with Dukes’ B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes’ B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

PDF file - 55K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by NRAS and ERK cluster status.

PDF file - 67K, Odds Ratio and Hazard Ratio (with 95% Confidence Interval) with A Unit Increase in the Form of log10 Transformation in AQUA Scores by Biomarker.

PDF file - 61K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by PIK3CA, NRAS, and PTEN cluster status.

PDF file - 53K, Kaplan-Meier estimates of (a) overall survival, (b) progression-free survival by PIK3CA, PTEN, and Akt cluster status.

Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

Background: We hypothesized that a serum proteomic profile predictive of survival benefit in non–small cell lung cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) reflects tumor EGFR dependency regardless of site of origin or class of therapeutic agent.Methods: Pretreatment serum or plasma from 230 patients treated with cetuximab, EGFR-TKIs, or chemotherapy for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or colorectal cancer (CRC) were analyzed by mass spectrometry. Each sample was classified into “good” or “poor” groups using VeriStrat, and survival analyses of each cohort were done based on this classification. For the CRC cohort, this classification was correlated with the tumor EGFR ligand levels and KRAS mutation status.Results: In the EGFR inhibitor–treated cohorts, the classification predicted survival (HNSCC: gefitinib, P = 0.007 and erlotinib/bevacizumab, P = 0.02; CRC: cetuximab, P = 0.0065) whereas the chemotherapy cohort showed no survival difference. For CRC patients, tumor EGFR ligand RNA levels were significantly associated with the proteomic classification, and combined KRAS and proteomic classification provided improved survival classification.Conclusions: Serum proteomic profiling can detect clinically significant tumor dependence on the EGFR pathway in non–small cell lung cancer, HNSCC, and CRC patients treated with either EGFR-TKIs or cetuximab. This classification is correlated with tumor EGFR ligand levels and provides a clinically practical way to identify patients with diverse cancer types most likely to benefit from EGFR inhibitors. Prospective studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 19(2); 358–65

PDF file - 64K, Summary of Biomarker AQUA Scores at Baseline.

List of Supplemental Materials: Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

PDF file - 65K, REMARK Flow Chart of E2303 translational research study.

Purpose: We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial.Experimental Design: Sixty-three eligible patients with operable stage III/IV head and neck squamous cell cancer (HNSCC) participated in the Eastern Cooperative Oncology Group (ECOG) 2303 phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel, and carboplatin followed by chemoradiation with the same regimen. A tissue microarray (TMA) was constructed and EGF receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-κB, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were estimated by the Kaplan–Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate HRs and test for significance.Results: Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor extracellular signal–regulated kinase (ERK)1/2 levels were significantly associated with PFS [HR (low/high), 3.29; P = 0.026] and OS [HR (low/high), 4.34; P = 0.008]. On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (P = 0.024) and PFS (P = 0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis.Conclusions: These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results. Clin Cancer Res; 20(11); 3023–32. ©2014 AACR.

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.

Head and neck squamous cell carcinomas (HNSCCs) arising in the mucosal linings of the upper aerodigestive tract are highly heterogeneous, aggressive, and multifactorial tumors affecting more than half a million patients worldwide each year. Classical etiological factors for HNSCC include alcohol, tobacco, and human papillomavirus (HPV) infection. Current treatment options for HNSCCs encompass surgery, radiotherapy, chemotherapy, or combinatorial remedies. Comprehensive integrative genomic analysis of HNSCC has identified mutations in TP53 gene as the most frequent of all somatic genomic alterations. TP53 mutations are associated with either loss of wild-type p53 function or gain of functions that promote invasion, metastasis, genomic instability, and cancer cell proliferation. Interestingly, disruptive TP53 mutations in tumor DNA are associated with aggressiveness and reduced survival after surgical treatment of HNSCC. This review summarizes the current evidence and impact of TP53 mutations in HNSCC.

Introduction: Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southeast Asia, particularly Southern China. The classical non-keratinising cell type is almost unanimously associated with latent Epstein-Barr virus (EBV) infection. Circulating plasma EBV DNA can be a useful biomarker in various clinical aspects, but comprehensive recommendations and international guidelines are still lacking. We conducted a systematic review of all original articles on the clinical application of plasma EBV DNA for NPC; we further evaluated its strengths and limitations for consideration as standard recommendations. Methods: The search terms 'nasopharyngeal OR nasopharynx', and 'plasma EBV DNA OR cell-free EBV OR cfEBV' were used to identify full-length articles published up to December 2020 in the English literature. Three authors independently reviewed the article titles, removed duplicates and reviewed the remaining articles for eligibility. Results: A total of 81 articles met the eligibility criteria. Based on the levels of evidence and grades of recommendation assessed, it is worth considering the inclusion of plasma EBV DNA in screening, pre-treatment work-up for enhancing prognostication and tailoring of treatment strategy, monitoring during radical treatment, post-treatment surveillance for early detection of relapse, and monitoring during salvage treatment for recurrent or metastatic NPC. One major limitation is the methodology of measurement requiring harmonisation for consistent comparability. Conclusions: The current comprehensive review supports the inclusion of plasma EBV DNA in international guidelines in the clinical aspects listed, but methodological issues must be resolved before global application. 2021 Elsevier Ltd. All rights reserved.

Background Patients with advanced head and neck cancer have identified pain, fatigue, and difficulties swallowing, breathing, and communicating as high‐priority disease‐related symptoms. The Functional Assessment of Cancer Therapy‐Head and Neck Symptom Index‐10 (FHNSI‐10) assesses these symptoms. We sought to validate the FHNSI‐10, another brief symptom index (FHNSI‐7), and individual symptom endpoints representing these high‐rated priority disease symptoms among patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Methods Patients (N = 239) were enrolled in a phase III randomized clinical trial (E1302) and completed the FHNSI‐10 at multiple time points. We assessed the internal consistencies and test–retest reliabilities of the FHNSI‐10 and FHNSI‐7 scores, and the known‐groups validity, predictive criterion validity, and responsiveness‐to‐change of the symptom indexes and individual symptom endpoint scores. Results The FHNSI‐10 and FHNSI‐7 indexes showed satisfactory internal consistencies (Cronbach's alpha coefficient range 0.60‐0.75) and acceptable test–retest reliabilities (intraclass correlation coefficients = 0.75 and 0.74, respectively). The FHNSI‐10, FHNSI‐7, and the pain, fatigue, swallowing, and breathing symptom scores showed evidence of known‐groups validity by performance status at baseline. The FHNSI‐10, FHNSI‐7, and the pain, fatigue, and breathing symptom scores at baseline showed evidence of predictive criterion validity for overall survival, but not time‐to‐progression (TTP). Changes in the symptom indexes and individual symptom scores were not associated with changes in performance status over 4 weeks, though most patients had stable performance status. Conclusions There is initial evidence of validity for the FHNSI‐10 and FHNSI‐7 indexes and selected individual symptom endpoints as brief disease‐related symptom assessments for patients with recurrent or metastatic SCCHN., The patient‐centered FHNSI‐10 and FHNSI‐7 symptom indexes show evidence of validity and reliability for use among patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Individual symptom endpoints (1‐2 items each) are also valid for assessing pain, fatigue, swallowing, and breathing in this population.

Studies suggest that adjuvant chemotherapy should be initiated at the earliest possible time. The Eastern Cooperative Oncology Group (ECOG) and Intergroup evaluated the effect of perioperative fluorouracil (5-FU) on overall survival (OS) for colon cancer.This phase III trial randomized patients to receive continuous infusional 5-FU for 7 days starting within 24 h after curative resection (arm A) or no perioperative 5-FU (arm B). Patients with Dukes' B3 and C disease received adjuvant chemotherapy per standard of care. The primary endpoint of the trial was overall survival in patients with Dukes' B3 and C disease. The secondary objective was to determine whether a week of perioperative infusion would affect survival in patients with Dukes' B2 colon cancer with no additional chemotherapy.From August 1993 to May 2000, 859 patients were enrolled and 855 randomized (arm A: 427; arm B: 428). The trial was terminated early due to slow accrual. The median follow-up is 15.4 years (0.03-20.3 years). Among patients with Dukes' B3 and C disease, there was no statistically significant difference in OS [median 10.3 years (95% CI 8.4, 13.2) for perioperative chemotherapy and 9.3 years (95% CI 5.7, 12.3) for no perioperative therapy, one-sided log-rank p = 0.178, HR = 0.88 (95% CI 0.66, 1.16)] or disease-free survival (DFS). For patients with Dukes' B2 disease, there was also no significant difference in OS (median 16.1 versus 12.9 years) or DFS. There was no difference between treatment arms in operative complications. One week of continuous infusion of 5-FU was tolerable; 18% of arm A patients experienced grade 3 or greater toxicity.

PURPOSE We evaluated the addition of bevacizumab, a humanized monoclonal antibody that targets vascular endothelial growth factor, to platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS Patients with chemotherapy-naïve (or with prior platinum as part of multimodal therapy completed ≥ 4 months earlier) recurrent or metastatic SCCHN were randomly assigned to receive a platinum-based chemotherapy doublet with or without bevacizumab 15 mg/kg given intravenously every 3 weeks until disease progression. Chemotherapy could be discontinued after six cycles if a maximum response was achieved. RESULTS The study randomly assigned 403 patients. Median overall survival (OS) was 12.6 months with bevacizumab plus chemotherapy (BC) and 11.0 months with chemotherapy alone (hazard ratio, 0.87; 95% CI, 0.70 to 1.09; P = .22). At 2, 3, and 4 years, the OS rates were 25.2% v 18.1%, 16.4% v 10.0%, and 11.8% v 6.4% for BC versus chemotherapy, respectively. In an analysis of 365 eligible patients who started treatment, the hazard ratio was 0.82 (95% CI, 0.65 to 1.04; P = .10), with a median OS of 14.2 months on BC v 11.1 months on chemotherapy. Median progression-free survival with BC was 6.0 months v 4.3 months with chemotherapy ( P = .0014). Overall response rates were 35.5% with BC and 24.5% with chemotherapy ( P = .016). There was increased toxicity, including a higher rate of treatment-related grade 3 to 5 bleeding events (6.7% v 0.5%; P < .001) and treatment-related deaths (9.3% v 3.5%; P = .022) with BC versus chemotherapy. CONCLUSION The addition of bevacizumab to chemotherapy did not improve OS but improved the response rate and progression-free survival with increased toxicities. These results encourage biomarker-driven studies of angiogenesis inhibitors with better toxicity profiles in select patients with SCCHN.

Gastroesophageal junction (GEJ) cancer remains a clinically significant disease in Western countries due to its increasing incidence, which mirrors that of esophageal cancer, and poor prognosis. To develop novel and effective approaches for prevention, early detection, and treatment of patients with GEJ cancer, a better understanding of the mechanisms driving pathogenesis and malignant progression of this disease is required. These efforts have been limited by the small number of available cell lines and appropriate pre-clinical animal models for in vitro and in vivo studies. We have established and characterized a novel GEJ cancer cell line, GEAMP, derived from the malignant pleural effusion of a previously treated GEJ cancer patient. Comprehensive genetic analyses confirmed a clonal relationship between GEAMP cells and the primary tumor. Targeted next-generation sequencing identified 56 non-synonymous alterations in 51 genes including TP53 and APC, which are commonly altered in GEJ cancer. In addition, multiple copy-number alterations were found including EGFR and K-RAS gene amplifications and loss of CDKN2A and CDKN2B. Histological examination of subcutaneous flank xenografts in nude and NOD-SCID mice showed a carcinoma with mixed squamous and glandular differentiation, suggesting GEAMP cells contain a sub-population with multi-potent potential. Finally, pharmacologic inhibition of the EGFR signaling pathway led to downregulation of key downstream kinases and inhibition of cell proliferation in vitro. Thus, GEAMP represents a valuable addition to the limited number of bona fide GEJ cancer cell lines.

Contains fulltext : 235407.pdf (Publisher’s version ) (Closed access) BACKGROUND: Randomised, controlled trials and meta-analyses have shown the survival benefit of concomitant chemoradiotherapy or hyperfractionated radiotherapy in the treatment of locally advanced head and neck cancer. However, the relative efficacy of these treatments is unknown. We aimed to determine whether one treatment was superior to the other. METHODS: We did a frequentist network meta-analysis based on individual patient data of meta-analyses evaluating the role of chemotherapy (Meta-Analysis of Chemotherapy in Head and Neck Cancer [MACH-NC]) and of altered fractionation radiotherapy (Meta-Analysis of Radiotherapy in Carcinomas of Head and Neck [MARCH]). Randomised, controlled trials that enrolled patients with non-metastatic head and neck squamous cell cancer between Jan 1, 1980, and Dec 31, 2016, were included. We used a two-step random-effects approach, and the log-rank test, stratified by trial to compare treatments, with locoregional therapy as the reference. Overall survival was the primary endpoint. The global Cochran Q statistic was used to assess homogeneity and consistency and P score to rank treatments (higher scores indicate more effective therapies). FINDINGS: 115 randomised, controlled trials, which enrolled patients between Jan 1, 1980, and April 30, 2012, yielded 154 comparisons (28 978 patients with 19 253 deaths and 20 579 progression events). Treatments were grouped into 16 modalities, for which 35 types of direct comparisons were available. Median follow-up based on all trials was 6·6 years (IQR 5·0-9·4). Hyperfractionated radiotherapy with concomitant chemotherapy (HFCRT) was ranked as the best treatment for overall survival (P score 97%; hazard ratio 0·63 [95% CI 0·51-0·77] compared with locoregional therapy). The hazard ratio of HFCRT compared with locoregional therapy with concomitant chemoradiotherapy with platinum-based chemotherapy (CLRT(P)) was 0·82 (95% CI 0·66-1·01) for overall survival. The superiority of HFCRT was robust to sensitivity analyses. Three other modalities of treatment had a better P score, but not a significantly better HR, for overall survival than CLRT(P) (P score 78%): induction chemotherapy with taxane, cisplatin, and fluorouracil followed by locoregional therapy (IC(TaxPF)-LRT; 89%), accelerated radiotherapy with concomitant chemotherapy (82%), and IC(TaxPF) followed by CLRT (80%). INTERPRETATION: The results of this network meta-analysis suggest that further intensifying chemoradiotherapy, using HFCRT or IC(TaxPF)-CLRT, could improve outcomes over chemoradiotherapy for the treatment of locally advanced head and neck cancer. FUNDINGS: French Institut National du Cancer, French Ligue Nationale Contre le Cancer, and Fondation ARC.

Human papilloma virus (HPV) is a well-established causative factor in a subset of squamous cell carcinomas of the head and neck (HNSCC). Although HPV can be detected in various anatomical subsites, HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) is the most common HPV-related malignancy of the head and neck, and its worldwide incidence is constantly rising. Patients with OPSCC are generally younger, have less co-morbidities and generally have better prognosis due to different biological mechanisms of carcinogenesis. These facts have generated hypotheses on potential treatment modifications, aiming to minimize treatment-related toxicities without compromising therapy efficacy. Numerous randomized clinical trials have been designed to verify this strategy and increasingly real-world evidence data from retrospective, observational studies is becoming available. Until now, the data do not support any modification in contemporary treatment protocols. In this narrative review, we outline recent data provided by both randomized controlled trials and real-world evidence of HPV-positive OPSCC in terms of clinical value. We critically analyze the potential value and drawbacks of the available data and highlight future research directions. This article was written by members and invitees of the International Head and Neck Scientific Group.(www.IHNSG.com). ispartof: ORAL ONCOLOGY vol:123 ispartof: location:England status: published

Background We conducted a correlative study for E2399, a function preservation trial for resectable locally advanced oropharynx and larynx cancer, to prospectively assess effects of chemoradiation (CCR) on quality of life (QOL), swallowing and voice. We correlated the results of swallow assessments done via questionnaires and objective assessments by modified barium swallow (MBS). Methods The Functional Assessment of Cancer-HN (FACT-HN), the Performance Status Scale – Head and Neck (PSS-HN), swallow assessments (including modified barium swallow studies), and voice assessments: Voice Handicap Index (VHI), the Voice Disability Assessment (VDA), and American Speech-Language Hearing Association’s Functional Communication Measure (FCM) were conducted at baseline and periodically post-treatment for 2 years. Results Baseline QOL and swallowing function predicted overall survival. Patients experienced a marked decrease in QOL, swallowing, and speech post CCR although the decrease in vocal function was modest. Function and QOL returned towards baseline in the majority of patients by 12 months post treatment. Less than 10% of patients had severe dysphagia and were PEG dependent at 12 months post treatment. There was a high degree of correlation between the FACT-HN and PSS-HN swallow items. Statistically significant correlations were found between subjective and objective measures of swallow function. Conclusions Patients experience marked loss in swallowing function post CCR which returned to baseline in the majority of patients. The correlations between the FCM and self-report swallow items on the PSS and FACT-HN appear to be sufficiently strong to justify their use as a surrogate marker for swallowing disability in large therapeutic trials.

Background We analyzed systemic therapy plans submitted for commercially insured patients with untreated, newly diagnosed squamous cell carcinoma of the head and neck (SCCHN) to investigate patterns of practice. Methods Consecutive chemotherapy treatment plans were submitted using Eviti Connect (https://www.marylandphysicianscare.com/content/dam/centene/maryland/pdfs/evitiConnectFactSheet.pdf) portal for preauthorization between June 1, 2011, and June 30, 2015, were analyzed. Results A total of 387 treatment plans were submitted for 340 patients; 68 and 272 patients were from academic centers and community practices, respectively. Single agent cisplatin (57%), cetuximab (18%), and carboplatin (9%) were the most commonly proposed regimens concurrent with definitive radiotherapy (RT). The frequency of cetuximab use was not significantly different between academic centers and community practices. A clinical trial was proposed in only 15% of patients. Conclusion Among commercially insured patients with newly diagnosed, nonmetastatic SCCHN, the choice of systemic therapy in initial treatment plans was not significantly different between academic centers and community practices. Clinical trials are underutilized and should be encouraged.

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 .

Background The primary goal of treatment in advanced laryngeal cancer is to achieve optimal oncologic outcomes while preserving function and quality of life. Combination of chemotherapy and radiation has been popularized as an alternative to surgery for patients facing total laryngectomy. However, survival analyses from large, population-based databases have not duplicated results reported from randomized trials. Methods A comprehensive literature review was undertaken to try to better understand the reasons why results differ among randomized trials and population cohort studies. Results A variety of reasons are discussed, including differences in patient staging, selection bias, complexity bias, inconsistent terminology, patient compliance and treatment expertise. Conclusions Personalized treatment considering all factors is critical for optimal outcomes. In general, evidence supports total laryngectomy for patients with T4 cancers. Definitive chemoradiotherapy strategies are acceptable alternatives for T3 cancers, provided that all resources for the administration of the treatment, follow-up and surgical salvage are available.

Purpose Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). Methods and Materials A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m 2 , and irinotecan, 50 mg/m 2 , on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m 2 , and irinotecan, 65 mg/m 2 day 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m 2 , and paclitaxel, 50 mg/m 2 , day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m 2 , and paclitaxel, 175 mg/m 2 , day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. Results In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression- or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months ( P =.046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. Conclusions Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens.

Introduction Cetuximab, a monoclonal antibody to the epidermal growth factor receptor (EGFR), extends survival in combination with standard therapy in head and neck squamous cell carcinoma (HNSCC). However, as effects are modest, and patients experience side effects, a biomarker to predict resistance and personalize therapy is needed. Activation of signaling pathways downstream from receptor tyrosine kinases predicts resistance to such therapies in other cancers. The most common abnormalities downstream from EGFR in HNSCC are in the PI3K pathway, activated via loss of expression of the regulator PTEN, or via PI3K mutation. We studied whether PTEN and/or PI3K abnormalities predict resistance to cetuximab. Methods Tumor PTEN and PIK3CA/PI3K p110α were analyzed in samples from subjects treated on two trials of cetuximab-based therapy for patients with metastatic or recurrent HNSCC: E5397, a randomized trial of cisplatin plus placebo versus cisplatin plus cetuximab; and NCI-8070, a randomized trial of cetuximab plus sorafenib versus cetuximab. In situ quantification of PTEN and PI3K p110 α was performed using the AQUA™ method of quantitative immunofluorescence. PI3KCA hot spot mutations were determined with BEAMing. Results For E5397, in multivariable analysis, PTEN expressing/PIK3CA WT patients tended to improve PFS with cetuximab compared to placebo (N = 48; HR = 0.54, Wald p = 0.0502). High PTEN expression was significantly associated with superior PFS among patients treated on NCI-8070 (N = 37; HR = 0.35, p = 0.008). Conclusion Loss of PTEN expression may be associated with lack of benefit from cetuximab. This analysis is limited by small sample size, and PTEN as a potential predictive biomarker merits validation in larger sample sets.

Purpose To provide a review of the clinical data, controversies, and limitations that underpin current recommendations for approaches to larynx preservation for locally advanced larynx cancer requiring total laryngectomy. Methods The key findings from pivotal randomized controlled trials are discussed, including quality of life, late effects, and function assessments. Trials investigating taxane inclusion in induction chemotherapy and trials of epidermal growth factor receptor inhibition for radiosensitization are put into perspective for larynx cancer. Controversies in the management of T4 primaries and the opportunities for conservation laryngeal surgery are reviewed. Results There are data from clinical trials to support induction chemotherapy, followed by radiotherapy (preferred approach in Europe) and concomitant cisplatin plus radiotherapy (preferred in North America) for nonsurgical preservation of the larynx. Treatment intensification by a sequential approach of induction, followed by concomitant treatment, is investigational. Transoral laryngeal microsurgery and transoral robotic partial laryngectomy have application in selected patients. Conclusion The management of locally advanced larynx cancer is challenging and requires an experienced multidisciplinary team for initial evaluation, response assessment, and support during and after treatment to achieve optimal function, quality of life, and overall survival. Patient expectations, in addition to tumor extent, pretreatment laryngeal function, and coexisting chronic disease, are critical factors in selecting surgical or nonsurgical primary treatment.

As one solution to reducing costs and medical bank- ruptcies, experts have suggested that patients and physicians should discuss the cost of care up front. Whether these discus- sions are possible in an oncology setting and what their effects on the doctor-patient relationship are is not known. Methods: We used the National Comprehensive Cancer Network (NCCN) Guidelines and the eviti Advisor platform to show patients with metastatic breast, lung, or colorectal cancer the costs associated with their chemotherapy and/ or targeted therapy options during an oncology consulta- tion. We measured provider attitudes and assessed patient satisfaction when consultations included discussion of costs. Results: We approached 107 patients; 96 (90%) enrolled onto the study, three (3%) asked if they could be interviewed at a later date, and eight (7%) did not want to participate. Onlyfive of 18 oncologists (28%) felt comfortable discussing costs, and only one of 18 (6%) regularly askedpatientsaboutfinancialdifficulties.Themajorityofpatients(80%) wanted cost information, and 84% reported that these conversations wouldbeevenmoreimportantiftheirco-paysweretoincrease.Intotal, 72% of patients responded that no health care professional has ever discussed costs with them. The majority of patients (80%) had no negative feelings about hearing cost information. Conclusion: In an era of rising co-pays, patients with cancer want cost-of-treatment discussions, and these conversations do not lead to negative feelings in the majority of patients. Additional training to pre- pare clinicians for how to discuss costs with their patients is needed.

associated with treatment. The goals of HNSCC therapy can be categorized as either curative, employing either surgery and/or radiotherapy as a therapeutic backbone, or palliative, where symptom management and maintenance or improvement of quantity and quality of life are the primary focus. Systemic therapies (chemotherapy and targeted molecular therapeutics) have been an important addition to the therapeutic armamentarium against HNSCC. Although generally palliative when employed as a single treatment modality, systemic therapy concurrent with radiation has become an important curative option for patients with advanced locoregional disease as initial therapy or in the high-risk postoperative setting. Randomized clinical trials have demonstrated that systemic therapy concurrent with Introduction

Purpose To update the guideline recommendations on the use of larynx-preservation strategies in the treatment of laryngeal cancer. Methods An Expert Panel updated the systematic review of the literature for the period from January 2005 to May 2017. Results The panel confirmed that the use of a larynx-preservation approach for appropriately selected patients does not compromise survival. No larynx-preservation approach offered a survival advantage compared with total laryngectomy and adjuvant therapy as indicated. Changes were supported for the use of endoscopic surgical resection in patients with limited disease (T1, T2) and for initial total laryngectomy in patients with T4a disease or with severe pretreatment laryngeal dysfunction. New recommendations for positron emission tomography imaging for the evaluation of regional nodes after treatment and best measures for evaluating voice and swallowing function were added. Recommendations Patients with T1, T2 laryngeal cancer should be treated initially with intent to preserve the larynx by using endoscopic resection or radiation therapy, with either leading to similar outcomes. For patients with locally advanced (T3, T4) disease, organ-preservation surgery, combined chemotherapy and radiation, or radiation alone offer the potential for larynx preservation without compromising overall survival. For selected patients with extensive T3 or large T4a lesions and/or poor pretreatment laryngeal function, better survival rates and quality of life may be achieved with total laryngectomy. Patients with clinically involved regional cervical nodes (N+) who have a complete clinical and radiologic imaging response after chemoradiation do not require elective neck dissection. All patients should undergo a pretreatment baseline assessment of voice and swallowing function and receive counseling with regard to the potential impact of treatment options on voice, swallowing, and quality of life. Additional information is available at www.asco.org/head-neck-cancer-guidelines and www.asco.org/guidelineswiki .

For TP53-mutated head and neck squamous cell carcinomas (HNSCCs), the codon and specific amino acid sequence change resulting from a patient's mutation can be prognostic. Thus, developing a framework to predict patient survival for specific mutations in TP53 would be valuable. There are many bioinformatics and functional methods for predicting the phenotypic impact of genetic variation, but their overall clinical value remains unclear. Here, we assess the ability of 15 different methods to predict HNSCC patient survival from TP53 mutation, using TP53 mutation and clinical data from patients enrolled in E4393 by the Eastern Cooperative Oncology Group (ECOG), which investigated whether TP53 mutations in surgical margins were predictive of disease recurrence. These methods include: server-based computational tools SIFT, PolyPhen-2, and Align-GVGD; our in-house POSE and VEST algorithms; the rules devised in Poeta et al. with and without considerations for splice-site mutations; location of mutation in the DNA-bound TP53 protein structure; and a functional assay measuring WAF1 transactivation in TP53-mutated yeast. We assessed method performance using overall survival (OS) and progression-free survival (PFS) from 420 HNSCC patients, of whom 224 had TP53 mutations. Each mutation was categorized as "disruptive" or "non-disruptive". For each method, we compared the outcome between the disruptive group vs. the non-disruptive group. The rules devised by Poeta et al. with or without our splice-site modification were observed to be superior to others. While the differences in OS (disruptive vs. non-disruptive) appear to be marginally significant (Poeta rules + splice rules, P = 0.089; Poeta rules, P = 0.053), both algorithms identified the disruptive group as having significantly worse PFS outcome (Poeta rules + splice rules, P = 0.011; Poeta rules, P = 0.027). In general, prognostic performance was low among assessed methods. Further studies are required to develop and validate methods that can predict functional and clinical significance of TP53 mutations in HNSCC patients.

Background The purpose of this article was to study the association of human papillomavirus (HPV) with clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Archival baseline tumor specimens were obtained from patients treated on two clinical trials in recurrent or metastatic SCCHN: E1395, a phase III trial of cisplatin and paclitaxel versus cisplatin and 5-fluorouracil, and E3301, a phase II trial of irinotecan and docetaxel. HPV DNA was detected by in situ hybridization (ISH) with a wide-spectrum probe. p16 status was evaluated by immunohistochemistry. Clinical outcomes of interest were objective response, progression-free survival (PFS) and overall survival (OS). Results We analyzed 64 patients for HPV ISH and 65 for p16. Eleven tumors (17%) were HPV+, 12 (18%) were p16+, whereas 52 (80%) were both HPV- and p16-. The objective response rate was 55% for HPV-positive versus 19% for HPV-negative (P = 0.022), and 50% for p16-positive versus 19% for p16-negative (P = 0.057). The median survival was 12.9 versus 6.7 months for HPV-positive versus HPV-negative patients (P = 0.014), and 11.9 versus 6.7 months for p16-positive versus p16-negative patients (P = 0.027). After adjusting for other covariates, hazard ratio for OS was 2.69 (P = 0.048) and 2.17 (P = 0.10), favoring HPV-positive and p16-positive patients, respectively. The other unfavorable risk factor for OS was loss of ≥5% weight in previous 6 months (P = 0.0021 and 0.023 for HPV and p16 models, respectively). Conclusion HPV is a favorable prognostic factor in recurrent or metastatic SCCHN that should be considered in the design of clinical trials in this setting. Clinical Trial Identifier NCT01487733 Clinicaltrials.gov.

Purpose: We sought to evaluate the correlation between tissue biomarker expression (using standardized, quantitative immunofluorescence) and clinical outcome in the E2303 trial. Experimental Design: Sixty-three eligible patients with operable stage III/IV head and neck squamous cell cancer (HNSCC) participated in the Eastern Cooperative Oncology Group (ECOG) 2303 phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel, and carboplatin followed by chemoradiation with the same regimen. A tissue microarray (TMA) was constructed and EGF receptor (EGFR), ERK1/2, Met, Akt, STAT3, β-catenin, E-cadherin, EGFR Variant III, insulin-like growth factor-1 receptor, NF-κB, p53, PI3Kp85, PI3Kp110a, PTEN, NRAS, and pRb protein expression levels were assessed using automated quantitative protein analysis (AQUA). For each dichotomized biomarker, overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) were estimated by the Kaplan–Meier method and compared using log-rank tests. Multivariable Cox proportional hazards models were used to estimate HRs and test for significance. Results: Forty-two of 63 patients with TMA data on at least one biomarker were included in the biomarker analysis. Tumor extracellular signal–regulated kinase (ERK)1/2 levels were significantly associated with PFS [HR (low/high), 3.29; P = 0.026] and OS [HR (low/high), 4.34; P = 0.008]. On multivariable Cox regression analysis, ERK1/2 remained significantly associated with OS (P = 0.024) and PFS (P = 0.022) after controlling for primary site (oropharynx vs. non-oropharynx) and disease stage (III vs. IV), respectively. Clustering analysis revealed that clusters indicative of activated RAS/MAPK/ERK and/or PI3K/Akt pathways were associated with inferior OS and/or PFS and maintained significance in multivariable analysis. Conclusions: These results implicate PI3K/Akt and RAS/MAPK/ERK pathways in resistance to cetuximab-containing chemoradiation in HNSCC. Large prospective studies are required to validate these results. Clin Cancer Res; 20(11); 3023–32. ©2014 AACR.

Item does not contain fulltext The pattern of clinical behaviour and response to treatment of recurrent and/or metastatic head and neck squamous cell carcinoma is heterogeneous. Treatment strategies that can be employed vary from potentially curative salvage surgery and re-irradiation to palliative systemic therapies and best supportive care. The advent of new therapeutic options, in terms of more sophisticated surgical approaches and techniques, highly conformal and precise radiation techniques and immunotherapy may offer improved control of disease and longer survival. Moreover, the epidemiological changes during the last decades, including the increase of human papilloma virus-related oropharyngeal primary tumors, are also reflected in the recurrent and metastatic setting. In this complex context the identification of predictive and prognostic factors is urgently needed to tailor treatment, to increase its efficacy, and to avoid unnecessary toxicities. A better knowledge of prognosis may also help the patients and caregivers in decision making on the optimal choice of care. The purpose of our review is to highlight the current evidence and shortcomings in this field.

Objectives/Hypothesis To examine associations between quality of care, survival, and costs in elderly patients treated for laryngeal squamous cell cancer (SCCA). Study Design Retrospective analysis of Surveillance, Epidemiology, and End Results Medicare data. Methods We evaluated 2,370 patients diagnosed with laryngeal SCCA from 2004 to 2007 using multivariate regression and survival analysis. Using quality indicators derived from guidelines for recommended care, summary measures of quality were calculated for diagnosis, initial treatment, surveillance, treatment of recurrence, end-of-life care, performance, and an overall summary measure of quality. Results High-quality care was associated with significant differences in survival for diagnosis [HR = 0.80, 95% CI (0.66–0.97)], initial treatment [HR = 0.75 (0.63–0.88)], surveillance [HR = 0.54 (0.44–0.66)], treatment of recurrence [HR = 1.54 (1.26–1.89)], end-of-life care [HR = 0.69 (0.52–0.92)], performance [HR = 0.41 (0.33–0.52)], and an overall summary measure of quality [HR = 0.66 (0.54–0.80)], which was significantly associated with lower mean incremental costs [−$24,958 (−$35,873 – −$14,042)]. There was a significant survival advantage for initial treatment with surgery and postoperative radiation [HR = 0.66 (0.53–0.82)] and high-volume surgical care [HR = 0.64 (0.43–0.96)] after controlling for all other variables, including quality of care. Conclusions High-quality larynx cancer care in elderly patients was associated with improved survival and reduced costs; however, high-quality care for treatment of recurrence was associated with poorer survival. These data suggest that survival outcomes in elderly patients with laryngeal cancer are not entirely explained by differences in the receipt of quality care using existing treatment and performance quality indicators and also suggest a need to develop sensitive and valid quality indicators of larynx cancer care in this population. Level of Evidence 2c. Laryngoscope, 124:2049–2056, 2014

Purpose: Promoter hypermethylation is a well-documented mechanism for tumor-specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16INK4a in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes. Experimental Design: Methylation was assessed by quantitative methylation-specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable. Clinical data including demographics, stage, risk factor exposure, treatment, and outcome were collected by ECOG and RTOG. Methylation status was also correlated with mutation of TP53 (previously reported) and human papilloma virus status. Results: Methylation results were available for 368 cases, 353 of which also have p53 mutation status. At least one methylation event was present in all tumors. In multivariate analysis of the entire cohort, methylation of p16 was associated with decreased survival (HR = 1.008; P = 0.045). However, in tumors with disruptive TP53 mutation (poor prognostic group), the additional presence of methylation of p16 was protective (P = 0.019 considering p16 methylation as a continuous variable). Conclusion: Methylation of tumor-related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events. Clin Cancer Res; 19(9); 2528–40. ©2013 AACR.

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Purpose To report the long-term results of the Intergroup Radiation Therapy Oncology Group 91-11 study evaluating the contribution of chemotherapy added to radiation therapy (RT) for larynx preservation. Patients and Methods Patients with stage III or IV glottic or supraglottic squamous cell cancer were randomly assigned to induction cisplatin/fluorouracil (PF) followed by RT (control arm), concomitant cisplatin/RT, or RT alone. The composite end point of laryngectomy-free survival (LFS) was the primary end point. Results Five hundred twenty patients were analyzed. Median follow-up for surviving patients is 10.8 years. Both chemotherapy regimens significantly improved LFS compared with RT alone (induction chemotherapy v RT alone: hazard ratio [HR], 0.75; 95% CI, 0.59 to 0.95; P = .02; concomitant chemotherapy v RT alone: HR, 0.78; 95% CI, 0.78 to 0.98; P = .03). Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR, 1.25; 95% CI, 0.98 to 1.61; P = .08). Concomitant cisplatin/RT significantly improved the larynx preservation rate over induction PF followed by RT (HR, 0.58; 95% CI, 0.37 to 0.89; P = .0050) and over RT alone (P < .001), whereas induction PF followed by RT was not better than treatment with RT alone (HR, 1.26; 95% CI, 0.88 to 1.82; P = .35). No difference in late effects was detected, but deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8% v 20.8% with induction chemotherapy and 16.9% with RT alone). Conclusion These 10-year results show that induction PF followed by RT and concomitant cisplatin/RT show similar efficacy for the composite end point of LFS. Locoregional control and larynx preservation were significantly improved with concomitant cisplatin/RT compared with the induction arm or RT alone. New strategies that improve organ preservation and function with less morbidity are needed.

Significant correlations between the response to induction chemotherapy and success of subsequent radiotherapy have been reported and suggest that the response to induction chemotherapy is able to predict a response to radiotherapy. Therefore, induction chemotherapy may be used to tailor the treatment plan to the individual patient with head and neck cancer: following the planned subsequent (chemo) radiation schedule, planning a radiation dose boost, or reassessing the modality of treatment (eg, upfront surgery). Findings from reported trials suggest room for improvement in clinical response assessment after induction chemotherapy, but an optimal method has yet to be identified. Historically, indices of treatment efficacy in solid tumors have been based solely on systematic assessment of tumor size. However, functional imaging (eg, fluorodeoxyglucose-positron emission tomography (FDG-PET) potentially provides an earlier indication of response to treatment than conventional imaging techniques. More advanced imaging techniques are still in an exploratory phase and are not ready for use in clinical practice.

Contains fulltext : 126002.pdf (Publisher’s version ) (Closed access) In the past two decades, major modifications in the way we treat head and neck cancers, due to advances in technology and medical oncology, have led to a decline in the use of open surgery as first-line treatment of cancers arising from several primary tumor sites. The incidence of tobacco- and alcohol-related squamous cell carcinoma of the pharynx and larynx has been steadily decreasing, with a rise in the incidence of human papillomavirus-related oropharyngeal tumors and the use of minimally invasive endoscopic surgery and non-surgical treatment modalities has increased in the treatment of all of these tumors. However, open surgery remains the initial definitive treatment modality for other tumors, including tumors of the skin, oral cavity, sinonasal cavities and skull base, salivary glands, thyroid and sarcomas. Selected group of nasal, paranasal, base of the skull and thyroid tumors are also candidates for minimally invasive procedures. For some indications, the rate of open surgery has actually increased in the past decade, with an increase in the incidence of oral cavity, thyroid and skin cancer, an increase in the number of neck dissections performed, and an increase in salvage surgery and free flap reconstruction. The use of minimally invasive, technology-based surgery-with the use of lasers, operating microscopes, endoscopes, robots and image guidance-has increased. Technology, epidemiology and advances in other domains such as tissue engineering and allotransplantations may further change the domains of competencies for future head and neck surgeons.

Purpose Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. Methods and Materials A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m 2 i.v. on days 1, 22, and 43 (RT + CT). Results At 10 years, the local-regional failure rates were 28.8% vs 22.3% ( P =.10), disease-free survival was 19.1% vs 20.1% ( P =.25), and overall survival was 27.0% vs 29.1% ( P =.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs 21.0% ( P =.02), disease-free survival was 12.3% vs 18.4% ( P =.05), and overall survival was 19.6% vs 27.1% ( P =.07), respectively. Conclusion At a median follow-up of 9.4 years for surviving patients, no significant differences in outcome were observed in the analysis of all randomized eligible patients. However, analysis of the subgroup of patients who had either microscopically involved resection margins and/or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy. The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT.

Purpose Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. Methods and Materials This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube ≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors. Results A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P =.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P =.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome. Conclusions Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.

Background. To assess volumetric changes of human papillomavirus (HPV)-related lymph nodes (LN) before, during, and after a course of intensity-modulated radiation therapy (IMRT) � chemotherapy. Methods. Each ''pathologic'' LN (� 1 cm) was contoured on the available diagnostic/planning CTs before, during each week, and after treatment. Results. Seventy-nine LNs in 50 patients were identified. Beyond the first week of treatment, 3 patterns of LN change were recorded: consistently shrinking LN (n ¼ 33; 41.8%), inconsistently shrinking LN with temporary enlargement limited to the first week (n ¼ 14; 17.7%), or also during the subsequent weeks (n ¼ 32; 40.5%). Nodal density at planning is highly predictive of group assignment, with a larger mean density for consistently over incon- sistently shrinking LNs (p ¼ .009). Also, this grouping predicts the response at the end of treatment. Conclusion. HPV-related LN behavior during IMRT is extremely variable but somewhat predictable on the basis of nodal density at planning. V C 2012 Wiley Periodicals, Inc. Head Neck 00: 000-000, 2012

Purpose The Head and Neck Intergroup conducted a Phase III randomized trial to determine whether the addition weekly cisplatin to daily radiation therapy (RT) would improve survival in patients with unresectable squamous cell head-and-neck carcinoma. Methods and Materials Eligible patients were randomized to RT (70 Gy at 1.8–2 Gy/day) or to the identical RT with weekly cisplatin dosed at 20 mg/m 2 . Failure-free survival (FFS) and overall survival (OS) curves were estimated with the Kaplan-Meier method and compared with the log rank test. Results Between 1982 and 1987, 371 patients were accrued, and 308 patients were found eligible for analysis. Median follow-up was 62 months. The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups, respectively ( p = 0.30). The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS (compared to a p = 0.30 in univariate analysis). Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities. Late toxicities were not significantly different except for significantly more esophageal (9% vs. 3%, p = 0.03) and laryngeal (11% vs. 4%, p = 0.05) late toxicities in the RT + cisplatin group. Conclusion The addition of concurrent weekly cisplatin at 20 mg/m 2 to daily radiation did not improve survival, although there was evidence of activity. Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications.

Purpose XL184 (cabozantinib) is a potent inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2), and RET, with robust antiangiogenic, antitumor, and anti-invasive effects in preclinical models. Early observations of clinical benefit in a phase I study of cabozantinib, which included patients with medullary thyroid cancer (MTC), led to expansion of an MTC-enriched cohort, which is the focus of this article. Patients and Methods A phase I dose-escalation study of oral cabozantinib was conducted in patients with advanced solid tumors. Primary end points included evaluation of safety, pharmacokinetics, and maximum-tolerated dose (MTD) determination. Additional end points included RECIST (Response Evaluation Criteria in Solid Tumors) response, pharmacodynamics, RET mutational status, and biomarker analyses. Results Eighty-five patients were enrolled, including 37 with MTC. The MTD was 175 mg daily. Dose-limiting toxicities were grade 3 palmar plantar erythrodysesthesia (PPE), mucositis, and AST, ALT, and lipase elevations and grade 2 mucositis that resulted in dose interruption and reduction. Ten (29%) of 35 patients with MTC with measurable disease had a confirmed partial response. Overall, 18 patients experienced tumor shrinkage of 30% or more, including 17 (49%) of 35 patients with MTC with measurable disease. Additionally, 15 (41%) of 37 patients with MTC had stable disease (SD) for at least 6 months, resulting in SD for 6 months or longer or confirmed partial response in 68% of patients with MTC. Conclusion Cabozantinib has an acceptable safety profile and is active in MTC. Cabozantinib may provide clinical benefit by simultaneously targeting multiple pathways of importance in MTC, including MET, VEGFR2, and RET. A global phase III pivotal study in MTC is ongoing ( ClinicalTrials.gov number NCT00215605).

To evaluate the impact of surgeon and hospital case volume and other related variables on short-term outcomes after surgery for oropharyngeal cancer.The Maryland Health Service Cost Review Commission database was queried for oropharyngeal cancer surgical case volumes from 1990 to 2009. Multivariable regression models were used to identify significant associations between surgeon and hospital case volume, as well as independent variables predictive of in-hospital death, postoperative wound complications, length of hospitalization, and hospital-related cost of care.Overall, 1,534 oropharyngeal cancer surgeries were performed during the study period. Complete financial data was available for 1,482 oropharyngeal cancer surgeries, performed by 233 surgeons at 36 hospitals. The only independently significant factors associated with the risk of in-hospital death were an APR-DRG mortality risk score of 4 (odds ratio [OR] = 14.0, P.001) and total glossectomy (OR = 5.6, P = .020). Wound fistula or dehiscence was associated with an increased mortality risk score (OR = 5.9, P.001), total glossectomy (OR = 6.9, P.001), mandibulectomy (OR = 3.4, P.001), and flap reconstruction (OR = 2.1, P = .038). Increased mortality risk score, total glossectomy, pharyngectomy, mandibulectomy, flap reconstruction, neck dissection, and Black race were associated with an increased length of stay and hospital-related costs. After controlling for all other variables, a statistically significant negative correlation was observed between surgery at a high-volume hospital and length of hospitalization and hospital-related costs.After controlling for other factors, high-volume hospital care is associated with a shorter length of hospitalization and lower hospital-related cost of care for oropharyngeal cancer surgery.