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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.

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.

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.

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.

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 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.

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.

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 .

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.

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.

Lesson Learned Panitumumab plus irinotecan is not active for the treatment of esophageal adenocarcinoma. Background Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence. Panitumumab (Pa) is a fully humanized IgG2 monoclonal antibody against human EGFR. Cetuximab (Cx) combined with irinotecan (Ir) is active for second-line treatment of colorectal cancer. This phase II study was designed to evaluate Pa plus Ir as second-line therapy for advanced EAC. Methods The primary endpoint was response rate (RR). Patients with one prior treatment were given Pa 9 mg/m2 on day 1 and Ir 125 mg/m2 on days 1 and 8 of each 21-day cycle. Inclusion criteria were confirmed EAC, measurable disease, no prior Ir or Pa, performance status Results Twenty-four patients were enrolled; 18 were eligible and evaluable. These patients were all white, with a median age of 62.5 years (range, 33–79 years), and included 15 men and 3 women. The median number of cycles was 3.5. The most common grade 1–2 adverse events were fatigue, diarrhea, anemia, leukopenia, and hypoalbuminemia. Grade 3–4 adverse events included hematologic, gastrointestinal, electrolyte, rash, fatigue, and weight loss. The median follow-up was 7.2 months (range, 2.3–14 months). There were no complete remissions. The partial response rate was 6% (1/18; 95% confidence interval [CI], 0.01–0.26). The clinical benefit (partial response [PR] plus stable disease [SD]) rate was 50%. The median overall survival was 7.2 months (95% CI, 4.1–8.9) with an 11.1% 1-year survival rate. The median progression-free survival was 2.9 months (95% CI, 1.6–5.3). Conclusion Irinotecan and panitumumab as second-line treatment for advanced EAC are not active.

Biomarker research provides the opportunity to risk stratify patients based on identified prognostic and predictive markers. The need for such biomarkers is ­evident to improve response and survival outcomes in head and neck cancer through more rational patient selection for intensive curative regimens as well as palliative treatments. Increasing numbers of molecularly targeted therapeutics are in preclinical and clinical evaluation in head and neck cancer. These compounds, added to current chemotherapy and radiotherapy regimens, are costly and potentially add to normal tissue toxicity. This chapter focuses on markers with potential for testing in large validation clinical trials. As yet, no one marker has validated predictive capacity of utility in the selection of therapy for individuals with head and neck cancer. HPV-16 appears to be prognostic for better outcome while high EGFR expression is prognostic for poor outcome. Validated diagnostic tests that are widely available and collaboration among investigators are additional future challenges in biomarker research for head and neck cancer.

Squamous cell carcinoma arises from multiple anatomic subsites in the head and neck region. The risk factors for development of cancers of the oral cavity, oropharynx, hypopharynx, and larynx include tobacco exposure and alcohol dependence, and infection with oncogenic viruses is associated with cancers developing in the nasopharynx, palatine, and lingual tonsils of the oropharynx. The incidence of human papillomavirus-associated oropharyngeal cancer is increasing in developed countries, and by 2020, the annual incidence could surpass that of cervical cancer. The treatment for early-stage squamous cell cancers of the head and neck is generally single modality, either surgery or radiotherapy. The treatment for locally advanced head and neck cancers is multimodal, with either surgery followed by adjuvant radiation or chemoradiation as indicated by pathologic features or definitive chemoradiation. For recurrent disease that is not amenable to a salvage local or regional approach and for metastatic disease, chemotherapy with or without a biological agent is indicated. To date, molecular testing has not influenced treatment selection in head and neck cancer. This review will focus on the changing epidemiology, advances in diagnosis, and treatment options for squamous cell cancers of the head and neck, along with data on risk stratification specific to oropharyngeal cancer, and will highlight the direction of current trials.

Author(s): Chung, CH; Lee, JW; Slebos, RJ; Howard, JD; Perez, J; Kang, H; Fertig, EJ; Considine, M; Gilbert, J; Murphy, BA; Nallur, S; Paranjape, T; Jordan, RC; Garcia, J; Burtness, B; Forastiere, AA; Weidhaas, JB | Abstract: BackgroundA germline mutation in the 3'-untranslated region of KRAS (rs61764370, KRAS-variant: TG/GG) has previously been associated with altered patient outcome and drug resistance/sensitivity in various cancers. We examined the prognostic and predictive significance of this variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).Patients and methodsWe conducted a retrospective study of 103 HNSCCs collected from three completed clinical trials. KRAS-variant genotyping was conducted for these samples and 8 HNSCC cell lines. p16 expression was determined in a subset of 26 oropharynx tumors by immunohistochemistry. Microarray analysis was also utilized to elucidate differentially expressed genes between KRAS-variant and non-variant tumors. Drug sensitivity in cell lines was evaluated to confirm clinical findings.ResultsKRAS-variant status was determined in 95/103 (92%) of the HNSCC tumor samples and the allelic frequency of TG/GG was 32% (30/95). Three of the HNSCC cell lines (3/8) studied had the KRAS-variant. No association between KRAS-variant status and p16 expression was observed in the oropharynx subset (Fisher's exact test, P = 1.0). With respect to patient outcome, patients with the KRAS-variant had poor progression-free survival when treated with cisplatin (log-rank P = 0.002). Conversely, KRAS-variant patients appeared to experience some improvement in disease control when cetuximab was added to their platinum-based regimen (log-rank P = 0.04).ConclusionsThe TG/GG rs61764370 KRAS-variant is a potential predictive biomarker for poor platinum response in R/M HNSCC patients.Clinical trial registration numbersNCT00503997, NCT00425750, NCT00003809.

6000 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B showed promising efficacy in R/M SCCHN (Argiris et al. JCO 2011). E1305 was designed to evaluate the addition of B to a platinum doublet in R/M SCCHN. Methods: B-eligible pts with performance status 0-1, not having received chemotherapy for R/M SCCHN (prior chemotherapy for locally advanced disease allowed ≥ 4 months) and without factors predisposing to bleeding (history of bleeding due to SCCHN, anticoagulation, central cavitary lung metastasis, carotid invasion) were randomized to: A) one of 4 regimens (investigator's choice) given every 3 weeks: A1, cisplatin (C) 100 mg/m2, 5-FU 1000 mg/m2/day x 4 days; A2, carboplatin (Cb) AUC 6, 5-FU 1000 mg/m2/day x 4 days; A3, C 75 mg/m2, docetaxel (D) 75 mg/m2; A4, Cb AUC 6, D 75 mg/m2, or B) the same regimen (B1, B2, B3, B4) plus B 15 mg/Kg IV, every 3 weeks, until progression. Chemotherapy could be stopped after 6 cycles after maximum response. All pts received prophylactic antibiotics. The primary endpoint was overall survival (OS). Control median OS of 8.5 months (mo) was projected; the addition of B was hypothesized to increase median OS to 11.5 mo with a hazard ratio (HR) of 0.74. Results: 403 pts were randomized (200 in arm A; 203 in arm B). Baseline characteristics were well balanced. 38% in arm A/42% in arm B had an oropharyngeal primary; 87% received C or Cb plus D. With a median follow-up of 23.1 mo, median OS was 11 mo in arm A and 12.6 mo in arm B; HR 0.84 (95% CI 0.67-1.05), p = 0.13. The 1-, 2-, 3-, and 4-year OS were 46% vs 51%, 18% vs 26%, 8% vs 16%, 6% vs 13%, in arm A vs B, respectively. Median PFS was 4.4 mo in arm A and 6.1 mo in arm B (HR 0.71, 95% CI 0.58-0.87; p = 0.0012). Objective response rate was 25% in arm A vs 36% in arm B (p = 0.013). Grade 3-5 bleeding occurred in 3.5% in arm A vs 7.7% in arm B (p = 0.08). Conclusions: B added to a standard platinum doublet improved response rate and PFS but not OS in first-line treatment of R/M SCCHN. The control arm in this study performed better than expected. Clinical trial information: NCT00588770.

6074 Background: HPV HNC pts are younger and have a higher cure rate than smoking-related pts, and therefore carry treatment toxicities longer. Dose deintensification and conformal RT may result in decreased toxicity. We report the impact of these techniques on patient outcomes in E2399 and E1308 as measured through PROs. Methods: Longitudinal data on acute and late toxicities were recorded prospectively at baseline, post-treatment, and at 6, 12, 24 and 30 months in HPV+ pts on E1308 and HIV+/- pts on E2399 using the following measures: E1308: FACT-HN, KATZ Index of Independence (ADL), Brief Fatigue Index (BFI), Instrumental Activities of Daily Living (IADL), and the Vanderbilt Head and Neck Symptom Survey Version 2 (VHNSS V2); on E2399: FACT-HN. We correlated acute and late toxicities with de-escalation of RT dose (69.3Gy to 54Gy) on E1308, and with IMRT (E1308) vs. conformal RT (E2399). Results: 38 pts on E1308 completed 12 mo VHNSS V2; 32 received low dose IMRT and 6 standard dose, and 56 E2399 pts completed 12 mo FACT-HN. Items from the VHNSS V2 showed that difficulty eating solids (40% vs. 89%, p = 0.011) and improved nutrition (10% vs 44%, p = 0.025) were statistically improved at 12 months by lowering IMRT dose from 69.3Gy to 54Gy. The FACT-HN showed an improvement in eating solids at 12 mo when comparing low dose IMRT vs. 3DRT (65% vs. 33% had no or minimal solid food problems, p = 0.057). No other statistically significant reductions in toxicity were noted on any of the other PRO instruments. Conclusions: Both FACT-HN and VHNSS V2 demonstrated an improvement in eating solids by reducing IMRT dose. FACT-HN demonstrated that IMRT is associated with an improvement in eating solids when compared to 3DRT. Analyses are exploratory and need to be validated using randomized data.Future studies should stress accurate and complete PRO data. The KATZ, BFI, and IADL were not sensitive to detecting differences in toxicities from IMRT dose reduction on E1308. The VHNSS V2 and FACT-HN instruments corroborated specific toxicities both by RT technique as well as IMRT dose, and will therefore be utilized in future ECOG-ACRIN HNC studies. Clinical trial information: NCT01084083.

6066Background: Multiple standard of care options exist for locally advanced SCCHN. We analyzed treatment plans submitted for commercially insured patients by practicing medical oncologists for pre...

6022 Background: The addition of B, an anti-VEGF monoclonal antibody, to chemotherapy has improved outcomes in several solid tumors. Pemetrexed plus B in R/M SCCHN showed promising efficacy but sig...

e17036 Background: In preclinical HNSCC models, combined EGFR and Src inhibition with radiation has additive and possibly synergistic effects. We conducted a 3+3 standard Ph1 trial to determine the...