Dose-escalated intensity-modulated radiotherapy in patients with locally advanced laryngeal and hypopharyngeal cancers: ART DECO, a phase III randomised controlled trial.

BACKGROUND: Radical (chemo)radiotherapy offers potentially curative treatment for patients with locally advanced laryngeal or hypopharyngeal cancer. We aimed to show that dose-escalated intensity-modulated radiotherapy (DE-IMRT) improved locoregional control. METHODS: We performed a phase III open-label randomised controlled trial in patients with laryngeal or hypopharyngeal cancer (AJCC III-IVa/b, TNM 7). Patients were randomised (1:1) to DE-IMRT or standard dose IMRT (ST-IMRT) using a minimisation algorithm, balancing for centre, tumour site, nodal status and chemotherapy use. DE-IMRT was 67.2 gray (Gy) in 28 fractions (f) to the primary tumour and 56Gy/28f to at-risk nodes; ST-IMRT was 65Gy/30f to primary tumour and 54Gy/30f to at-risk nodes. Suitable patients received 2 cycles of concomitant cisplatin and up to 3 cycles of platinum-based induction chemotherapy. The primary end-point was time to locoregional failure analysed by intention-to-treat analysis using competing risk methodology. FINDINGS: Between February 2011 and October 2015, 276 patients (138 ST-IMRT; 138 DE-IMRT) were randomised. A preplanned interim futility analysis met the criterion for early closure. After a median follow-up of 47.9 months (interquartile range 37.5-60.5), there were locoregional failures in 38 of 138 (27.5%) ST-IMRT patients and 42 of 138 (30.4%) DE-IMRT patients; an adjusted subhazard ratio of 1.16 (95% confidence interval: 0.74-1.83, p = 0.519) indicated no evidence of benefit with DE-IMRT. Acute grade 2 pharyngeal mucositis was reported more frequently with DE-IMRT than with ST-IMRT (42% vs. 32%). No differences in grade ≥3 acute or late toxicity rates were seen. CONCLUSION: DE-IMRT did not improve locoregional control in patients with laryngeal or hypopharyngeal cancer. The trial is registered: ISRCTN01483375.

Copy number gain of 11q13.3 genes associates with pathological stage in hypopharyngeal squamous cell carcinoma.

Squamous cell carcinomas of the hypopharynx (HPSCC) and oropharynx (OPSCC) have markedly different patient outcomes. Differences in HPV prevalence between these two patient groups may account for some of this difference, but other molecular markers of prognosis or pathological phenotype have not been established. Copy number gain of oncogenes is a well-established molecular change contributing to HNSCC development. Quantitative PCR was used to explore copy number gains of specific genes (3q-PIK3CA, TP63; 11q13.3-CCND1, ANO1) in tumor DNA recovered from HPSCC (n = 48) and OPSCC (n = 52) patients. Associations between copy number gain, patient demographics, HPV/p16INK4a status and pathological stage were examined. HPV/p16 prevalence in HPSCC and OPSCC groups was 2.1% and 46.0%, respectively. HPSCCs had frequent gains of CCND1 (56.3%) and ANO1 (56.3%) but few gains of PIK3CA (6.3%). By contrast, OPSCCs had significantly fewer CCND1 (23.1%) and ANO1 (17.3%) gains, and significantly more PIK3CA (26.9%) gains. A mutually exclusive relationship between HPV/p16 and 11q13.3 gains was observed in OPSCCs, while PIK3CA and TP63 gains were similar across HPV-associated and smoking/alcohol-associated patients. ANO1 gain was significantly linked to tumor pathology in HPSCC, associating with nodal metastasis and smaller and less invasive tumors at presentation (P = 0.010). Our results provide a convincing link between a specific molecular change and disease phenotype that appears unique to our HPSCC population, supporting a model of 11q13.3 in promoting metastatic disease progression in HNSCC, and suggest a role for ANO1 as a molecular marker of metastatic disease. © 2016 Wiley Periodicals, Inc.

HPV-Related Oropharynx Cancer in the United Kingdom: An Evolution in the Understanding of Disease Etiology.

A rising incidence of oropharyngeal squamous cell carcinoma (OPSCC) incidence has occurred throughout the developed world, where it has been attributed to an increasing impact of human papillomavirus (HPV) on disease etiology. This report presents the findings of a multicenter cross-sectional retrospective study aimed at determining the proportion of HPV-positive and HPV-negative OPSCC within the United Kingdom. Archival tumor tissue blocks from 1,602 patients previously diagnosed with OPSCC (2002-2011) were collated from 11 centers. HPV status was determined with three validated commercial tests to provide valid data for 1,474 cases in total. Corresponding national incidence data from the same decade were obtained from UK Cancer registries. The overall proportion of HPV+ OPSCC between 2002 and 2011 was 51.8% [95% confidence interval (CI), 49.3-54.4], and this remained unchanged throughout the decade [unadjusted RR = 1.00 (95% CI, 0.99-1.02)]. However, over the same period, the incidence of OPSCC in the broader UK population underwent a 2-fold increase [age-standardized rate 2002: 2.1 (95% CI, 1.9-2.2); 2011: 4.1 (95% CI, 4.0-4.3)]. Although the number of OPSCCs diagnosed within the United Kingdom from 2002 to 2011 nearly doubled, the proportion of HPV+ cases remained static at approximately 50%. Our results argue that the rapidly increasing incidence of OPSCC in the United Kingdom cannot be solely attributable to the influence of HPV. The parallel increase in HPV+ and HPV- cases we documented warrants further investigation, so that appropriate future prevention strategies for both types of disease can be implemented. Cancer Res; 76(22); 6598-606. ©2016 AACR.

PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer.

BACKGROUND: The role of image-guided surveillance as compared with planned neck dissection in the treatment of patients with squamous-cell carcinoma of the head and neck who have advanced nodal disease (stage N2 or N3) and who have received chemoradiotherapy for primary treatment is a matter of debate. METHODS: In this prospective, randomized, controlled trial, we assessed the noninferiority of positron-emission tomography-computed tomography (PET-CT)-guided surveillance (performed 12 weeks after the end of chemoradiotherapy, with neck dissection performed only if PET-CT showed an incomplete or equivocal response) to planned neck dissection in patients with stage N2 or N3 disease. The primary end point was overall survival. RESULTS: From 2007 through 2012, we recruited 564 patients (282 patients in the planned-surgery group and 282 patients in the surveillance group) from 37 centers in the United Kingdom. Among these patients, 17% had nodal stage N2a disease and 61% had stage N2b disease. A total of 84% of the patients had oropharyngeal cancer, and 75% had tumor specimens that stained positive for the p16 protein, an indicator that human papillomavirus had a role in the causation of the cancer. The median follow-up was 36 months. PET-CT-guided surveillance resulted in fewer neck dissections than did planned dissection surgery (54 vs. 221); rates of surgical complications were similar in the two groups (42% and 38%, respectively). The 2-year overall survival rate was 84.9% (95% confidence interval [CI], 80.7 to 89.1) in the surveillance group and 81.5% (95% CI, 76.9 to 86.3) in the planned-surgery group. The hazard ratio for death slightly favored PET-CT-guided surveillance and indicated noninferiority (upper boundary of the 95% CI for the hazard ratio, <1.50; P=0.004). There was no significant difference between the groups with respect to p16 expression. Quality of life was similar in the two groups. PET-CT-guided surveillance, as compared with neck dissection, resulted in savings of £1,492 (approximately $2,190 in U.S. dollars) per person over the duration of the trial. CONCLUSIONS: Survival was similar among patients who underwent PET-CT-guided surveillance and those who underwent planned neck dissection, but surveillance resulted in considerably fewer operations and it was more cost-effective. (Funded by the National Institute for Health Research Health Technology Assessment Programme and Cancer Research UK; PET-NECK Current Controlled Trials number, ISRCTN13735240.).

Geographic variation in human papillomavirus-related oropharyngeal cancer: Data from 4 multinational randomized trials.

BACKGROUND: There are variations in the proportions of head and neck cancers caused by the human papillomavirus (HPV) between countries and regions. It is unclear if these are true variations or due to different study designs and assays. METHODS: We tested formalin-fixed paraffin-embedded diagnostic biopsies for p16 immunohistochemistry and HPV-DNA (by polymerase chain reaction [PCR] and in situ hybridization [ISH]) using validated protocols on samples from 801 patients with head and neck cancer recruited prospectively between 2006 and 2011 in 4 randomized controlled trials (RCTs). RESULTS: Twenty-one percent of patients (170 of 801) showed both HPV-DNA and p16-positivity, detected almost exclusively in oropharyngeal cancer (55%; 15 of 302); and only 1% of the patients (5 of 499) with nonoropharyngeal cancer were HPV positive. HPV-positive oropharyngeal cancer differed between Western and Eastern Europe (37%, 155 of 422 vs 6%, 8 of 144; p < .0001) and between Western Europe and Asia (37% vs 2%; 4 of 217; p < .0001). Other independent determinants of HPV positivity were tumor site and smoking. CONCLUSION: This is the first study to establish geographic variability as an independent risk factor in HPV-positive oropharyngeal cancer prevalence, with higher prevalence in Western Europe. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E1863-E1869, 2016.

Treatment, comorbidity and survival in stage III laryngeal cancer.

BACKGROUND: The purpose of this study was for us to identify factors associated with survival and laryngeal function in a contemporary, population-based study of stage III laryngeal carcinoma. METHODS: Patients presenting to a tertiary center with stage III laryngeal carcinoma between 1999 and 2010 were included in the study. Kaplan-Meier and Cox proportional hazards analyses were utilized. RESULTS: Of 137 patients receiving either surgery ± adjuvant therapy (SURG±Adj = 24.1%), chemoradiotherapy (CRT = 32.8%), or radiotherapy alone (RT = 36.5%), 5-year cause-specific survival (5-year CSS) was 81.0% and 2-year local relapse rate was 27.5%. RT had higher recurrence (p < .01), lower 5-year CSS (90.8% vs 87.8% vs 68.9%/SURG±Adj vs CRT vs RT/p = .0026) and lower overall survival (p = .001). Adjusting for excess of severe comorbidity in the RT group, there was no difference in 5-year CSS between treatment modality. CONCLUSION: SURG±Adj and CRT had similar survival. Severe comorbidity was associated with selection bias to RT and reduced 5-year CSS. Comorbidity is a key prognostic variable and should be considered in the interpretation of treatment outcomes.

A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy.

PURPOSE: Oral mucositis (OM) causes significant morbidity during the course of radiotherapy (RT) treatment of head-and-neck cancer. It is hypothesized that infection plays a role in the development of OM. We tested the efficacy of iseganan HCl (iseganan), a synthetic peptide with broad-spectrum antimicrobial activity, for preventing RT-associated OM. METHODS: A multinational, randomized, double-blind, controlled trial was performed on patients receiving primary RT, primary chemoradiotherapy or postoperative RT. Patients were randomized to receive iseganan oral solution plus standard-of-care oral hygiene (SOC), placebo plus SOC, or SOC alone throughout the RT administration period. The severity of OM was assessed by NCI-CTC scoring and clinical symptoms by patient questionnaire. RESULTS: A total of 545 patients were randomized to the study. Nine percent of the patients in both the iseganan and placebo groups did not develop ulcerative OM (Grades 2, 3, 4) (p = 0.998) whereas only 2% of the patients receiving SOC alone remained free of oral ulceration (p = 0.049). The maximum severity of mouth pain and difficulty swallowing did not differ in patients treated with iseganan or placebo. However, patients in both intervention groups reported less mouth pain and difficulty swallowing than did patients receiving SOC alone. Nausea was the only adverse event that occurred with >/=5% increased frequency in the iseganan group than in either the placebo or SOC groups (51% vs. 42% vs. 46%). Adverse events leading to study drug discontinuation and death did not differ significantly between groups. CONCLUSION: Iseganan oral solution was safe but did not reduce the risk for developing ulcerative OM relative to placebo. Intensified oral hygiene or the administration of the vehicle used to deliver study drug in this trial appears to have reduced the risk and severity of OM. Our results suggest that antimicrobial intervention may not meaningfully affect the pathogenesis of radiation-induced OM.