Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial.

BACKGROUND: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. METHODS: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. FINDINGS: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1-52·3). Median event-free survival was not reached (95% CI 44·7 months-not reached) in the pembrolizumab group and 46·6 months (27·5-not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68-1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). INTERPRETATION: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Prospective manipulation of the gut microbiome with microbial ecosystem therapeutic 4 (MET4) in HPV-related locoregionally-advanced oropharyngeal cancer squamous cell carcinoma (LA-OPSCC) undergoing primary chemoradiation: ROMA2 study.

BACKGROUND: Gut microbiome modulation to boost antitumor immune responses is under investigation. METHODS: ROMA-2 evaluated the microbial ecosystem therapeutic (MET)-4 oral consortia, a mixture of cultured human stool-derived immune-responsiveness associated bacteria, given with chemoradiation (CRT) in HPV-related oropharyngeal cancer patients. Co-primary endpoints were safety and changes in stool cumulative MET-4 taxa relative abundance (RA) by 16SRNA sequencing. Stools and plasma were collected pre/post-MET-4 intervention for microbiome and metabolome analysis. RESULTS: Twenty-nine patients received ≥1 dose of MET-4 and were evaluable for safety: drug-related adverse events (AEs) occurred in 13/29 patients: all grade 1-2 except one grade 3 (diarrhea). MET-4 was discontinued early in 7/29 patients due to CRT-induced toxicity, and in 1/29 due to MET-4 AEs. Twenty patients were evaluable for ecological endpoints: there was no increase in stool MET-4 RA post-intervention but trended to increase in stage III patients (p = 0.06). MET-4 RA was higher in stage III vs I-II patients at week 4 (p = 0.03) and 2-month follow-up (p = 0.01), which correlated with changes in plasma and stool targeted metabolomics. CONCLUSIONS: ROMA-2 did not meet its primary ecologic endpoint, as no engraftment was observed in the overall cohort. Exploratory findings of engraftment in stage III patients warrants further investigation of microbiome interventions in this subgroup.

Increased rates of invasive bacterial disease in late 2022.

Invasive bacterial disease is associated with significant morbidity and mortality. In winter 2022, there was an apparent increased rate of invasive bacterial disease compared to preceding years. Cross-site retrospective analysis of the three Children's Health Ireland (CHI) hospitals looking at children admitted between 1st October 2022-31st December 2022 (Q4) with community-acquired invasive bacterial disease, defined as an abscess in a normally sterile site in the head, neck and chest or isolation or PCR detection of Streptococcus pneumoniae, Neisseria meningitidis, Streptococcus pyogenes (Group A streptococcus) or Haemophilus influenzae from a normally sterile site. Case numbers were compared to Q4 in each of 2018-2021. Eighty-two children met the case definition in Q4 2022 vs 97 (Q4 2018-2021). In 2022, 42/82 (51%) were female, median age 3.75 years (1.5-8.25 years). Only 2 (2%) were immunosuppressed and 2 others (2%) had underlying neurodisability. Fifty (61%) were admitted on second or subsequent presentation to a healthcare setting. Fifty-six (68%) had an abscess in a sterile site. Bloodstream infection (positive blood culture or PCR: 24 (29%)) was the most common site of infection, followed by neck 22 (27%) and intracranial 12 (15%). Group A streptococcus (GAS) 27 (33%) was the most common organism isolated. Seven cases (9%) died in 2022 compared to 2 patients (2%) from 2018 to 2021 (p < 0.05). More children had Paediatric Overall Performance Category (POPC) scores > 1 in 2022 than 2018-2021 (p = 0.003).  Conclusion: Invasive bacterial diseases increased in Q4 2022 with higher morbidity and mortality than in the preceding 4 years. Group A streptococcal infection was the most significant organism in 2022. What is known: • Invasive bacterial disease is the leading cause of childhood mortality globally. • There was an increase in cases of invasive Group A streptococcus infections reported in many countries (including Ireland) during the winter of 2022/23. What is new: • Head, neck and chest abscesses increased in Q4 of 2022 compared to the previous 4 years combined. • Invasive bacterial infections in Q4 of 2022 were associated with higher rates of mortality (9%), paediatric intensive care unit (PICU) admission (24%) and requirement for surgical drainage or intervention (67%) than in the preceding years.

The Quantification of Radiation Fibrosis Using Clinically Indicated Magnetic Resonance Imaging for Head and Neck Cancer Patients.

Currently, no objective method exists to measure the extent of fibrosis in swallowing musculature in head and neck cancer (HNC) patients. We developed and psychometrically tested a method of quantifying fibrosis volume using magnetic resonance imaging (MRI). The overall aim of this study was to determine if clinical MRI is a reliable tool to measure fibrosis of the pharyngeal musculature in patients with HNC managed with RT and to assess its potential to capture changes in fibrosis over time. Eligible participants were adults with HNC treated with radiation therapy (RT) who received minimally two MRIs and videofluoroscopic swallow (VFS) studies from baseline (pre-RT) up to 1-year post-RT. Two neuroradiologists independently contoured fibrosis volume in batches from MRIs using Vitrea™. Sufficient inter-rater reliability was set at Intraclass Correlation Coefficient (ICC) > 0.75. Two speech-language pathologists independently rated VFSs for swallowing impairment using standardized scales, with discrepancies resolved by consensus. MRI and VFS scores were correlated using Spearman's rank coefficient. Participants included 42 adults (male = 33); mean age 59 (SD = 8.8). ICC (95% Confidence Interval) for fibrosis volume was 0.34 (0, 0.76) for batch one and 0.43 (0, 0.82) for batch two. Consensus meetings were held after each batch. Sufficient reliability was reached by batch three (ICC = 0.95 (0.79, 0.99)). Fibrosis volume increased significantly from 3 to 12 months (mean change = 1.28 mL (SD = 5.21), p = 0.006), as did pharyngeal impairment from baseline to 12 months (mean score change = 3.05 (SD = 3.02), p = 0.003). Fibrosis volume moderately correlated with pharyngeal impairment at 3 and 12 months (0.49, p = 0.004 and 0.59, p = 0.005, respectively). We demonstrated a reliable measure of fibrosis volume in swallowing musculature from existing clinical MRIs and identified that larger fibrosis volume was associated with worse swallowing function. The reliable capture of fibrosis volume offers a pragmatic method for early detection of fibrosis and concomitant dysphagia.

Cigarette smoking cessation, duration of smoking abstinence, and head and neck squamous cell carcinoma prognosis.

BACKGROUND: Tobacco use is a major risk factor for developing head and neck squamous cell carcinoma (HNSCC). However, the prognostic associations with smoking cessation are limited. The authors assessed whether smoking cessation and increased duration of abstinence were associated with improved overall (OS) and HNSCC-specific survival. METHODS: Clinicodemographic and smoking data from patients with HNSCC at Princess Margaret Cancer Center (2006-2019) were prospectively collected. Multivariable Cox and Fine and Gray competing-risk models were used to assess the impact of smoking cessation and duration of abstinence on overall mortality and HNSCC-specific/noncancer mortality, respectively. RESULTS: Among 2482 patients who had HNSCC, former smokers (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.58-0.87; p = .001; N = 841) had a reduced risk of overall mortality compared with current smokers (N = 931). Compared with current smokers, former smokers who quit >10 years before diagnosis (long-term abstinence; n = 615) had the most improved OS (aHR, 0.72; 95% CI, 0.56-0.93; p = .001). The 5-year actuarial rates of HNSCC-specific and noncancer deaths were 16.8% and 9.4%, respectively. Former smokers (aHR, 0.71; 95% CI, 0.54-0.95; p = .019) had reduced HNSCC-specific mortality compared with current smokers, but there was no difference in noncancer mortality. Abstinence for >10 years was associated with decreased HNSCC-specific death compared with current smoking (aHR, 0.64; 95% CI, 0.46-0.91; p = .012). Smoking cessation with a longer duration of quitting was significantly associated with reduced overall and HNSCC-specific mortality in patients who received primary radiation. CONCLUSIONS: Smoking cessation before the time of diagnosis reduced overall mortality and cancer-specific mortality among patients with HNSCC, but no difference was observed in noncancer mortality. Long-term abstinence (>10 pack-years) had a significant OS and HNSCC-specific survival benefit.

Active strike-slip faults and an outer frontal thrust in the Himalayan foreland basin.

The Himalayan foreland basin formed by flexure of the Indian Plate below the advancing orogen. Motion on major thrusts within the orogen has resulted in damaging historical seismicity, whereas south of the Main Frontal Thrust (MFT), the foreland basin is typically portrayed as undeformed. Using two-dimensional seismic reflection data from eastern Nepal, we present evidence of recent deformation propagating >37 km south of the MFT. A system of tear faults at a high angle to the orogen is spatially localized above the Munger-Saharsa basement ridge. A blind thrust fault is interpreted in the subsurface, above the sub-Cenozoic unconformity, bounded by two tear faults. Deformation zones beneath the Bhadrapur topographic high record an incipient tectonic wedge or triangle zone. The faults record the subsurface propagation of the Main Himalayan Thrust (MHT) into the foreland basin as an outer frontal thrust, and provide a modern snapshot of the development of tectonic wedges and lateral discontinuities preserved in higher thrust sheets of the Himalaya, and in ancient orogens elsewhere. We estimate a cumulative slip of ∼100 m, accumulated in <0.5 Ma, over a minimum slipped area of ∼780 km2 These observations demonstrate that Himalayan ruptures may pass under the present-day trace of the MFT as blind faults inaccessible to trenching, and that paleoseismic studies may underestimate Holocene convergence.

Treatment outcomes and survival following definitive (chemo)radiotherapy in HPV-positive oropharynx cancer: Large-scale comparison of DAHANCA vs PMH cohorts.

We compare outcomes in two large-scale contemporaneously treated HPV-positive (HPV+) oropharynx cancer (OPC) cohorts treated with definitive radiotherapy/chemoradiotherapy (RT/CRT). p16-confirmed HPV+ OPC treated between 2007 and 2015 at PMH and DAHANCA were identified. Locoregional failure (LRF), distant metastasis (DM), and overall survival (OS) were compared. Multivariable analysis (MVA) calculated adjusted-hazard-ratio (aHR) with 95% confidence interval (95% CI), adjusting for cohort, age, gender, performance status, smoking pack-years, T-category and N-category and chemotherapy. Compared to PMH (n = 701), DAHANCA (n = 1174) contained lower TNM-8T-categories (T1-T2: 77% vs 56%), N-categories (N0-N1: 77% vs 67%) and stages (stage I: 63% vs 44% (all P < .001). PMH used standard-fractionation CRT in 69% (481) while 31% (220) received hypofractionated or moderately accelerated RT-alone. All DAHANCA patients were treated with moderately accelerated RT; 96% (1129) received nimorazole (NIM) and 73% (856) concurrent weekly cisplatin. DAHANCA had shorter overall-treatment-time (P < .001), lower gross tumor (66-68 vs 70 Gy) and elective neck (50 vs 56 Gy) doses. Median follow-up was 4.8 years. DAHANCA had higher 5-year LRF (13% vs 7%, aHR = 0.47 [0.34-0.67]), comparable DM (7% vs 12%, aHR = 1.32 [0.95-1.82]), but better OS (85% vs 80%, aHR = 1.30 [1.01-1.68]). CRT patients had a lower risk of LRF (aHR 0.56 [0.39-0.82]), DM (aHR 0.70 [0.50-1.00]) and death (aHR 0.39 [0.29-0.52]) vs RT-alone. We observed exemplary outcomes for two large-scale trans-Atlantic HPV+ OPC cohorts treated in a similar manner. Concurrent chemotherapy was a strong, independent prognostic factor for all endpoints. Our findings underscore the need for a very careful approach to de-intensification of treatment for this disease.

Clinical presentation and outcome of human papillomavirus-positive nasopharyngeal carcinoma in a North American cohort.

BACKGROUND: The objective of this study was to describe the clinical presentation and outcomes of human papillomavirus (HPV)-positive nasopharyngeal cancer (NPC) versus Epstein-Barr virus (EBV)-positive NPC and HPV-positive oropharyngeal cancer (OPC). METHODS: Clinical characteristics and presenting signs/symptoms were compared between patients who had viral-related NPC versus viral-related OPC treated with intensity-modulated radiotherapy from 2005 to 2020 and who were matched 1:1 (by tumor and lymph node categories, smoking, age, sex, histology, and year of diagnosis). Locoregional control (LRC), distant control (DC), and overall survival (OS) were compared using the 2005-2018 cohort to maintain 2 years of minimum follow-up. Multivariable analysis was used to evaluate the cohort effect. RESULTS: Similar to HPV-positive OPC (n = 1531), HPV-positive NPC (n = 29) occurred mostly in White patients compared with EBV-positive NPC (n = 422; 86% vs. 15%; p < .001). Primary tumor volumes were larger in HPV-positive NPC versus EBV-positive NPC (median volume, 51 vs. 23 cm3 ; p = .002), with marginally more Level IB nodal involvement. More patients with HPV-positive NPC complained of local pain (38% vs. 3%; p = .002). The median follow-up for the 2005-2018 cohort was 5.3 years. Patients who had HPV-positive NPC (n = 20) had rates of 3-year LRC (95% vs. 90%; p = .360), DC (75% vs. 87%; p = .188), and OS (84% vs. 89%; p = .311) similar to the rates in those who had EBV-positive NPC (n = 374). Patients who had HPV-positive NPC also had rates of LRC (95% vs. 94%; p = .709) and OS (84% vs. 87%; p = .440) similar to the rates in those who had HPV-positive OPC (n = 1287). The DC rate was lower in patients who had HPV-positive disease (75% vs. 90%; p = .046), but the difference became nonsignificant (p = .220) when the analysis was adjusted for tumor and lymph node categories, smoking, and chemotherapy. CONCLUSIONS: HPV-positive NPC and EBV-positive NPC seem to be mutually exclusive diseases. Patients who have HPV-positive NPC have greater local symptom burden and larger primary tumors but have similar outcomes compared with patients who have EBV-positive NPC or HPV-positive OPC.

Elective neck dissection versus positron emission tomography-computed tomography-guided management of the neck in clinically node-negative early oral cavity cancer: A cost-utility analysis.

BACKGROUND: In early oral cavity cancer, elective neck dissection (END) for the clinically node-negative (cN0) neck improves survival compared with observation. This paradigm has been challenged recently by the use of positron emission tomography-computed tomography (PET-CT) imaging in the cN0 neck. To inform this debate, we performed an economic evaluation comparing PET-CT-guided therapy with routine END in the cN0 neck. METHODS: Patients with T1-2N0 lateralized oral tongue cancer were analyzed. A Markov model over a 40-year time horizon simulated treatment, disease recurrence, and survival from a US health care payer perspective. Model parameters were derived from a review of the literature. RESULTS: The END strategy was dominant, with a cost savings of $1576.30 USD, an increase of 0.055 quality-adjusted life years (QALYs), a net monetary benefit of $4303 USD, and a 0.22 life-year advantage. END was sensitive to variation in cost and utilities in deterministic and probabilistic sensitivity analyses. PET-CT became the preferred strategy when decreasing occult nodal disease to 18% and increasing the negative predictive value (NPV) of PET-CT to 89% in 1-way sensitivity analyses. In probabilistic sensitivity analysis, assuming a cost effectiveness threshold of $50,000 USD/QALY, END was dominant in 64% of simulations and cost effective in 69.8%. CONCLUSION: END is a cost-effective strategy compared with PET-CT in patients who have node-negative oral cancer. Although lower PET standardized uptake value thresholds would result in fewer false negatives and improved NPV, it is still uncertain that PET-CT would be cost effective, as this would likely result in more false positive tests.

A cost-utility analysis comparing CT surveillance, PET-CT surveillance, and planned postradiation neck dissection for advanced nodal HPV-positive oropharyngeal cancer.

BACKGROUND: The cost utility of image-guided surveillance using computed tomography (CT) and positron emission tomography (PET)-CT to planned postradiation neck dissection (PRND) was compared for the management of advanced nodal human papillomavirus-positive oropharyngeal cancer following chemoradiation. METHODS: A universal payer perspective was adopted. A Markov model was designed to simulate four treatment approaches with 3-month cycles over a lifetime horizon: 1) CT surveillance, 2) standard PET-CT surveillance, 3) a novel PET-CT approach with repeat PET at 6 months postchemoradiation for equivocal responders, and 4) PRND. Parameters including probabilities of CT nodal progression/resolution, PET avidity, recurrence, and survival were obtained from the literature. Costs were reported in 2019 Canadian dollars and utilities were expressed in quality-adjusted life years (QALYs). Deterministic and probabilistic sensitivity analyses were performed to evaluate model uncertainty. RESULTS: PET-CT surveillance dominated CT surveillance and PRND in the base case scenario, and the novel PET-CT approach was the most cost-effective strategy across a wide range of variables tested in one-way sensitivity analysis. On probabilistic sensitivity analysis, novel PET-CT surveillance was the most cost-effective strategy in 78.1% of model iterations at a willingness-to-pay of $50,000/QALYs. Novel PET-CT surveillance resulted in a 49% lower rate of neck dissection compared with traditional PET-CT, and yielded an incremental benefit of 0.14 QALYs with average cost savings of $1309. CONCLUSIONS: Image-guided surveillance including PET-CT and CT are more cost effective than PRND. The novel PET-CT approach with repeat PET for equivocal responders was the dominant strategy and yielded both higher benefit and lower costs compared with standard PET-CT surveillance.

Transitions in oral and gut microbiome of HPV+ oropharyngeal squamous cell carcinoma following definitive chemoradiotherapy (ROMA LA-OPSCC study).

BACKGROUND: Oral and gut microbiomes have emerged as potential biomarkers in cancer. We characterised the oral and gut microbiomes in a prospective observational cohort of HPV+ oropharyngeal squamous cell carcinoma (OPSCC) patients and evaluated the impact of chemoradiotherapy (CRT). METHODS: Saliva, oropharyngeal swabs over the tumour site and stool were collected at baseline and post-CRT. 16S RNA and shotgun metagenomic sequencing were used to generate taxonomic profiles, including relative abundance (RA), bacterial density, α-diversity and ß-diversity. RESULTS: A total of 132 samples from 22 patients were analysed. Baseline saliva and swabs had similar taxonomic composition (R2 = 0.006; p = 0.827). Oropharyngeal swabs and stool taxonomic composition varied significantly by stage, with increased oral RA of Fusobacterium nucleatum observed in stage III disease (p < 0.05). CRT significantly reduced the species richness and increased the RA of gut-associated taxa in oropharyngeal swabs (p < 0.05), while it had no effect in stool samples. These findings remained significant when adjusted by stage, smoking status and antibiotic use. CONCLUSIONS: Baseline oral and gut microbiomes differ by stage in this HPV+ cohort. CRT caused a shift towards a gut-like microbiome composition in oropharyngeal swabs. Stage-specific features and the transitions in oral microbiome might have prognostic and therapeutic implications.

Hypofractionated radiotherapy alone with 2.4 Gy per fraction for head and neck cancer during the COVID-19 pandemic: The Princess Margaret experience and proposal.

BACKGROUND: The objective of this study was to identify a subgroup of patients with head and neck squamous cell carcinoma (HNSCC) who might be suitable for hypofractionated radiotherapy (RT-hypo) during the COVID-19 pandemic. METHODS: HNSCC cases (oropharynx/larynx/hypopharynx) treated with definitive RT-hypo (60 Gy in 25 fractions over 5 weeks), moderately accelerated radiotherapy (RT-acc) alone (70 Gy in 35 fractions over 6 weeks), or concurrent chemoradiotherapy (CCRT) during 2005-2017 were included. Locoregional control (LRC) and distant control (DC) after RT-hypo, RT-acc, and CCRT were compared for various subgroups. RESULTS: The study identified 994 human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma cases (with 61, 254, and 679 receiving RT-hypo, RT-acc, and CCRT, respectively) and 1045 HPV- HNSCC cases (with 263, 451, and 331 receiving RT-hypo, RT-acc, and CCRT, respectively). The CCRT cohort had higher T/N categories, whereas the radiotherapy-alone patients were older. The median follow-up was 4.6 years. RT-hypo, RT-acc, and CCRT produced comparable 3-year LRC and DC for HPV+ T1-2N0-N2a disease (seventh edition of the TNM system [TNM-7]; LRC, 94%, 100%, and 94%; P = .769; DC, 94%, 100%, and 94%; P = .272), T1-T2N2b disease (LRC, 90%, 94%, and 97%; P = .445; DC, 100%, 96%, and 95%; P = .697), and T1-2N2c/T3N0-N2c disease (LRC, 89%, 93%, and 95%; P = .494; DC, 89%, 90%, and 87%; P = .838). Although LRC was also similar for T4/N3 disease (78%, 84%, and 88%; P = .677), DC was significantly lower with RT-hypo or RT-acc versus CCRT (67%, 65%, and 87%; P = .005). For HPV- HNSCC, 3-year LRC and DC were similar with RT-hypo, RT-acc, and CCRT in stages I and II (LRC, 85%, 89%, and 100%; P = .320; DC, 99%, 98%, and 100%; P = .446); however, RT-hypo and RT-acc had significantly lower LRC in stage III (76%, 69%, and 91%; P = .006), whereas DC rates were similar (92%, 85%, and 90%; P = .410). Lower LRC in stage III predominated in patients with laryngeal squamous cell carcinoma receiving RT-acc (62%) but not RT-hypo (80%) or CCRT (92%; RT-hypo vs CCRT: P = .270; RT-acc vs CCRT: P = .004). CCRT had numerically higher LRC in comparison with RT-hypo or RT-acc in stage IV (73%, 65%, and 66%; P = .336). CONCLUSIONS: It is proposed that RT-hypo be considered in place of CCRT for HPV+ T1-T3N0-N2c (TNM-7) HNSCCs, HPV- T1-T2N0 HNSCCs, and select stage III HNSCCs during the COVID-19 outbreak.

Pembrolizumab given concomitantly with chemoradiation and as maintenance therapy for locally advanced head and neck squamous cell carcinoma: KEYNOTE-412.

Current treatment guidelines for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) recommend multimodal treatment, including chemoradiation therapy (CRT) or surgery followed by radiation, with or without chemotherapy. The immune checkpoint inhibitor pembrolizumab has previously demonstrated antitumor activity in recurrent and/or metastatic HNSCC in large Phase III trials. For patients with locally advanced disease, Phase Ib data on the use of pembrolizumab in combination with chemoradiation have shown the approach to be safe and feasible. We describe here the design and rationale for KEYNOTE-412, a randomized, double-blind, Phase III trial investigating pembrolizumab or placebo administered concurrently with CRT and as maintenance treatment in patients with locally advanced HNSCC. Clinical Trial Registration: NCT03040999 (ClinicalTrials.gov).

The prevalence and determinants of return to work in head and neck cancer survivors.

PURPOSE: To determine the prevalence of and factors associated with the reduction or complete cessation of employment following treatment in head and neck cancer survivors. METHODS: This cross-sectional study was conducted among head and neck cancer survivors visiting outpatient clinics at the Princess Margaret Cancer Centre over a period of 18 months. Participants at any point along their survivorship course completed a survey that included demographic information, the Radiation Therapy Oncology Group (RTOG) Work Status Questionnaire, the Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), the M.D. Anderson Symptom Inventory-Head and Neck (MDASI-HN), the Cancer Survivors' Unmet Needs Measure (CaSUN), and the EuroQol EQ-5D-5L utility scale. RESULTS: Among 130 participants, 64 were employed at diagnosis. At the time of study, 31 (48%) had reduced their work, among whom, 21 (32.8%) had not returned to work at all following treatment. Pre-treatment employment status, cancer-related symptoms, quality of life, and health utility were associated with employment outcomes. CONCLUSION: A high proportion of head and neck cancer survivors reduced their work capacity and many did not return following cancer treatment. Further research is needed to understand the barriers to work return in these survivors and to explore strategies to encourage resumption of employment and employment satisfaction.

Osteoradionecrosis of the mandible in patients with oropharyngeal carcinoma treated with intensity-modulated radiotherapy.

BACKGROUND: Osteoradionecrosis (ORN) of the mandible is a late toxicity affecting patients treated with radiotherapy for head and neck malignancies. To the authors' knowledge, ORN has no standardized grading system and its reporting is based on retrospective findings in heterogeneous patient populations. The rate of ORN in the era of intensity-modulated radiotherapy (IMRT) still is unknown. METHODS: The authors report the incidence of ORN from prospectively collected data regarding 1196 patients who were diagnosed with squamous cell carcinoma of the oropharynx and treated with curative-intent IMRT, with or without concomitant systemic treatment, from January 2005 to December 2014. Each case of ORN was graded according to its severity. Clinical and dosimetric comparisons were performed between patients with ORN and a matched control cohort of patients without ORN. RESULTS: The actuarial rate of ORN of the mandible was 3% at 1 year, 5% at 3 years, and 7% at 5 years. On multivariable analysis, smoking (hazard ratio, 1.9; 95% confidence interval, 1.07-3.4 [P = .03]) and T classification (hazard ratio, 1.78; 95% confidence interval, 1.02-3.1 [P = .041]) were found to be statistically significant risk factors. The presence of cardiovascular comorbidities, use of bisphosphonates, and pre-IMRT dental extractions were found to be different between the matched cohorts. The mandibular volume receiving 50 grays (Gy) (in cm3 ) and the volume receiving 60 Gy (in cm3 ) were found to be associated with ORN on multivariable analysis in the matched cohort patients receiving an IMRT regimen of 2 Gy per fraction. CONCLUSIONS: ORN is relatively uncommon among patients with oropharyngeal carcinoma who are treated with IMRT, but continues to occur beyond 5 years after treatment. Modifiable risk factors that are associated with higher rates of ORN include smoking and the use of bisphosphonates. Minimizing the volumes of the mandible receiving >50 Gy or > 60 Gy also may have an effect on the ORN rate. Cancer 2017;123:3691-3700. © 2017 American Cancer Society.

Phase I trial of dacomitinib, a pan-human epidermal growth factor receptor (HER) inhibitor, with concurrent radiotherapy and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (XDC-001).

Background Curative-intent, non-surgical treatment options for locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) include radiotherapy with/without chemotherapy or radiotherapy with cetuximab. This single institution phase I dose escalation trial tested the pan-human epidermal growth factor receptor (HER) oral tyrosine kinase inhibitor, dacomitinib, in combination with standard cisplatin-based chemoradiotherapy. Methods Patients received oral dacomitinib once daily at 3 protocol-defined dose levels (15 mg, 30 mg, and 45 mg). Cisplatin was given intravenously at 100 mg/m(2) every 3 weeks. Radiotherapy was delivered using intensity modulated radiation therapy (IMRT) to a dose of 70Gy in 35 daily fractions to the primary and nodal disease. Dose escalation was performed using a standard 3 + 3 design. Results Twelve patients with LA-SCCHN were enrolled between January 2013 and August 2014. No dose limiting toxicities (DLTs) were observed in the 15 mg and 30 mg dose levels. In the 45 mg dose level, one of four evaluable patients developed a DLT with intolerable grade 2 diarrhea requiring discontinuation of therapy. Adverse events (AEs) attributed to dacomitinib alone include diarrhea, hypertension, and acneiform and maculopapular rash. The most common non-hematological AEs include weight loss, diarrhea, dry mouth, mucositis, nausea, hypoalbuminemia, and hyponatremia. Frequency and severity of AEs did not increase with increasing dose levels of dacomitinib. All patients completed the full course of radiotherapy on schedule and the median dose of cisplatin was 200 mg/m(2), which is comparable to historical standards. Of the 10 patients evaluable for response, 1 patient relapsed with metastatic disease. Conclusions The triple combination has a tolerable side effect profile and dose levels 15 mg and 30 mg were cleared safely. The addition of dacomitinib did not preclude delivery of standard chemoradiotherapy. Studies testing the addition of other HER-targeted therapies to platinum-based concurrent chemo-radiotherapy in LA-SCCHN have failed to demonstrate improved patient outcomes and have reported trends towards excessive toxicities. These results generated uncertainty regarding the future of these agents in combination with chemo-radiation for the treatment of LA-SCCHN, which ultimately led to the early termination of this study.

Integrated omic analysis of oropharyngeal carcinomas reveals human papillomavirus (HPV)-dependent regulation of the activator protein 1 (AP-1) pathway.

HPV-positive oropharyngeal carcinoma (OPC) patients have superior outcomes relative to HPV-negative patients, but the underlying mechanisms remain poorly understood. We conducted a proteomic investigation of HPV-positive (n = 27) and HPV-negative (n = 26) formalin-fixed paraffin-embedded OPC biopsies to acquire insights into the biological pathways that correlate with clinical behavior. Among the 2,633 proteins identified, 174 were differentially abundant. These were enriched for proteins related to cell cycle, DNA replication, apoptosis, and immune response. The differential abundances of cortactin and methylthioadenosine phosphorylase were validated by immunohistochemistry in an independent cohort of 29 OPC samples (p = 0.023 and p = 0.009, respectively). An additional 1,124 proteins were independently corroborated through comparison to a published proteomic dataset of OPC. Furthermore, utilizing the Cancer Genome Atlas, we conducted an integrated investigation of OPC, attributing mechanisms underlying differential protein abundances to alterations in mutation, copy number, methylation, and mRNA profiles. A key finding of this integration was the identification of elevated cortactin oncoprotein levels in HPV-negative OPCs. These proteins might contribute to reduced survival in these patients via their established role in radiation resistance. Through interrogation of Cancer Genome Atlas data, we demonstrated that activation of the ß1-integrin/FAK/cortactin/JNK1 signaling axis and associated differential regulation of activator protein 1 transcription factor target genes are plausible consequences of elevated cortactin protein levels.

A multi-institution pooled analysis of gastrostomy tube dependence in patients with oropharyngeal cancer treated with definitive intensity-modulated radiotherapy.

BACKGROUND: Severe swallowing dysfunction necessitating enteral support is a well known late sequela of nonsurgical therapy for oropharyngeal cancer, but its incidence after intensity-modulated radiotherapy has not been quantified comprehensively outside of small single-institution series. METHODS: This was a multi-institution, institutional review board-approved, retrospective study. Consecutive patients with oropharyngeal squamous cell carcinoma who had received definitive intensity-modulated radiotherapy from 1998 to 2011 were identified from 3 academic centers. RESULTS: In total, 2315 patients were included. The American Joint Committee on Cancer staging distribution was as follows: stage I, 2.1%; stage II, 4.4%; stage III, 14.7%; and stage IV, 77.3%. Among 1459 patients (63%) who received a gastrostomy tube (g-tube), placement was prophylactic in 52% and reactive in 48%. Among patients with stage III and IV disease, 58% received concurrent chemotherapy. The median follow-up was 43.7 months (range, 0.1-164 months). The g-tube dependence rate was 7% at 1 year and 3.7% at 2 years. Among 1238 patients with stage III and IV disease who received concurrent chemotherapy, the 1-year and 2-year rates of g-tube dependence were 8.6% and 4.4%, respectively. The 1-year g-tube dependence rate was 5% for patients with stage I and II disease; 5.2% for patients with stage III and IV, T1-T2/N0-N2 disease; and 10.1% for patients with stage III and IV, T3-T4 or N3 disease. On multivariate analysis, advanced age (odds ratio [OR], 1.066; P<.001), greater number of smoking pack-years (OR, 1.008; P=.04), advanced N-category (OR, 1.13; P=.049), and receipt of cytotoxic chemotherapy (OR, 2.26; P=.02) were predictive of g-tube dependence at 1 year. CONCLUSIONS: This multi-institution series of 2315 patients treated at 3 institutions demonstrates that modern nonsurgical therapy for oropharyngeal cancer is associated with a low rate of long-term g-tube dependence.

Prognostic value of pretreatment circulating neutrophils, monocytes, and lymphocytes in oropharyngeal cancer stratified by human papillomavirus status.

BACKGROUND: The objective of this study was to investigate the prognostic value of the pretreatment circulating neutrophil count (CNC), circulating monocyte count (CMC), and circulating lymphocyte count (CLC) in human papillomavirus (HPV)-related (HPV+) and HPV-unrelated (HPV-) oropharyngeal cancer (OPC). METHODS: All p16-confirmed HPV+ and HPV- OPC cases treated with chemoradiotherapy from 2000 to 2010 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared for high and low CNCs, CMCs, and CLCs (dichotomized by median values). A multivariate analysis (MVA) confirmed their prognostic value in HPV+ and HPV- tumors, respectively. RESULTS: Five hundred ten HPV+ OPC cases and 192 HPV- OPC cases were included. The HPV+ cohort had lower CNC and CMC values but a CLC similar to that of the HPV- patients (P < .01). The median follow-up was 4.8 years. In the HPV+ cohort, a high CNC or CMC correlated with reduced OS and RFS in comparison with a low CNC or CMC (P < .01 for all), but no difference was evident in OS (P = .30) or RFS (P = .10) with the CLC. MVA confirmed that a higher CNC or CMC independently predicted lower OS (hazard ratio [HR] for CNC, 1.14, P < .01; HR for CMC, 2.95, P < .01) and lower RFS (HR for CNC, 1.11, P < .01; HR for CMC, 3.39, P < .01), whereas a higher CLC was associated with higher RFS (HR, 0.66, P = .03) and marginally higher OS (HR, 0.80, P = .08). In the HPV- cohort, CNC, CMC, and CLC were not predictive of OS (P = .16, P = .86, and P = .14) or RFS (P = .61, P = .59, and P = .62). CONCLUSIONS: This relatively large cohort study demonstrates that a high CNC and a high CMC independently predict inferior OS and RFS, whereas a high CLC predicts better RFS and marginally better OS in HPV+ OPC patients. This association was not apparent in HPV- patients.

External validation of a prognostic CT-based radiomic signature in oropharyngeal squamous cell carcinoma.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) is one of the fastest growing disease sites of head and neck cancers. A recently described radiomic signature, based exclusively on pre-treatment computed tomography (CT) imaging of the primary tumor volume, was found to be prognostic in independent cohorts of lung and head and neck cancer patients treated in the Netherlands. Here, we further validate this signature in a large and independent North American cohort of OPSCC patients, also considering CT artifacts. METHODS: A total of 542 OPSCC patients were included for which we determined the prognostic index (PI) of the radiomic signature. We tested the signature model fit in a Cox regression and assessed model discrimination with Harrell's c-index. Kaplan-Meier survival curves between high and low signature predictions were compared with a log-rank test. Validation was performed in the complete cohort (PMH1) and in the subset of patients without (PMH2) and with (PMH3) visible CT artifacts within the delineated tumor region. RESULTS: We identified 267 (49%) patients without and 275 (51%) with visible CT artifacts. The calibration slope (ß) on the PI in a Cox proportional hazards model was 1.27 (H0: ß = 1, p = 0.152) in the PMH1 (n = 542), 0.855 (H0: ß = 1, p = 0.524) in the PMH2 (n = 267) and 1.99 (H0: ß = 1, p = 0.002) in the PMH3 (n = 275) cohort. Harrell's c-index was 0.628 (p = 2.72e-9), 0.634 (p = 2.7e-6) and 0.647 (p = 5.35e-6) for the PMH1, PMH2 and PMH3 cohort, respectively. Kaplan-Meier survival curves were significantly different (p < 0.05) between high and low radiomic signature model predictions for all cohorts. CONCLUSION: Overall, the signature validated well using all CT images as-is, demonstrating a good model fit and preservation of discrimination. Even though CT artifacts were shown to be of influence, the signature had significant prognostic power regardless if patients with CT artifacts were included.