Search

PURPOSE CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570 ) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration of response in the all randomly assigned and CPS ≥ 20 populations. RESULTS Among 947 patients randomly assigned, 38.3% had CPS ≥ 20. There were no statistically significant differences in OS with nivolumab plus ipilimumab versus EXTREME in the all randomly assigned (median: 13.9 v 13.5 months; hazard ratio [HR], 0.95; 97.9% CI, 0.80 to 1.13; P = .4951) and CPS ≥ 20 (median: 17.6 v 14.6 months; HR, 0.78; 97.51% CI, 0.59 to 1.03; P = .0469) populations. In patients with CPS ≥ 1, the median OS was 15.7 versus 13.2 months (HR, 0.82; 95% CI, 0.69 to 0.97). Among patients with CPS ≥ 20, the median progression-free survival was 5.4 months (nivolumab plus ipilimumab) versus 7.0 months (EXTREME), objective response rate was 34.1% versus 36.0%, and median duration of response was 32.6 versus 7.0 months. Grade 3/4 treatment-related adverse events occurred in 28.2% of patients treated with nivolumab plus ipilimumab versus 70.7% treated with EXTREME. CONCLUSION CheckMate 651 did not meet its primary end points of OS in the all randomly assigned or CPS ≥ 20 populations. Nivolumab plus ipilimumab showed a favorable safety profile compared with EXTREME. There continues to be a need for new therapies in patients with R/M SCCHN.

Summary of the mutational state of the expressed genes in each control SCC-PDX, and the acquired mutations in GefR and GefT SCC-PDXs, as compared to their respective control PDXs

This table summarizes clinical information of patient cSCC samples used for PDXs generation, and results of the analysis of Gene expression changes in GefR SCC-PDXs vs control SCC-PDXs.

Supplementary Figures and legend figures Supplementary Methods

Purpose:Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy.Experimental Design:We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance.Results:cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors.Conclusions:EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

There is a lack of effective clinical management of oral epithelial dysplasias to reduce their risk of malignant transformation and considerable gaps in knowledge regarding the most effective means of treating such lesions. A retrospective cohort of biopsy-confirmed oral epithelial dysplasias consecutively diagnosed in the period 1995–2014 and followed-up until 2017 was identified from pathology department files. Demographic, clinical and follow-up information was collected. Multivariate Cox proportional-hazards models were performed to evaluate sociodemographic, clinical and pathological factors associated with progression to oral squamous cell carcinoma. The study included 144 oral epithelial dysplasias, of which 42% progressed to oral cancer at the end of follow-up (21 years). Clinical aspect of the lesion was described for 77 (53.5%) of the patients. Treatment, age, grade of the lesion and diagnostic period were independent prognostic factors for progression. When considering only patients with described clinical aspect, only treatment and grade of the lesion were independently associated with cancer. The results from this non-selected retrospective cohort of oral epithelial dysplasias underscore the existing limitations of the current standard-of-care of the patients and provide novel insights on the management of these lesions with and without described clinical aspect. Well-designed, robust prospective studies, a homogenized staging system and multidisciplinary treatment guidelines are warranted.

ObjectiveThis study aimed to evaluate the effectiveness of computed tomography and positron emission tomography-computed tomography prior to salvage surgery after head and neck carcinoma treated with bioradiotherapy and to look at the role of neck dissection in this setting.MethodThis study was a retrospective chart review of a series of consecutive patients with locally advanced head and neck squamous cell carcinoma treated with bioradiotherapy. Radiological and pathological stages were compared to evaluate the accuracy of computed tomography and positron emission tomography-computed tomography in detecting occult neck metastasis in the context of recurrence of primary tumour. In order to assess the impact of neck dissection on survival, Kaplan–Meier survival curves after salvage surgery with and without neck dissection were derived.ResultsA total of 268 patients were identified, of which 22 underwent salvage surgery. The negative predictive value of computed tomography and positron emission tomography-computed tomography was excellent. Neck dissection did not represent an improvement on overall, disease specific and regional recurrence free survival (p = 0.67, p = 0.91 and p = 0.62, respectively) amongst clinically and radiologically negative necks.ConclusionConservative treatment of the neck should be considered when dealing with patients with primary site recurrence or persistent disease after bioradiotherapy without evidence of neck disease.

Efforts in the pharmaceutical market have been aimed at ensuring that the benefits obtained from the introduction of new therapies justify the associated costs. In recent years, drug payment models in healthcare have undergone a dramatic shift from focusing on volume (i.e., size of the target clinical population) to focusing on value (i.e., drug performance in real-world settings). In this context, value-based contracts (VBCs) were designed to align the payment of a drug to its clinical performance outside clinical trials by evaluating the effectiveness using real-word evidence (RWE). Despite their widespread implementation, different factors jeopardize the application of VBCs to most marketed drugs in a near future, including the need for easily measurable and relevant outcomes associated with clinical improvements, and access to a large patient population to assess said outcomes. Here, we argue that the extraction and analysis of massive amounts of RWE captured in patients’ electronic health records (EHRs) will circumvent these issues and optimize negotiations in VBCs. Particularly, the use of Natural Language Processing (NLP) has proven successful in the analysis of structured and unstructured clinical information in EHRs in multicenter research studies. Thus, the application of NLP to analyze patient-centered information in EHRs in the context of innovative contracting can be utterly beneficial as it enables the real-time evaluation of treatment response and financial impact in real-world settings.

Cisplatin is the standard of treatment for squamous cell carcinoma of the head and neck (SCCHN) that has demonstrated efficacy, either in locally advanced disease when combined with radiotherapy at high doses, or in metastatic/recurrent disease when combined with other agents. However, the usual toxicities related to cisplatin, such as neurotoxicity, nephrotoxicity, ototoxicity, and hematologic toxicities, especially when high doses have been administered, have important implications in the patients’ quality of life. The decision to administer cisplatin depends on several patient factors, such as age, performance status, weight loss, comorbidities, previous toxicities, chronic viral infection, or even the current SARS-CoV-2 pandemic. In order to establish recommendations for the management of patients with SCCHN, a group of experts in medical and radiation oncology from Spain and Latin-American discussed how to identify patients who are not candidates for cisplatin to offer them the most suitable therapeutic alternative.

Background: Computed tomography images acquired during routine cancer care provide an opportunity to determine body composition with accuracy and precision. Quantification of skeletal muscle is of interest owing to its association with clinical outcomes. However, the standards of precision testing considered mandatory in other areas of radiology are lacking from the literature in this area. We aim to describe the change in skeletal muscle over time at different anatomical levels using the precision error. Methods: Thirty-eight male patients with squamous cell carcinoma of the head and neck were evaluated at two time points encompassing their treatment plan. Precision testing consisted of analyzing the crosssectional area (CSA) of the skeletal muscle and total adipose tissue of 76 CT studies (38 images at baseline repeated twice and 38 follow-up images repeated twice) measured by a skilled observer. The % coeffi-cient of variation (%CV), the root-mean-square standard deviation (RMS SD) and the corresponding 95% least significant change (LSC) were calculated for four anatomical levels: upper arm, thigh, chest and abdomen. Results: The median time between scans was 223.6 (SD 31.2) days. Precision error (% CV) for total skeletal muscle cross sectional area was 0.86% for upper arm, 0.26% for thigh, 0.39% for chest and 0.63% for abdomen. The corresponding LSC values in upper arm, thigh, chest and abdomen were 2.4%, 0.7%, 1.1% and 1.8%, respectively. Based on the LSC for RMS SD, patients were classified in two categories according to muscle crosssectional area: stable (i.e within LSC value) or gained and loss. To compare the four anatomical levels, the proportion of patients with muscle loss exceeding the LSC value was 74.3% for arm, 86.2% for thigh, 82.9% for chest and 76.3% for abdomen. For these same anatomic regions, the mean muscle loss for those patients classified below the LSC was 14.6% (SD 9.3), 13.4% (SD 7.8), 11.9% (SD 6.5) and 11.6% (SD 5.5), respectively. Only the loss of muscle area was significantly higher in thigh (p = 0.023), using L3 as the reference level. Conclusions: We recommend the uniform use of a standard precision test when reporting muscle change over time. LSC values vary from 0.7 to 2.4% depending on anatomic site; with the lowest precision error to detect change in the thigh. Based on this analysis, muscle wasting appears to be systemic and while present in limbs and trunk is significantly higher in the thigh than in the chest, abdomen or upper arm. (C) 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Concurrent chemoradiotherapy is the standard treatment for patients with unresectable, locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN); induction chemotherapy (ICT) may provide survival benefits in some patients. This study aimed to demonstrate the noninferiority of concomitant cetuximab plus radiotherapy (cet+RT) vs cisplatin plus radiotherapy (cis+RT) in patients with unresectable LA-SCCHN who were responsive to ICT.This randomized, open-label, phase 3 trial studied patients with unresectable LA-SCCHN who received 3 cycles of ICT (docetaxel, cisplatin, and 5-fluorouracil; TPF) followed by cis+RT (standard arm) or cet+RT (experimental arm). The primary endpoint was noninferiority of the experimental arm vs the standard arm in terms of overall survival (OS), based on a hazard ratio (HR) of lt; 1.3. Secondary endpoints included progression-free survival, overall response, safety, and quality of life (QOL).Between July 15, 2008, and July 5, 2013, 519 patients were recruited and started ICT; 407 patients received post-ICT treatment (cis+RT, n = 205; cet+RT, n = 202). At a median follow-up of 43.9 (cis+RT) and 41.1 (cet+RT) months, median OS was 63.6 and 42.9 months with cis+RT and cet+RT, respectively (HR [90% CI] = 1.106 [0.888-1.378], P =.4492). There were no differences in progression-free survival, overall response rates, or adverse event rates between groups. There was greater late neurotoxicity with cis+RT than cet+RT (P =.0058). Several QOL dimensions improved with cet+RT vs cis+RT (physical functioning, P =.0287; appetite loss, P =.0248; social contact, P =.0153).Noninferiority of cet+RT over cis+RT was not demonstrated.

Purpose of review The systemic therapies available in recurrent and metastatic head and neck squamous cell carcinoma to date are palliative-intent treatments in most cases. However, a small subgroup of patients derives unconventional benefit and become long-term survivors, achieving cure in some cases. This review focusses on this group of patients, discusses recent literature and suggests plausible molecular hypothesis. Recent findings Human papillomavirus-related disease is known to confer a better prognosis in metastatic patients, probably because of its greater sensitivity to systemic therapies. This group of patients seems to have a greater immune activation, which could partly explain this fact. Moreover, the use of antiepidermal growth factor receptor therapies in the metastatic setting has doubled the prevalence of long-term survivors. One of the most plausible explanations is the immune-modulatory effect of cetuximab mediated by antibody-dependent cell-mediated cytotoxicity.These facts, along with the recent encouraging results of checkpoint inhibitors in this disease, give hope that these therapies will not only improve survival but also increase the prevalence of long-term survivors. Summary Long-term survivors merit our utmost attention as an in-depth study of these patients could help us to better understand the tumour biology and allow us to develop robust biomarkers and effective targeted therapies, which could in turn lead to a true paradigm shift.

e18744 Background: Evidence regarding the clinical predictors of bleeding risk in patients with cancer and venous thromboembolism (VTE) is lacking. Our aim was to develop a predictive model to assess the risk of major bleeding (MB) in anticoagulant-treated patients with active cancer during the first 6 months following VTE diagnosis. Methods: Observational, retrospective, and multicenter study based on the secondary analysis of unstructured clinical data in electronic health records (EHRs). Using the EHRead technology, based on Natural Language Processing (NLP) and machine learning (ML), data were collected from EHRs from 9 Spanish hospitals between 2014 and 2018. The study population comprised all adult cancer patients with a diagnosis of VTE under anticoagulant treatment and no history of MB. This population was downsampled to prevent bias and class imbalance. A total of 94 patient characteristics were explored, and Random Forest (RF) feature selection was performed to identify the most relevant predictors. Multiple algorithms were used to train different prediction models, which were subsequently validated in a hold-out dataset. The model with the best performance metrics (i.e., ROC-AUC) was selected as the final model. Results: Among a source population of 2,893,208 patients, 21,227 anticoagulant-treated patients with VTE and active cancer were identified from EHRs. Of these, 53.9% men, with a median age (Q1, Q3) of 70 (59,80) years. The median duration of follow up across all patients was 0.7 (0.11, 2.03) years. During the study period, estimated in-hospital prevalence of cancer-related VTE was 5.8 %. The most common type of VTE at baseline was deep vein thrombosis (68.2 % of patients), followed by pulmonary embolism (28.4%). The most frequent primary cancers were colorectal (10.1%) and lung cancer (8.5 %). Of all trained and validated models, the RF approach yielded the best performance, with a ROC-AUC = 0.7. The following predictors of MB were identified: hemoglobin levels, presence of metastasis, patient’s age, platelet count, leukocyte count, and serum creatinine levels. Conclusions: This is the first multicenter study to use NLP to extract the unstructured information from EHRs to develop a predictive model for MB in anticoagulated cancer patients with VTE. These results may improve the prevention and management of bleeding in these patients.

Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCCs) represent a distinct clinical entity compared with HPV-negative tumors with particular regard to treatment response and survival outcome. The aim of this study was to assess the AmpFire Multiplex HR-HPV tests, for the detection and genotyping of 15 high-risk (HR) HPV types in formalin-fixed, paraffin-embedded (FFPE) samples and identify HPV-driven OPSCC. DNA from 160 OPSCC FFPE specimens plus 23 samples from other head and neck primary sites was tested. Results were compared with those obtained using Linear Array HPV-DNA Genotyping Test. Linear Array and AmpFire Multiplex HR-HPV tests showed, for all samples and specifically for OPSCCs, an overall concordance agreement of 98.9% and 99.4% and a Cohen ¿ coefficient of 0.972 and 0.984, respectively. A concordance of 100% for HPV16 and HPV18 was observed. The overall agreement between p16INK4a overexpression and HPV detection by the AmpFire Multiplex HR-HPV assay in 145 OPSCC samples was 93.8%, with a Cohen ¿ coefficient of 0.848. The AmpFire HPV Tests are simple assays for detection and genotyping of HPV-DNA in OPSCC FFPE samples and can be easily implemented in the clinical practice setting for HPV-DNA detection.

Purpose: Recurrent and/or metastatic unresectable cutaneous squamous cell carcinomas (cSCCs) are treated with chemotherapy or radiotherapy, but have poor clinical responses. A limited response (up to 45% of cases) to EGFR-targeted therapies was observed in clinical trials with patients with advanced and metastatic cSCC. Here, we analyze the molecular traits underlying the response to EGFR inhibitors, and the mechanisms responsible for cSCC resistance to EGFR-targeted therapy. Experimental Design: We generated primary cell cultures and patient cSCC–derived xenografts (cSCC-PDXs) that recapitulate the histopathologic and molecular features of patient tumors. Response to gefitinib treatment was tested and gefitinib-resistant (GefR) cSCC-PDXs were developed. RNA sequence analysis was performed in matched untreated and GefR cSCC-PDXs to determine the mechanisms driving gefitinib resistance. Results: cSCCs conserving epithelial traits exhibited strong activation of EGFR signaling, which promoted tumor cell proliferation, in contrast to mesenchymal-like cSCCs. Gefitinib treatment strongly blocked epithelial-like cSCC-PDX growth in the absence of EGFR and RAS mutations, whereas tumors carrying the E545K PIK3CA-activating mutation were resistant to treatment. A subset of initially responding tumors acquired resistance after long-term treatment, which was induced by the bypass from EGFR to FGFR signaling to allow tumor cell proliferation and survival upon gefitinib treatment. Pharmacologic inhibition of FGFR signaling overcame resistance to EGFR inhibitor, even in PIK3CA-mutated tumors. Conclusions: EGFR-targeted therapy may be appropriate for treating many epithelial-like cSCCs without PIK3CA-activating mutations. Combined EGFR- and FGFR-targeted therapy may be used to treat cSCCs that show intrinsic or acquired resistance to EGFR inhibitors.

The incidence of human papillomavirus (HPV)-related oropharyngeal cancer is increasing in some regions. Nevertheless, the epidemiology of this disease has not been extensively investigated in southern Europe. We conducted a retrospective cohort study of patients diagnosed with primary oropharyngeal cancer from 1991 to 2016. Cancer tissues underwent histopathological evaluation, DNA quality control, HPV-DNA detection and p16INK4a immunohistochemistry. Data were collected from medical records. Factors associated with HPV positivity and time trends were evaluated with multivariable Bayesian models. The adjusted prevalence of HPV-related cases in 864 patients with a valid HPV-DNA result was 9.7%, with HPV-DNA/p16INK4a double positivity being considered. HPV-related oropharyngeal cancer was likely to occur in non-smokers and non-drinkers, to be located in the tonsil or diagnosed at advanced stages. Time-trend analysis showed an increasing risk of HPV-related oropharyngeal cancer in the most recent periods (5-year period increase of 30%). This increase was highest and with a clear increasing trend only in the most recent years (2012–2016). The prevalence of HPV-related oropharyngeal cancer started to sharply increase in the most recent years in our setting, as occurred two decades ago in areas where most oropharyngeal cancer cases are currently HPV-related. Our results provide a comprehensive assessment of the epidemiological landscape of HPV-related oropharyngeal cancer in a region of southern Europe.

BACKGROUND Clinical natural language processing (cNLP) systems are of crucial importance due to their increasing capability in extracting clinically important information from free text contained in electronic health records (EHRs). The conversion of a nonstructured representation of a patient’s clinical history into a structured format enables medical doctors to generate clinical knowledge at a level that was not possible before. Finally, the interpretation of the insights gained provided by cNLP systems has a great potential in driving decisions about clinical practice. However, carrying out robust evaluations of those cNLP systems is a complex task that is hindered by a lack of standard guidance on how to systematically approach them. OBJECTIVE Our objective was to offer natural language processing (NLP) experts a methodology for the evaluation of cNLP systems to assist them in carrying out this task. By following the proposed phases, the robustness and representativeness of the performance metrics of their own cNLP systems can be assured. METHODS The proposed evaluation methodology comprised five phases: (1) the definition of the target population, (2) the statistical document collection, (3) the design of the annotation guidelines and annotation project, (4) the external annotations, and (5) the cNLP system performance evaluation. We presented the application of all phases to evaluate the performance of a cNLP system called “EHRead Technology” (developed by Savana, an international medical company), applied in a study on patients with asthma. As part of the evaluation methodology, we introduced the Sample Size Calculator for Evaluations (SLiCE), a software tool that calculates the number of documents needed to achieve a statistically useful and resourceful gold standard. RESULTS The application of the proposed evaluation methodology on a real use-case study of patients with asthma revealed the benefit of the different phases for cNLP system evaluations. By using SLiCE to adjust the number of documents needed, a meaningful and resourceful gold standard was created. In the presented use-case, using as little as 519 EHRs, it was possible to evaluate the performance of the cNLP system and obtain performance metrics for the primary variable within the expected CIs. CONCLUSIONS We showed that our evaluation methodology can offer guidance to NLP experts on how to approach the evaluation of their cNLP systems. By following the five phases, NLP experts can assure the robustness of their evaluation and avoid unnecessary investment of human and financial resources. Besides the theoretical guidance, we offer SLiCE as an easy-to-use, open-source Python library. CLINICALTRIAL

We assessed forty HNC patients receiving treatment with curative intent. Specific quantitative muscle and fat changes were evaluated using CT. Nutrition support was provided according to ESPEN guidelines, with adjusted body weight (ABW) in overweight/obese patients used to define their nutritional targets. Linear regression models were used to evaluate clinical predictors of tissue loss. Mean overall losses were body weight (-10.5%), and CT-defined muscle (-8.4%) and fat mass (-24.8%), p 0.001. A subset of 20 patients had high muscle loss (-14.7%) with concurrent negative energy balance as reflected by considerable fat loss (-29.7%); those tended to have higher baseline body mass index (26.2 vs. 23.3 kg/m

The core function of a multidisciplinary team (MDT) is to bring together a group of healthcare professionals from different fields in order to determine patients' treatment plan. Most of head and neck cancer (HNC) units are currently led by MDTs that at least include ENT and maxillofacial surgeons, radiation and medical oncologists. HNC often compromise relevant structures of the upper aerodigestive tract involving functions such as speech, swallowing and breathing, among others. The impairment of these functions can significantly impact patients' quality of life and psychosocial status, and highlights the crucial role of specialized nurses, dietitians, psycho-oncologists, social workers, and onco-geriatricians, among others. Hence, these professionals should be integrated in HNC MDTs. In addition, involving translational research teams should also be considered, as it will help reducing the existing gap between basic research and the daily clinical practice. The aim of this comprehensive review is to assess the role of the different supportive disciplines integrated in an MDT and how they help providing a better care to HNC patients during diagnosis, treatment and follow up.

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p, This research was funded by the health research program of the “Instituto de Salud Carlos III” (PI14/00071) co financed with FEDER founds and for the Health Regional Management of the Junta de Castilla y León (GRS1385/A/16). J. Fernández-Mateos was partially supported by a predoctoral research grant from the Consejería de Educación—Junta de Castilla y León and the European Social Fund to CC-B (EDU/1084/2012).

Background: After promising results from TPEx phase II trial in first line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), this trial compared the TPEx regimen (docetaxel-platinum-cetuximab) to the standard EXTREME regimen. Methods: Patients with R/M HNSCC unsuitable for curative treatment were randomized between TPEx (four cycles docetaxel-cisplatin-cetuximab followed by cetuximab maintenance 500 mg/m² every two weeks) and EXTREME (six cycles 5FU-cisplatin-cetuximab followed by weekly cetuximab 250 mg/m² maintenance). Main inclusion criteria were patients fit for cisplatin, performance status (PS) ≤1, creatinine clearance >60ml/min, and age

Background Clinical natural language processing (cNLP) systems are of crucial importance due to their increasing capability in extracting clinically important information from free text contained in electronic health records (EHRs). The conversion of a nonstructured representation of a patient’s clinical history into a structured format enables medical doctors to generate clinical knowledge at a level that was not possible before. Finally, the interpretation of the insights gained provided by cNLP systems has a great potential in driving decisions about clinical practice. However, carrying out robust evaluations of those cNLP systems is a complex task that is hindered by a lack of standard guidance on how to systematically approach them. Objective Our objective was to offer natural language processing (NLP) experts a methodology for the evaluation of cNLP systems to assist them in carrying out this task. By following the proposed phases, the robustness and representativeness of the performance metrics of their own cNLP systems can be assured. Methods The proposed evaluation methodology comprised five phases: (1) the definition of the target population, (2) the statistical document collection, (3) the design of the annotation guidelines and annotation project, (4) the external annotations, and (5) the cNLP system performance evaluation. We presented the application of all phases to evaluate the performance of a cNLP system called “EHRead Technology” (developed by Savana, an international medical company), applied in a study on patients with asthma. As part of the evaluation methodology, we introduced the Sample Size Calculator for Evaluations (SLiCE), a software tool that calculates the number of documents needed to achieve a statistically useful and resourceful gold standard. Results The application of the proposed evaluation methodology on a real use-case study of patients with asthma revealed the benefit of the different phases for cNLP system evaluations. By using SLiCE to adjust the number of documents needed, a meaningful and resourceful gold standard was created. In the presented use-case, using as little as 519 EHRs, it was possible to evaluate the performance of the cNLP system and obtain performance metrics for the primary variable within the expected CIs. Conclusions We showed that our evaluation methodology can offer guidance to NLP experts on how to approach the evaluation of their cNLP systems. By following the five phases, NLP experts can assure the robustness of their evaluation and avoid unnecessary investment of human and financial resources. Besides the theoretical guidance, we offer SLiCE as an easy-to-use, open-source Python library.

High-risk human papillomavirus (HPV) is now recognised as the principal cause of the increasing incidence rates of oropharyngeal squamous cell carcinoma (OPSCC) in some parts of the world. The primary risk factor for developing HPV-related OPSCC is oral HPV-infection and the majority of oral HPV-infections are acquired by oral sex. Progression into an OPSCC includes persistent infection with evasion of immune response in the microenvironment, the activation of viral early genes (E6, E7) in basal epithelial cells, the deregulation of cell cycle and the accumulation of chromosomal instability. Patients affected by HPV-related OPSCC tend to be younger and have better outcomes. This observation has lead current research to evaluate treatment de-escalation options to reduce long-term associated morbidity. Moreover, a different molecular profile for HPV-related OPSCC has been described, opening new options for targeted therapy and immunotherapy approaches. This paper comprehensively reviews our accumulated knowledge regarding the role of HPV in OPSCC spanning from infection to cancer development, including its clinical diagnosis, management and preventive strategies.

BACKGROUND Sexual behavior and oral human papillomavirus (HPV) infection are risk factors for oral squamous cell carcinoma (OSCC). The effects of OSCC diagnosis and treatment on subsequent relationship stress and sexual behavior are unknown. METHODS Incident cases of HPV-positive or HPV-negative OSCC in patients who had a partnered relationship and partners of patients with oropharyngeal cancer were eligible for a study in which surveys were administered at diagnosis and at the 6-month follow-up time point to assess relationship distress, HPV transmission and concerns about health consequences, and sexual behavior. The frequency distributions of responses, stratified by tumor HPV status, were compared at baseline and follow-up. RESULTS In total, 262 patients with OSCC and 81 partners were enrolled. Among the patients, 142 (54.2%) had HPV-positive OSCC, and 120 (45.8%) had HPV-negative OSCC. Relationship distress was infrequently reported, and 69% of patients felt that their relationship had strengthened since the cancer diagnosis. Both HPV-positive patients (25%) and their partners (14%) reported feelings of guilt or responsibility for the diagnosis of an HPV-caused cancer. Concern over sexual, but not nonsexual, HPV transmission to partners was reported by 50%. Significant declines in the frequency of vaginal and oral sexual behaviors were reported at follow-up, regardless of tumor HPV status. From baseline to 6 months, significant increases in abstinence from vaginal sex (from 10% to 34%; P

ObjectivesTo examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab.Material and methodsMulticenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods.ResultsAcneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p

Background LIPI, based on derived NLR (neutrophils/(leucocytes-neutrophils)) and lactate dehydrogenase (LDH) level, has been correlated to ICI outcomes in advanced non small cell lung cancer. We evaluated if HN-LIPI could offer the same role in R/M SCCHN. Methods This is a multicentric (9 European centers) retrospective study including R/M SCCHN patients (pts) treated with ICI from September 2014 to May 2019 and a control cohort (N = 83) only treated with chemotherapy. Baseline biological and clinicaldata were collected from medical records. According to dNLR>3 and LDH > upper limit of normal, HN-LIPI defines 3 groups (Good: 0 factor; Intermediate: 1 factor; Poor: 2 factors).The primary endpoint was overall survival (OS), and secondary endpoints was progression free survival (PFS). Results We included 273 pts (84% male, 84% smokers and 87% with PS ≤ 1, median age 59 years). Primary tumor locations were: oropharynx (37%), oral cavity (23%) and hypopharynx (17%). p16by immunohistochemistry was positive in 33% oropharynx pts. ICI were administered in 53% of patients as monotherapy and in 47% in combination. The median number of prior lines was 2 (1-7) with 65% of pts receiving ≥2. Median follow up of 13.2 months (mo).The median (m) PFS and OS were 2.84 mo [2.53-3.52] and 11.8mo [9.4-15.8]. dNLR >3 was associated to poor OS(HR 1.6, 95%CI: 1.1-2.3) but not with PFS (p = 0.11). LDH was not associated with endpoints. Median OS for good, intermediate and poor LIPI groups were: 15.9mo, 8.9mo and 6.2mo, respectively (p=.03). In univariate analysis, Intermediate and Poor risk groups were associated with OS (HR:1.5 95%CI:1.1-2.2 and HR:2 95%CI:1.0-4. respectively ). There was trend to better objective response rate in the good risk group compared with intermediate and poor (36%, 22% and 18%, p = 0.09). Conclusions Baseline HN-LIPI is associated with worse OS for ICI in R/M SCCHN but not with PFS. Control cohort results and multivariate models will be further presented at the congress, which would elucidate the prognostic and/or predictive impact in R/M SCCHN population. Legal entity responsible for the study Neus Baste. Funding Has not received any funding. Disclosure V. Cristina: Advisory / Consultancy: Merck-Serono; Advisory / Consultancy: Ely Lilly; Advisory / Consultancy: Servier; Advisory / Consultancy: Celgene; Travel / Accommodation / Expenses: Bayer; Travel / Accommodation / Expenses: Merck-Serono. A. Garcia Castano: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: MSD; Advisory / Consultancy: BMS; Advisory / Consultancy: Pierre Fabre; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Pierre Fabre. R. Mesia Nin: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: MSD. M. Taberna: Non-remunerated activity/ies: Merck Serono; Non-remunerated activity/ies: AstraZeneca; Travel / Accommodation / Expenses: Merck Serono; Travel / Accommodation / Expenses: Nanobiotics; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Bristol-Myers. B. Besse: Travel / Accommodation / Expenses: AbbVie; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Biogen; Travel / Accommodation / Expenses: Blueprint Medicine; Travel / Accommodation / Expenses: BMS; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Eli Lilly; Travel / Accommodation / Expenses: GSK; Travel / Accommodation / Expenses: Ignyta; Travel / Accommodation / Expenses: IPSEN; Travel / Accommodation / Expenses: MERCK; Travel / Accommodation / Expenses: KGaA; Travel / Accommodation / Expenses: MSD; Travel / Accommodation / Expenses: Nektar; Travel / Accommodation / Expenses: Onxeo; Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Pharma Mar; Travel / Accommodation / Expenses: SANOFI; Travel / Accommodation / Expenses: Spectrum pharmaceuticals; Travel / Accommodation / Expenses: Tiziana Pharma; Travel / Accommodation / Expenses: Takeda. N. Baste-Rotllan: Advisory / Consultancy, Travel / Accommodation / Expenses: Merck Serono; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Nanobiotics; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Travel / Accommodation / Expenses: MSD. All other authors have declared no conflicts of interest.

Cetuximab remains to date the only targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a key role in the tumorigenesis and progression of this disease as well as in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 subclass monoclonal antibody against EGFR, is the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is a validated treatment option in LA-HNSCC. However, its use has been limited to patients who are considered unfit for standard of care chemoradiotherapy (CRT) with single agent cisplatin given the lack of direct comparison of these two regimens in randomized phase III trials and the inferiority suggested by metanalysis and phase II studies. The current use of cetuximab in HNSCC is about to change given the recent results from randomized prospective clinical trials in both the LA and R/M setting. Two phase III studies evaluating RT-cetuximab vs. CRT in Human Papillomavirus (HPV)-positive LA oropharyngeal squamous cell carcinoma (De-ESCALaTE and RTOG 1016) showed inferior overall survival and progression-free survival for RT-cetuximab combination, and therefore CRT with cisplatin remains the standard of care in this disease. In the R/M HNSCC, the EXTREME regimen has been the standard of care as first-line treatment for the past 10 years. However, the results from the KEYNOTE-048 study will likely position the anti-PD-1 agent pembrolizumab as the new first line treatment either alone or in combination with chemotherapy in this setting based on PD-L1 status. Interestingly, cetuximab-mediated immunogenicity through antibody dependent cell cytotoxicity (ADCC) has encouraged the evaluation of combined approaches with immune-checkpoint inhibitors in both LA and R/M-HNSCC settings. This article reviews the accumulated evidence on the role of cetuximab in HNSCC in the past decade, offering an overview of its current impact in the treatment of LA and R/M-HNSCC disease and its potential use in the era of immunotherapy.

6057 Background: Up to 24% of patients (pts) newly-diagnosed with LA-HNSCC are 70 years old (yo). NCCN guidelines recommend a geriatric assessment to guide treatment decisions in this pts population. Comprehensive geriatric assessment (CGA) of older HNSCC pts was implemented at our institution in 2018. We evaluated the impact of CGA in treatment decision and outcome and compare it to a control cohort with no CGA treated within the same institution. Methods: Retrospective single-institution analysis of two consecutively-treated cohorts of newly-diagnosed elderly LA-HNSCC pts treated at the Catalan Institute of Oncology: a cohort treated based on CGA between 2018-2020; and a control cohort with no CGA treated based on physician criteria following tumor board decision between 2016-2018. Pts demographics and disease characteristics were obtained from our in-site prospective database. Treatment received (standard, adjusted, palliative-intent, best supportive care [BSC]), treatment completion rate (TCR) an overall response rate (ORR) after conservative treatment were collected and compared for both cohorts using chi-square. Results: A total of 197 pts were included: CGA cohort =81; Control cohort=96. Baseline characteristics were similar between cohorts (Table). Pts in CGA cohort were classified as fit (F) 35 (34.7%), medium-fit (MF) 51 (50.5%) and unfit (UF) 15 (14.9%) according to CGA results. CGA changed final treatment decision following tumor board in 31 % of the cases. Pts were more likely to receive standard treatment in the CGA cohort when compared control (36 vs 21%; p = 0.048), with no differences observed in TCR (84% vs 86%; p = 0.805). In pts who underwent conservative treatment, ORR was similar between CGA and control cohort (73.9% vs 66.7 %; p = 0.082), respectively. Tumor progression was the major cause of death in both groups. Conclusions: Older pts with LA-HNSCC who underwent CGA were more likely to receive standard treatment than those who did not, supporting the relevance of CGA for clinical decision-making in this pt population. No differences were observed in CRR, TCR or death cause. In-deep survival analysis are on-going.[Table: see text]

6061 Background: Treatment (ttm) of cancer patients (pts) was compromised during the first wave of COVID19 pandemic due to collapse of healthcare systems. Standard of care (SOC) for LA-HNSCC pts had to be adapted as operating rooms were temporarily unavailable, and to reduce risk of COVID19 exposure. The IMPACCT study evaluated the outcome of LA-HNSCC pts treated at the Catalan Institute of Oncology during the first semester of 2020 and compared it to a control cohort previously treated in the same institution. Methods: Retrospective single institution analysis of two consecutively-treated cohorts of newly-diagnosed HNSCC pts: from January to June of 2020 (CT20) and same period of 2018 and 2019 (CT18-19). Pt demographics and disease characteristics were obtained from our in-site prospective database. Ttm modifications from SOC as per COVID19-contingency protocol in CT20 for LA-HNSCC were collected. Chi-squared was used to compare variables and ttm response between cohorts. One-year recurrence-free survival (1yRFS) and overall survival (1yOS) of LA-HNSCC pts were estimated by Kaplan-Meier method and compared by Log-rank test. Results: A total of 306 pts were included: CT20=99; CT18-19=207. Baseline characteristics were balanced between cohorts (Table1). In pts treated with conservative ttm (non-surgical approach), persistence disease was higher in CT20 vs CT18-19 (26 vs. 10% p=0.02). Median follow-up of CT20 and CT18-19 was 6.8 months (IQR 5.1-7.9) and 12.3 (6.7-18.4), respectively. A trend towards lower 1yRFS and 1yOS was observed in CT20 vs CT18-19 (72 vs 83% p=0.06; 80 vs 84% p=0.07), respectively. Within CT20, 37 pts (37%) had one or more ttm modifications: switch from surgery to conservative ttm (n=13); altered radiotherapy fractionation (n=14); reduced cisplatin cumulative dose to 200mg/m2 (n=19); no adjuvant ttm (n=1). Pts who received modified ttm had no differences in 1yRFS vs those who did not (80 vs 66% p=0.31), but higher 1yOS was observed (97 vs 67% p

Background The purpose of this study was to describe the results and complications of primary site salvage surgery after head and neck squamous cell carcinoma (HNSCC) treated with bioradiotherapy. Methods We conducted a retrospective chart review of 268 patients treated with bioradiotherapy between March 2006 and December 2013 at the Hospital Universitari de Bellvitge-ICO. Results Fifty-nine patients developed local recurrence or had residual disease with a 1-year and 3-year overall survival of 47% and 15.4%, respectively. Salvage surgery was feasible in 22 patients (37.3%). There were 16 complications in these 22 patients (72.7%), 11 (50%) of which were major. Bilateral neck dissection was identified as a risk factor for complications. Conclusion Salvage surgery after bioradiotherapy is associated with a high rate of complications. Neck dissection seems to be related to an increased rate of complications with no survival improvement. © 2016 Wiley Periodicals, Inc. Head Neck 39: 116–121, 2017

Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.

Head and neck cancer is a highly heterogeneous disease comprising a large number of tumors located in the cervicofacial area. This study aimed to determine the epidemiological characteristics of squamous-cell carcinomas of the head and neck in the Spanish population, and the distribution of risk factors based on tumor locations. A cohort of 459 patients (75 oral cavity, 167 oro-/hypopharyngeal and 217 laryngeal cancers) recruited in 19 hospitals participating in the Spanish head and neck cancer cooperative group were included over 3 years (2012–2014). Epidemiological parameters and risk factors were obtained from a self-administered questionnaire, and tumor characteristics were obtained from clinical records. Multivariate multinomial logistic regression was used to assess factors associated with tumor location. Most patients were males (88.4 %), smokers (95 %) and drinkers (76.5 %). Relative to laryngeal cancer, pharyngeal cancer and oral cancer were more common in women than men (OR 3.58, p = 0.003 and 4.33, p = 0.001, respectively); pharyngeal cancer was more associated with rural environment (OR 1.81, p = 0.007) and weekly alcohol intake (10–140 g: OR 2.53, p = 0.012; 141–280 g: OR 2.47, p = 0.023; >280 g: OR 3.20, p = 0.001) and less associated with pack-years of smoking (21–40 packs: OR 0.46, p = 0.045; 41–70 packs: OR 0.43, p = 0.023; ≥71 packs: OR 3.20, p = 0.015). The distribution of these tumors differs between the sexes, with a higher proportion of oral cavity and pharyngeal tumors in women than in men. Oro-/hypopharyngeal cancers were more strongly associated with rural areas and with alcohol consumption, although less strongly associated with smoking than laryngeal tumors.

Purpose Despite treatment, prognosis of unresectable squamous cell carcinoma of the head and neck (SCCHC) is dismal. Cetuximab therapy has proven to increase the clinical activity of radiation therapy and chemotherapy in patients with locoregional advanced disease with an acceptable toxicity profile. We designed a phase 2 trial to evaluate the efficacy of docetaxel, cisplatin, and 5-fluorouracil (TPF) plus cetuximab (C-TPF) as an induction regimen in patients with unresectable SCCHN. Methods and Materials A single-arm phase 2 trial was conducted. Eligible patients included those with untreated unresectable SCCHC, World Health Organization performance status of 0 to 1, 18 to 70 years of age. Treatment consisted of four 21-day cycles of TPF (docetaxel, 75 mg/m 2 day 1; cisplatin, 75 mg/m 2 day 1; 5-fluorouracil [5-FU], 750 mg/m 2 day 1-5) and cetuximab, 250 mg/m 2 weekly (loading dose of 400 mg/m 2 ). Prophylactic granulocyte colony-stimulating factor and antibiotic support were given. After induction, sequential accelerated radiation therapy with concomitant boost (69.9 Gy) and weekly cetuximab therapy were delivered in the absence of disease progression. The primary endpoint was objective response rate (ORR) to C-TPF. Results Fifty patients were enrolled across 8 centers. Median age was 54 years; disease was stage IV; oropharynx and hypopharynx were the most common primary sites. Eighty-two percent received 4 cycles of C-TPF, and 86% started sequential treatment based on radiation therapy and cetuximab. ORR after C-TPF was 86% (95% confidence interval [CI]: 73%-94%) and 24% had complete response (CR). With a median follow-up of 40.7 months, median overall survival (OS) was 40.7 months. The 2-year actuarial locoregional control (LRC) rate was 57%. The most common drug-related grade 3 or 4 toxicities during induction were neutropenia (24%), neutropenic fever (24%), and diarrhea (20%). There were 3 treatment-related deaths (6%). Conclusions C-TPF yields high ORR and CR as induction treatment in unresectable SCCHN. However, hematologic toxicity is too high to recommend this regimen at the current dose.

Background VCN-01 is an oncolytic adenovirus with replication restricted to cells with a nonfunctional retinoblastoma pathway. Upon selective replication VCN-01 expresses the matrix remodeling-enzyme hyaluronidase to enhance virus spreading and tumor uptake of different therapeutics, including immune check-point inhibitors. In a phase I performed in pancreatic carcinoma VCN-01 reached tumors after systemic administration and induced CD8-infiltration, tumor inflammation and PD-1/PD-L1 up-regulation. We hypothesize these intratumor effects may help to overcome the observed resistance to Durvalumab and other PD-(L)-1 checkpoint inhibitors Trial Design NCT03799744 is a multi-center, open-label dose-escalation phase I study evaluating the safety, tolerability and efficacy of the combination of VCN-01 plus durvalumab in R/M HNSCC patients who have progressed on prior PD-(L)-1 checkpoint inhibitors. Patients need to have neutralizing antibodies levels against adenovirus ≤1/350 dilution to be included. The study follows a 3 + 3 design with two dose levels for VCN-01 (3,3.1012 & 1.1013 vp) combined with Durvalumab at a fixed dose of 1500mg intravenous (i.v.). Two treatment arms are explored: I) Concomitant single i.v. dose of VCN-01 with durvalumab on cycle 1 day 1 followed by durvalumab Q4W; II) Sequential single i.v. VCN-01 on cycle 1 day -14 plus durvalumab on cycle 1 day 1 followed by durvalumab Q4W. Patients continue durvalumab Q4W until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective of the study is to evaluate the safety and tolerability of VCN-01 with durvalumab in the two regimens of administration and to establish the recommended phase II dose. Secondary objectives are progression free survival, overall response rate by irRECIST /RECIST, VCN-01 pharmacokinetics and shedding in blood. Other exploratory biomarkers will be analyzed in tumor biopsies (immune markers), serum (hyaluronidase levels), stool (microbiome) and imaging (dynamic contrast-enhanced MRI, diffusion weighted imaging and T2 mapping). The study opened recruitment in April 2019 with 7 out of 18 planned patients enrolled at time of submission. Clinical trial identification NCT03799744. Legal entity responsible for the study Catalan Institute of Oncology (ICO). Funding VCN Biosciences, AstraZeneca. Disclosure M. Jove: Advisory / Consultancy: Boehringer Ingelheim. I. Brana: Advisory / Consultancy, Research grant / Funding (self): Orion Pharma; Speaker Bureau / Expert testimony, Research grant / Funding (self): Bristol-Myers Squibb; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: AstraZeneca; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Serono; Research grant / Funding (self): Celgene; Research grant / Funding (self): Gliknik; Research grant / Funding (self): GSK; Research grant / Funding (self): Janssen; Research grant / Funding (self): KURA; Research grant / Funding (self): MSD; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Shattuck; Research grant / Funding (self): Northern Biologics; Research grant / Funding (self): Rakutan Aspirian; Research grant / Funding (self): Naobiotics. M. Taberna: Honoraria (self), Advisory / Consultancy, Non-remunerated activity/ies: Merck; Honoraria (self), Non-remunerated activity/ies: AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Advisory / Consultancy: Nanobiotics. E. Garralda: Leadership role, Research grant / Funding (institution): Novartis; Leadership role: Principia Biopharma Inc; Leadership role: Lilly, S.A; Advisory / Consultancy, Leadership role: Roche / Genentech Inc; Leadership role: Loxo Oncology Inc; Advisory / Consultancy, Leadership role: F.Hoffmann La Roche Ltd; Leadership role: Symphogen A/S; Speaker Bureau / Expert testimony, Leadership role, Travel / Accommodation / Expenses: MSD; Leadership role: Incyte; Leadership role: Pharma Mar; Leadership role: Kura Oncology; Leadership role: Macrogenics; Leadership role, Travel / Accommodation / Expenses: Glycotope; Leadership role: Pierre Fabre; Leadership role: Cellestia Biotech; Leadership role, Travel / Accommodation / Expenses: Menarini Ricerche; Leadership role: Blueprint Medicines; Leadership role: Beigene; Leadership role: Sierra Oncology; Leadership role: Genmab; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Janssen Global Services ; Advisory / Consultancy: Ellipses Pharma; Advisory / Consultancy: NeoMed Therapeutics; Advisory / Consultancy: SeaGen; Speaker Bureau / Expert testimony: ThermoFisher. G. Capella: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences. R. Alemany: Advisory / Consultancy, Shareholder / Stockholder / Stock options: VCN Biosciences; Research grant / Funding (institution): Lokon Pharma; Research grant / Funding (institution): Mologen. E. Blasi: Full / Part-time employment: VCN Biosciences. C. Blasco: Full / Part-time employment: VCN Biosciences. M. Cascallo Piqueras: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Officer / Board of Directors: VCN Biosciences. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Serono; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche. All other authors have declared no conflicts of interest.

Background The objective of the present study is to assess differences in the competing causes of death in patients with oropharyngeal carcinoma (OPC) as a function of the human papillomavirus (HPV) status. Methods We studied retrospectively 423 patients with OPC with known HPV status. Among the patients included in the study, 53 (12.5%) were HPV-positive. We analyzed overall survival and competing causes of mortality according to the HPV status of the patients. Results Patients with HPV-negative tumors had lower OPC cancer-specific survival (P = .0001), second primary neoplasm survival (P = .0001), and noncancer-related causes survival (P = .13) than patients with HPV-positive tumors. This resulted in significant differences in overall survival depending on HPV status (P = .0001). Conclusion Conclusion: HPV-positive OPC has a better overall survival than HPV-negative OPC. Patients with HPV-positive tumors presented a significant lower OPC cancer-specific and second primary neoplasm mortality and a marginally nonsignificant lower noncancer mortality as compared to HPV-negative tumors.

Background: The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. Methods: We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16(INK4a)/pRb/p53/Cyclin-D1 immunohistochemistry. HPV-DNA positive and a random sample of HPV-DNA negative cases were subjected to HPV-E6*I mRNA detection. Demographic, tobacco/alcohol use, clinical and follow-up data were collected. Multivariate models were used to evaluate factors associated with HPV positivity as defined by four different HPV-relatedness definitions. Proportional-hazards models were used to compare the risk of death and recurrence among HPV-related and non-related OPC. Results: 788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16(INK4a), HPV-DNA, HPV-DNA/HPV-E6*I mRNA, and HPV-DNA/p16(INK4a), respectively. Being nonsmoker or non-drinker was consistently associated across HPV-relatedness definitions with HPV positivity. A suggestion of survival differences between anatomic sub-sites and treatments was observed. Double positivity for HPV-DNA/p16(INK4a) showed strongest diagnostic accuracy and prognostic value. Conclusions: Double positivity for HPV-DNA/p16(INK4a), a test that can be easily implemented in the clinical practice, has optimal diagnostic accuracy and prognostic value. Our results have strong clinical implications for patients' classification and handling and also suggest that not all the HPV-related OPC behave similarly.

BACKGROUND: Given the different nature and better outcomes of oropharyngeal carcinoma (OPC) associated with human papillomavirus (HPV) infection, a novel clinical stage classification for HPV-related OPC has been accepted for the 8th edition AJCC TNM (ICON-S model). However, it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value. MATERIAL AND METHODS: The aim of this study was to compare different staging system models proposed for HPV-related OPC patients: 7th edition AJCC TNM, RPA stage with non-anatomic factors (Princess Margaret), RPA with N categories for nasopharyngeal cancer (MD-Anderson) and AHR-new (ICON-S), according to different HPV-relatedness definitions: HPV-DNA detection plus an additional positive marker (p16INK4a or HPV-mRNA), p16INK4a positivity alone or the combination of HPV-DNA/p16INK4a positivity as diagnostic tests. RESULTS: A total of 788 consecutive OPC cases diagnosed from 1991 to 2013 were considered eligible for the analysis. Of these samples, 66 (8.4%) were positive for HPV-DNA and (p16INK4a or HPV-mRNA), 83 (10.5%) were p16INK4a positive and 58 (7.4%) were double positive for HPV-DNA/p16INK4a. ICON-S model was the staging system, which performed better in our series when using at least two biomarkers to define HPV-causality. When the same analysis was performed considering only p16INK4a-positivity, RPA stage with non-anatomic factors (Princess Margaret) has the best classification based on AIC criteria. CONCLUSION: HPV-relatedness definition for classifying HPV-related OPC patient do impact on TNM classification and patients' survival. Further studies assessing HPV-relatedness definitions are warranted to better classify HPV-related OPC patients in the era of de-escalation clinical trials. This work was partially supported by grants from the Instituto de Salud Carlos III-ISCIII (Spanish Government) cofunded by FEDER funds/European Regional Development Fund (ERDF) - a way to build Europe (PI14/01819, PI15/00500 and PI11/02096); Ayudas Merck Serono-Fundación Salud 2000 de investigación 2015; Agéncia de Gestió d’Ajuts Universitaris i de Recerca, AGAUR (2017SGR1085 and 2017SGR1718), European Commission 7th Framework Programme COHEAHR (Health-F3-2013-603019) and Rio Hortega-SEOM (ISCIII-Spanish Society of Medical Oncology) (personal grant to MT). The funders did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Summary Background Multimodal treatment for locally advanced head and neck carcinomas (LAHNC) has been reported to improve survival. However, it is less clear to what extent this survival gain is given at the expense of an impact on the quality of life of our patients. Our aim is to analyze the ongoing late toxic effects among long survivors, to determine how much these impairments affect their QoL, and if there is any factor that clearly impacts on this toxicity. Methods 152 Patients diagnosed with LAHNC were treated radically in our clinical practice, either with concomitant chemoradiotherapy or bioradiotherapy, with or without induction chemotherapy. We prospectively assessed these patients’ treatment-related late toxicities according to the Radiation Therapy Oncology Group scoring system, and patients answered a QoL question to subjectively evaluate the degree of impact caused by these sequelae in their daily life. Multivariate logistic regressions were performed to detect factors that could influence in toxicity. Results 21.9% Patients experienced grade 3–4 toxicity. Concomitant chemoradiation with cisplatin was found to be a risk factor of moderate and severe late toxicity compared to concomitant cetuximab in the adjusted analysis by RT fractionation. OR for moderate toxicity 0.292 (CI: 0.125–0.680, p = 0.004); OR for severe toxicity: 0.299 (CI: 0.0909–0.999, p = 0.05). Induction chemotherapy was found to be a protective factor for moderate late toxicity compared to concomitant treatment alone. Conclusion Patients treated with concomitant chemoradiation with cisplatin have significantly more late toxicity compared to bioradiotherapy, whereas induction chemotherapy prevents from developing moderate late toxicity.

The etiologic role of human papillomaviruses (HPV) in oropharyngeal cancer (OPC) is well established. Nevertheless, information on survival differences by anatomic sub-site or treatment remains scarce, and it is still unclear the HPV-relatedness definition with best diagnostic accuracy and prognostic value.We conducted a retrospective cohort study of all patients diagnosed with a primary OPC in four Catalonian hospitals from 1990 to 2013. Formalin-fixed, paraffin-embedded cancer tissues were subjected to histopathological evaluation, DNA quality control, HPV-DNA detection, and p16788 patients yielded a valid HPV-DNA result. The percentage of positive cases was 10.9%, 10.2%, 8.5% and 7.4% for p16Double positivity for HPV-DNA/p16

Objetivo: Identificar el uso clínico de la metadona como analgésico en el manejo del dolor oncológico enancianos.Material y métodos: Se realizó una revisión sistemática de la literatura sobre el uso específico de la meta-dona en ancianos con dolor oncológico en las bases de datos MEDLINE, COCHRANE DATABASE y SCOPUS.Se llevó a cabo una segunda búsqueda en MEDLINE de estudios clínicos y revisiones sistemáticas del usode metadona en dolor oncológico, seleccionando aquellos en los que la edad media de los pacientes fuese≥ 65 a˜nos.Resultados: En la primera búsqueda se obtuvieron 4 artículos y de la segunda 7 estudios, ninguno de ellosespecíficos del uso de la metadona en ancianos con cáncer.Conclusiones: No existen datos suficientes del uso de la metadona como analgésico en el anciano con cán-cer. Dadas sus peculiaridades características farmacológicas es necesario su uso por personal experto. Seproponen unas recomendaciones para su empleo como analgésico en el tratamiento del dolor oncológicoen el anciano. Objective: To identify the clinical use of methadone as an analgesic in the management of cancer pain inelderly patients.Material and methods: We performed a systemic review of the literature on the specific use of metha-done in elderly with cancer pain in MEDLINE, COCHRANE DATABASE and SCOPUS. A second search wasconducted in MEDLINE to look for clinical trials and systematic review of the use of methadone in cancerpain, selecting only those in which the mean age of patients was ≥ 65 years old.Results: Four articles were obtained in the first search, and from the second 7 clinical trials, none of themspecific to methadone use in elderly patients with cancer.Conclusions: There are insufficient data on the use of methadone as an analgesic in the elderly with cancer.Given its pharmacological characteristics it must be used by trained personnel. Several recommendationsare proposed for its use as an analgesic in the treatment of cancer pain in the elderly.

Background The etiologic role of human papillomavirus (HPV) in oropharyngeal cancer (OPC) is well established and it explains the increase of young patients (pts) affected with OPC. This is an observational study representing a real-world experience evaluating clinicopathologic features and prognosis in young ( Methods We conducted a retrospective cohort study of pts diagnosed with OPC in four Catalonian hospitals from 1991 to 2017. Data was collected from medical records. Unconditional logistic regression was used to compare age groups and Proportional hazards model (Cox regression) and Cumulative Incident Function (CIF) to analyze OPC-specific survival (OPC-sS) in locally advanced cases. Results A total of 865 pts were included, 49 in the young group (median age 42; range 28.5-45.0) and 816 in the old group (median age 61; range 45.1-93.9). There were no differences between age groups in terms of sex, anatomic subsite, toxic habits, HPV status (positivity defined as double p16/DNA positivity) or stage at diagnosis. There were more non-smokers HPV-related (HPV+) OPC pts than HPV-negative (HPV-) ones (p-value Conclusions HPV is the most important prognostic factor in OPC independent of age. Legal entity responsible for the study ICO (Catalan Institute of Oncology). Funding The Instituto de Salud Carlos III-ISCIII (Spanish Government) co funded by EDER funds/ European Regional Development Fund (ERDF) - a way to build Europe (References: PI1102096, PI1401918, PI1500500, PI1501205, RD12/0036/0056, CIBERESP, CIBERONC). Disclosure M. Nieva: Travel / Accommodation / Expenses: Takeda; Travel / Accommodation / Expenses: Merck. S. Tous: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK.: Merck. M. Mena: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene. R. Mesia Nin: Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: BMS; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy: AZ; Advisory / Consultancy: Roche; Advisory / Consultancy: Nanobiotix. L. Alemany: Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: GSK; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Seegene; Research grant / Funding (institution), Cancer Epidemiology Research Program (ST LA MM) has received sponsorship for grants from Merck and co, Seegene and GSK: Merck. M. Taberna: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AZ; Advisory / Consultancy: Nanobiotics; Speaker Bureau / Expert testimony: MSD; Speaker Bureau / Expert testimony: Bristol Myers. All other authors have declared no conflicts of interest.

Sexual behavior and oral human papillomavirus (HPV) infection are risk factors for oral squamous cell carcinoma (OSCC). The effects of OSCC diagnosis and treatment on subsequent relationship stress and sexual behavior are unknown.Incident cases of HPV-positive or HPV-negative OSCC in patients who had a partnered relationship and partners of patients with oropharyngeal cancer were eligible for a study in which surveys were administered at diagnosis and at the 6-month follow-up time point to assess relationship distress, HPV transmission and concerns about health consequences, and sexual behavior. The frequency distributions of responses, stratified by tumor HPV status, were compared at baseline and follow-up.In total, 262 patients with OSCC and 81 partners were enrolled. Among the patients, 142 (54.2%) had HPV-positive OSCC, and 120 (45.8%) had HPV-negative OSCC. Relationship distress was infrequently reported, and 69% of patients felt that their relationship had strengthened since the cancer diagnosis. Both HPV-positive patients (25%) and their partners (14%) reported feelings of guilt or responsibility for the diagnosis of an HPV-caused cancer. Concern over sexual, but not nonsexual, HPV transmission to partners was reported by 50%. Significant declines in the frequency of vaginal and oral sexual behaviors were reported at follow-up, regardless of tumor HPV status. From baseline to 6 months, significant increases in abstinence from vaginal sex (from 10% to 34%; P .01) and oral sex (from 25% to 80%; P .01) were reported.Diagnosis and treatment of OSCC are associated with significant declines in the frequency of vaginal and oral sex, regardless of tumor HPV status. Sexual behavior is an important quality-of-life outcome to assess within clinical trials. [See related editorial on pages 000-000, this issue.] Cancer 2017. © 2017 American Cancer Society. Cancer 2017;123:1156-1165. © 2016 American Cancer Society.

The incidence of human papillomavirus (HPV) positive oral squamous cell carcinoma (OSCC) continues to increase over time, challenging healthcare providers to address their patients' HPV-related concerns.This prospective study assessed health literacy, HPV knowledge, utilization and trust in information sources among patients with incident HPV-positive or HPV-negative OSCC diagnosed at the Ohio State University from 2011 to 2015. Health literacy was assessed with a standardized scale. Additional questions evaluated HPV knowledge (including transmission, prevalence, health consequences and treatment), the frequency and type of information sources sought, and trust in those sources.Surveys were collected from 372 OSCC cases (HPV-positive, n=188; HPV-negative, n=184). Despite high mean health literacy scores, only 45.2% of HPV-related knowledge questions were answered correctly. HPV was known to be a sexually transmitted infection and a cause of cervical and anal cancer by 66.0%, 56.5% and 15.2%, respectively. In all domains, cases with HPV-positive OSCC were significantly more informed than HPV-negative cases (for all, p0.01). Only 52.7% and 56.2% of patients with HPV-positive OSCC felt they knew enough to be comfortable discussing HPV with their doctor or sexual partner, respectively. The most frequently used information source was the internet (80.9%), which ranked 8th in trust of 15 possible sources. Although most (95.5%) patients trusted information from their doctors, only 37.9% used doctors as an information source.Doctors are a highly trusted, but infrequent utilized, information source and should facilitate patient access to high-quality HPV information sources.

Objectives: It has been reported that patients with HPV-positive oropharyngeal cancer (OPC) have a lower risk of appearance of second primary neoplasm (SPN) than HPV-negative OPC patients. The aim of our study was to analyze the risk of developing SPN in a large group of patients with OPC according to HPV status in the primary tumor. Materials and methods: We included 412 OPC patients treated at our center from 1991 to 2014 for which the HPV DNA positivity was evaluated by PCR in available tumor specimens. HPV DNA positive samples were further tested for HPV E6*I mRNA detection and/or p16(INK4a) immunohistochemistry. We estimated the incidence of SPN in all cancer sites and in cancer sites related to tobacco and alcohol consumption according to the HPV status in the primary tumor. Results: Fifty-one (12.4%) out of 412 OPCs included in the study were HPV-related. Five-year SPN-free survival for HPV-negative versus HPV-positive OPC patients was 57.0% and 89.0% (P < 0.001), respectively. Corresponding estimates for 10-year SPN-free survival were 35.2% versus 78.5% (P < 0.001). When restricting the analyses to tobacco/alcohol-related SPNs, the corresponding survival rates where 62.0% versus 97.6% (P < 0.001) and 42.2% versus 97.6%, (P < 0.001), for 5-year and 10-year survival rates, respectively. HPV status and previous toxic habits might allow classifying patients regarding the risk of tobacco/alcohol-related SPNs. Conclusion: HPV-related OPC patients have a significant lower risk of SPN development, particularly in those locations related to tobacco use or alcohol consumption. (C) 2016 Elsevier Ltd. All rights reserved.