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Agustín Falco,1 Thiago Bueno de Oliveira,2 Jon Cacicedo,3 Aylen Vanessa Ospina,4 Miguel Ángel Ticona,5 Héctor Galindo,6 Marcos David Pereira,7 José Luis Aguilar-Ponce,8 Antonio Rueda-Domínguez,9 Tannia Soria,10 Miren Taberna,11 Lara Iglesias,12 Taysser Sowley,13 Ricard Mesía14 On behalf of TTCC group (Spanish Group for the Treatment of the Head and Neck Cancer)1Instituto Alexander Fleming, Asociación Argentina de Oncología Clínica (AAOC), Buenos Aires, Argentina; 2AC Camargo Cancer Center, Sociedade Brasileira de Oncologia Clínica (SBOC), São Paulo, Brazil; 3Hospital Universitario Cruces/Biocruces Bizkaia Health Research Institute, Barakaldo, Bizkaia, Spain; 4ICCAL, Hospital Universitario Fundación Santa Fe de Bogotá, Asociación Colombiana de Hematología y Oncología (ACHO), Bogotá, Colombia; 5Hospital Nacional Edgardo Rebagliati Martins de Lima, Sociedad Peruana de Oncología Médica (SPOM), Lima, Perú; 6Pontificia Universidad Católica de Chile, Sociedad Chilena de Oncología Médica (SCOM), Santiago, Chile; 7Instituto de Oncología Ángel H. Roffo, Asociación Argentina de Oncología Clínica (AAOC), Buenos Aires, Argentina; 8Instituto Nacional de Cancerología, Sociedad Mexicana de Oncología (SMeO), Mexico City, Mexico; 9UGC Oncología Médica, Hospital Universitario Regional y Virgen de la Victoria, IBIMA, Málaga, Spain; 10Hospital SOLCA de Quito, Sociedad Ecuatoriana de Oncología (SEO), Quito, Ecuador; 11Institut Català d’Oncologia, ICO L’Hospitalet, Barcelona, Spain; 12Hospital 12 de Octubre, Madrid, Spain; 13Instituto Oncológico Nacional (ION) de Panamá, Sociedad Panameña de Oncología (SPO), Panama City, Panama; 14Institut Català d’Oncologia, ICO Badalona, Barcelona, SpainCorrespondence: Ricard MesíaInstitut Català d´Oncologia, ICO Badalona, Barcelona, SpainEmail rmesia@iconcologia.netAbstract: 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.Keywords: age, cisplatin, comorbidities, contraindication, frailty, toxicity

Simple Summary The utility of a diagnostic algorithm for the detection of HPV-driven oral cavity (OCC), oropharyngeal (OPC), and laryngeal (LC) carcinomas using HPV-DNA testing followed by p16(INK4a) immunohistochemistry, taking E6*I mRNA detection as the reference standard, was assessed in HPV-DNA-positive formalin-fixed paraffin-embedded samples from 29 countries. The concordance of p16(INK4a) and E6*I mRNA among 78, 257, and 51 HPV-DNA-positive OCC, OPC, and LC, respectively, was moderate to substantial in OCC and OPC but only fair in LC. A different p16(INK4a) expression pattern was observed in those cases HPV-DNA-positive for types other than HPV16, as compared to HPV16-positive cases. We concluded that the diagnostic algorithm of HPV-DNA testing followed by p16(INK4a) immunohistochemistry might be helpful in the diagnosis of HPV-driven OCC and OPC, but not LC. Our study provides new insights into the use HPV-DNA, p16(INK4a), and HPV-E6*I mRNA for diagnosing an HPV-driven head and neck carcinoma. Background: Tests or test algorithms for diagnosing HPV-driven oral cavity and laryngeal head and neck carcinomas (HNC) have not been yet validated, and the differences among oral cavity and laryngeal sites have not been comprehensively evaluated. We aimed to assess the utility of a diagnostic algorithm for the detection of HPV-driven oral cavity (OCC), oropharyngeal (OPC) and laryngeal (LC) carcinomas using HPV-DNA testing followed by p16(INK4a) immunohistochemistry, taking E6*I mRNA detection as the reference standard. Methods: Formalin-fixed paraffin-embedded OCC, OPC, and LC carcinomas were collected from pathology archives in 29 countries. All samples were subjected to histopathological evaluation, DNA quality control, and HPV-DNA detection. All HPV-DNA-positive samples (including 78 OCC, 257 OPC, and 51 LC out of 3680 HNC with valid HPV-DNA results) were also tested for p16(INK4a) immunohistochemistry and E6*I mRNA. Three different cutoffs of nuclear and cytoplasmic staining were evaluated for p16(INK4a): (a) >25%, (b) >50%, and (c) >= 70%. The concordance of p16(INK4a) and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was assessed. Results: A total of 78 OCC, 257 OPC, and 51 LC were HPV-DNA-positive and further tested for p16(INK4a) and E6*I mRNA. The percentage of concordance between p16(INK4a) (cutoff >= 70%) and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was 79.5% (95% CI 69.9-89.1%), 82.1% (95% CI 77.2-87.0%), and 56.9% (95% CI 42.3-71.4%), respectively. A p16(INK4a) cutoff of >50% improved the concordance although the improvement was not statistically significant. For most anatomical locations and p16(INK4a) cutoffs, the percentage of discordant cases was higher for HPV16- than HPV-non16-positive cases. Conclusions: The diagnostic algorithm of HPV-DNA testing followed by p16(INK4a) immunohistochemistry might be helpful in the diagnosis of HPV-driven OCC and OPC, but not LC. A different p16(INK4a) expression pattern was observed in those cases HPV-DNA-positive for types other than HPV16, as compared to HPV16-positive cases. Our study provides new insights into the use HPV-DNA, p16(INK4a), and HPV-E6*I mRNA for diagnosing an HPV-driven HNC, including the optimal HPV test or p16(INK4a) cutoffs to be used. More studies are warranted to clarify the role of p16(INK4a) and HPV status in both OPC and non-OPC HNC.

Background Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14.0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting. Methods This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2), both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m(2) on day 1 of cycle 1 and 250 mg/m(2) weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m(2) was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m(2) on day 1-4, cisplatin 100 mg/m(2) on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m(2) on day 1 of cycle 1 and 250 mg/m(2) weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m(2) cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695. Findings Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34.4 months (IQR 26.6-44.8) in the TPEx group and 30.2 months (25.5-45.3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14.5 months [95% CI 12.5-15.7] in the TPEx group and 13.4 months [12.2-15.4] in the EXTREME group; hazard ratio 0.89 [95% CI 0.74-1.08]; p=0.23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p

Purpose: To evaluate the efficacy and safety of induction chemotherapy (IC) followed by bioradiotherapy (BRT) to achieve functional larynx preservation in the setting of locally advanced head and neck tumors. Methods and Materials: This was a phase 2, open-label, multicenter study of patients with stage III and IVA laryngeal carcinoma who were candidates for total laryngectomy. The primary endpoint was the rate of survival with functional larynx (SFL) at 3 years, with a critical value to consider the study positive of SFL >59%. Patients received 3 cycles of IC with TPF (docetaxel, cisplatin, and 5-fluorouracil), and those who responded received conventional BRT with cetuximab. In patients with residual nodal disease after BRT, neck dissection was planned 2 months after BRT . Patients who did not respond to IC underwent total laryngectomy plus neck dissection and radiation therapy. Results: A total of 93 patients started TPF. Responses to IC on larynx target lesion were as follows: 37 patients (40%) showed a complete response; 38 patients (41%) showed a partial response; 8 patients (9%) showed stabilization; 2 patients (2%) showed progressive disease, and 8 patients (9%) were not evaluated (2 deaths, 5 adverse events, and 1 lost to follow-up). Seventy-three patients (78%) received BRT: 72 as per protocol, but 1 with only stable disease. Median follow-up was 53.7 months. Three-year actuarial rates were as follows: SFL: 70% (95% confidence interval [CI] 60%-79%); laryngectomy-free survival: 72% (95% CI 61%-81%); overall survival: 78% (95% CI: 63%-82%). The acute toxicity observed during both IC and BRT was as expected, with only 1 toxicity-related death (local bleeding) during BRT. Conclusions: According to this protocol, the SFL rate was clearly higher than the critical value, with acceptable levels of toxicity. The use of cetuximab added to radiation therapy in patients with stage III and IVA laryngeal cancer who respond to TPF could improve functional larynx preservation. A phase 3 trial is warranted. (C) 2016 Elsevier Inc. All rights reserved.

Objectives: To 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 methods: Multicenter, 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. Results: Acneiform 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 < 0.05); carriers of the G allele (genotypes TG + GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR = 0.287 [95% CI = 0.119-0.695]). Carriers of the A (GA + AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR = 0.345 [0.124-0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximabrelated toxicity (OR = 0.266 [0.114-0.622]). Conclusion: This pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients. (C) 2016 The Authors. Published by Elsevier Ltd.